PMID	cancer	gene	relation	sentence
28280249	Lung Carcinoma	CD28	Promote immunity (T cell function); Essential for immunotherapy	Here, we demonstrate that the CD28/B7 costimulatory pathway is essential for effective PD-1 therapy during chronic viral infection. Conditional gene deletion showed a cell-intrinsic requirement of CD28 for CD8 T cell proliferation after PD-1 blockade. B7-costimulation was also necessary for effective PD-1 therapy in tumor-bearing mice. In addition, we found that CD8 T cells proliferating in blood after PD-1 therapy of lung cancer patients were predominantly CD28-positive.
28280249	Lung Carcinoma	CD80	Promote immunity (T cell function); Essential for immunotherapy	Here, we demonstrate that the CD28/B7 costimulatory pathway is essential for effective PD-1 therapy during chronic viral infection. Conditional gene deletion showed a cell-intrinsic requirement of CD28 for CD8 T cell proliferation after PD-1 blockade. B7-costimulation was also necessary for effective PD-1 therapy in tumor-bearing mice. In addition, we found that CD8 T cells proliferating in blood after PD-1 therapy of lung cancer patients were predominantly CD28-positive.
28280037	Melanoma	TP53	Promote immunity	Hence, targeting the p53 pathway in TME can be exploited to reverse immunosuppression and augment therapeutic benefits beyond tumoricidal effects to harness tumor-specific, durable, and systemic antitumor immunity with minimal toxicity.
28276425	Breast Carcinoma	SHC1	Inhibit immunity; Resistant to immunotherapy	Herein we show that the ShcA pathway simultaneously activates STAT3 immunosuppressive signals and impairs STAT1-driven immune surveillance in breast cancer cells. Impaired Y239/Y240-ShcA phosphorylation selectively reduces STAT3 activation in breast tumours, profoundly sensitizing them to immune checkpoint inhibitors and tumour vaccines. Finally, the ability of diminished tyrosine kinase signalling to initiate STAT1-driven immune surveillance can be overcome by compensatory STAT3 hyperactivation in breast tumours.
28276425	Breast Carcinoma	STAT3	Inhibit immunity; Resistant to immunotherapy	Herein we show that the ShcA pathway simultaneously activates STAT3 immunosuppressive signals and impairs STAT1-driven immune surveillance in breast cancer cells. Impaired Y239/Y240-ShcA phosphorylation selectively reduces STAT3 activation in breast tumours, profoundly sensitizing them to immune checkpoint inhibitors and tumour vaccines. Finally, the ability of diminished tyrosine kinase signalling to initiate STAT1-driven immune surveillance can be overcome by compensatory STAT3 hyperactivation in breast tumours.
28276425	Breast Carcinoma	STAT1	Promote immunity	Herein we show that the ShcA pathway simultaneously activates STAT3 immunosuppressive signals and impairs STAT1-driven immune surveillance in breast cancer cells. Impaired Y239/Y240-ShcA phosphorylation selectively reduces STAT3 activation in breast tumours, profoundly sensitizing them to immune checkpoint inhibitors and tumour vaccines. Finally, the ability of diminished tyrosine kinase signalling to initiate STAT1-driven immune surveillance can be overcome by compensatory STAT3 hyperactivation in breast tumours.
28274999	Gastric Carcinoma	CD274	Inhibit immunity	Our results illuminate a novel mechanism of PD-L1 expression on tumour-activated neutrophils in GC, and also provide functional evidence for these novel GM-CSF-PD-L1 pathways to prevent, and to treat this immune tolerance feature of GC.
28274958	Prostate Carcinoma	TXK	Inhibit immunity (infiltration)	Here, we show that cabozantinib rapidly eradicates invasive, poorly differentiated PTEN/p53-deficient murine prostate cancer. This was associated with enhanced release of neutrophil chemotactic factors from tumor cells, including CXCL12 and HMGB1, resulting in robust infiltration of neutrophils into the tumor.
28274958	Prostate Carcinoma	CXCL12	Inhibit immunity	This was associated with enhanced release of neutrophil chemotactic factors from tumor cells, including CXCL12 and HMGB1, resulting in robust infiltration of neutrophils into the tumor.
28274958	Prostate Carcinoma	HMGB1	Promote immunity (infiltration)	This was associated with enhanced release of neutrophil chemotactic factors from tumor cells, including CXCL12 and HMGB1, resulting in robust infiltration of neutrophils into the tumor.
28262554	Plasma Cell Myeloma	TNFRSF17	Inhibit immunity (T cell function)	We constructed an IgG-based BCMA-T cell bispecific antibody (EM801) and showed that it increased CD3+ T cell/myeloma cell crosslinking, followed by CD4+/CD8+ T cell activation, and secretion of interferon-γ, granzyme B, and perforin.
28249897	Colon Carcinoma	IL33	Promote immunity (infiltration)	Moreover, IL33 recruited macrophages into the cancer microenvironment and stimulated them to produce prostaglandin E2, which supported colon cancer stemness and tumor growth.
28249894	Plasma Cell Myeloma	CD38	Inhibit immunity (T cell function)	Targeting CD38 Suppresses Induction and Function of T Regulatory Cells to Mitigate Immunosuppression in Multiple Myeloma.
28249894	Plasma Cell Myeloma	FOXP3	Inhibit immunity (T cell function)	We study CD38 levels in immunosuppressive CD4+CD25highFoxp3+regulatory T cells (Treg) and further define immunomodulating effects of a therapeutic CD38 mAb isatuximab/SAR650984 in multiple myeloma. Isatuximab reduces Foxp3 and IL10 in Tregs and restores proliferation and function of Tcons.
28249894	Plasma Cell Myeloma	IL10	Inhibit immunity (T cell function)	We study CD38 levels in immunosuppressive CD4+CD25highFoxp3+regulatory T cells (Treg) and further define immunomodulating effects of a therapeutic CD38 mAb isatuximab/SAR650984 in multiple myeloma. Isatuximab reduces Foxp3 and IL10 in Tregs and restores proliferation and function of Tcons.
28235946	Clear Cell Renal Cell Carcinoma	VHL	Promote immunity	Vascular cell adhesion molecule 1 (VCAM-1) is an adhesion molecule assigned to the activated endothelium mediating immune cells adhesion and extravasation. VHL promotes immune response against renal cell carcinoma via NF-κB-dependent regulation of VCAM-1.
28235946	Clear Cell Renal Cell Carcinoma	VCAM1	Promote immunity	Vascular cell adhesion molecule 1 (VCAM-1) is an adhesion molecule assigned to the activated endothelium mediating immune cells adhesion and extravasation.
28235946	Clear Cell Renal Cell Carcinoma	PDC	Promote immunity	Vascular cell adhesion molecule 1 (VCAM-1) is an adhesion molecule assigned to the activated endothelium mediating immune cells adhesion and extravasation. Our experiments in clear cell renal cell carcinoma (ccRCC) cell lines demonstrated that von Hippel Lindau (VHL) loss, hypoxia, or PHD (for prolyl hydroxylase domain-containing proteins) inactivation decreased VCAM-1 levels through a transcriptional mechanism that was independent of the hypoxia-inducible factor and dependent on the nuclear factor κB signaling pathway.
28228558	Breast Carcinoma; Ovarian Carcinoma	RPS19	Inhibit immunity (T cell function)	RPS19 also induces the production of immunosuppressive cytokines, including TGF-β, by myeloid-derived suppressor cells in tumor-draining lymph nodes, leading to T cell responses skewed toward Th2 phenotypes.
28223282	Breast carcinoma; Colon Carcinoma; Lung carcinoma	RAE1	Promote immunity (T cell function)	NKG2D-mediated immune surveillance is crucial for inhibiting tumor growth and metastases. High-profile studies have shown that restoring NKG2D ligand expression via genetic engineering inhibits tumor formation and progression.
28223282	Breast carcinoma; Colon Carcinoma; Lung carcinoma	IL12A	Promote immunity (T cell function)	NKG2D-mediated immune surveillance is crucial for inhibiting tumor growth and metastases. High-profile studies have shown that restoring NKG2D ligand expression via genetic engineering inhibits tumor formation and progression. We found that co-administration of an immune stimulatory signal (interleukin-12) and chemotherapy (doxorubicin) restored the NKG2D ligand Rae-1 in multiple tumor types, including a human tumor model.
28218497	Lymphoma	MAPK1	Inhibit immunity (T cell function)	Suppression of ERK by a chemical inhibitor or genetic silencing of ERK2 expression prevents drug-induced PD-L1 expression.
28212885	Myeloid Neoplasm	PTGS2	Inhibit immunity (T cell function)	Human macrophages exposed to epinephrine and TNFα, or macrophages generated in 6day cultures in the presence of epinephrine, expressed high levels of COX-2, IDO and IL-10, and strongly suppressed both the proliferation and IFNγ production of CD8+T cells.
28212885	Myeloid Neoplasm	IDO1	Inhibit immunity (T cell function)	Human macrophages exposed to epinephrine and TNFα, or macrophages generated in 6day cultures in the presence of epinephrine, expressed high levels of COX-2, IDO and IL-10, and strongly suppressed both the proliferation and IFNγ production of CD8+T cells.
28212885	Myeloid Neoplasm	IL10	Inhibit immunity (T cell function)	Human macrophages exposed to epinephrine and TNFα, or macrophages generated in 6day cultures in the presence of epinephrine, expressed high levels of COX-2, IDO and IL-10, and strongly suppressed both the proliferation and IFNγ production of CD8+T cells.
28196594	Colorectal Carcinoma	IFNAR1	Promote immunity	Genetic stabilization of IFNAR1 improved CTL survival and increased the efficacy of the chimeric antigen receptor T cell transfer and PD-1 inhibition.
28195343	Hepatocellular Carcinoma	LGALS9	Inhibit immunity	In the setting of viral hepatitis, increased expression of Gal-9 drives the expansion of regulatory T cells and contraction of effector T cells, thereby favoring viral persistence. The dichotomous nature of Gal-9 is evident in hepatocellular carcinoma, where loss of expression in hepatocytes promotes tumor growth and metastasis, whereas overexpression by Kupffer cells and endothelial cells inhibits the antitumor immune response.
28191009	Colon Carcinoma	NCF1	Inhibit immunity	Two prominent modulators of colon inflammation are represented by the closely related cytokines interleukin (IL)-12 and IL-23, which initiate adaptive Th1 and Th17 immune responses, respectively. In this study, we investigated the impact of the NADPH oxidase protein p47phox, which negatively regulates IL-12 in dendritic cells, on colon cancer development in a colitis-associated colon cancer model.
28191009	Colon Carcinoma	IL12A	Promote immunity	Two prominent modulators of colon inflammation are represented by the closely related cytokines interleukin (IL)-12 and IL-23, which initiate adaptive Th1 and Th17 immune responses, respectively.
28191009	Colon Carcinoma	IL23A	Inhibit immunity	In tumor tissue of p47phox-/- mice, the IL-23/IL-17 axis was crucially hampered. IL-23p19 protein expression in tumor tissue correlated with tumor stage.
28184224	Hepatocellular Carcinoma	CBLB	Inhibit immunity	Cbl-b Deficiency Mediates Resistance to Programmed Death-Ligand 1/Programmed Death-1 Regulation.
28179508	Colon Carcinoma	TLR4	Promote immunity (infiltration)	Tumor microenvironment colonization by engineered Salmonella appeared to induce the infiltration of abundant immune cells such as monocytes/macrophages and neutrophils via TLR4 signaling.
28179106	Glioblastoma	IDO1	Inhibit immunity	The enzymatic activity of IDO1 is associated with the conversion of tryptophan into downstream kynurenine (Kyn), which has previously been hypothesized to contribute toward the suppression of tumor immunity.
28177435	Squamous Cell Lung Carcinoma	PIK3CA	Inhibit immunity	Analysis of mutations with immune markers revealed that ADCY8 and PIK3CA mutations were associated with markedly decreased tumoral PD-L1 expression, LUSCs with PIK3CA mutations exhibited elevated CD45ro levels and CDKN2A-mutant tumors displayed an up-regulated immune response.
28167507	Breast Carcinoma	PARP1	Promote immunity (T cell function)	PARP Inhibitor Upregulates PD-L1 Expression and Enhances Cancer-Associated Immunosuppression.
28166197	Hepatocellular Carcinoma	RARRES2	Promote immunity (T cell function)	Chemerin has a protective role in hepatocellular carcinoma by inhibiting the expression of IL-6 and GM-CSF and MDSC accumulation.
28166197	Hepatocellular Carcinoma	IL6	Inhibit immunity (T cell function)	Chemerin has a protective role in hepatocellular carcinoma by inhibiting the expression of IL-6 and GM-CSF and MDSC accumulation.
28166197	Hepatocellular Carcinoma	CSF2	Inhibit immunity (T cell function)	Chemerin has a protective role in hepatocellular carcinoma by inhibiting the expression of IL-6 and GM-CSF and MDSC accumulation.
28153099	Lymphoma	CD47	Inhibit immunity	CD47 interacts with its counter-receptor SIRPα on macrophages and other myeloid cells to inhibit cancer cell phagocytosis and drive immune evasion.
28131992	Pancreatic Carcinoma	FASLG	Promote immunity (infiltration)	The Fas-FasL/CTLs and the MLL1-H3K4me3-PD-L1 axis play contrasting roles in pancreatic cancer immune surveillance and evasion.
28131992	Pancreatic Carcinoma	KMT2A	Inhibit immunity (T cell function)	The Fas-FasL/CTLs and the MLL1-H3K4me3-PD-L1 axis play contrasting roles in pancreatic cancer immune surveillance and evasion.
28129119	Pancreatic Carcinoma	IL4	Inhibit immunity	These findings support the benefit of combining the 4/7 ICR with CAR-PSCA to treat pancreatic cancer, a PSCA-expressing tumor characterized by a dense immunosuppressive environment rich in IL-4.
28128200	Hepatocellular Carcinoma	KLRK1	Promote immunity	Thus, the NKG2D/NKG2D-ligand pathway provides an additional mechanism linking chronic inflammation to tumour development in hepatocellular carcinoma.
28126925	Acute Myeloid Leukemia	MUC1	Inhibit immunity (T cell function)	MUC1 induces increased expression of c-myc in EVs that induces proliferation in the target MDSC population via downstream effects on cell cycle proteins.
28126925	Acute Myeloid Leukemia	MYC	Inhibit immunity (T cell function)	MUC1 induces increased expression of c-myc in EVs that induces proliferation in the target MDSC population via downstream effects on cell cycle proteins.
26787820	Lung Carcinoma	CD96	Inhibit immunity (NK cell function)	Blocking CD96 in Tigit(-/-)mice significantly reduced experimental and spontaneous metastases compared with its activity in wild-type mice.
26785144	Kidney Carcinoma	IL17A	Promote immunity	These findings suggest that synthetic agonists of RORγt should activate TC17/TH17 cells (with concomitant reduction in the Tregs population), repress PD-1, and produce IL17 in situ (a factor associated with good prognosis in cancer).
26785144	Kidney Carcinoma	RORC	Inhibit immunity	These findings suggest that synthetic agonists of RORγt should activate TC17/TH17 cells (with concomitant reduction in the Tregs population), repress PD-1, and produce IL17 in situ (a factor associated with good prognosis in cancer).
26773716	Leukemia; Lymphoma	TNFRSF9	Promote immunity	Furthermore, the signaling cytoplasmic tail of CD137 is a key component of anti-CD19 chimeric antigen receptors that are used to redirect T cells against leukemia and lymphoma in the clinic.
26768655	Hepatocellular Carcinoma; Cervical Carcinoma	DGKA	Inhibit immunity (T cell function)	A novel diacylglycerol kinase α-selective inhibitor, CU-3, induces cancer cell apoptosis and enhances immune response. CU-3 competitively reduced the affinity of DGKα for ATP, but not diacylglycerol or phosphatidylserine. Moreover, this compound induced apoptosis in HepG2 hepatocellular carcinoma and HeLa cervical cancer cells while simultaneously enhancing the interleukin-2 production of Jurkat T cells.
26768655	Hepatocellular Carcinoma; Cervical Carcinoma	IL2	Promote immunity (T cell function)	A novel diacylglycerol kinase α-selective inhibitor, CU-3, induces cancer cell apoptosis and enhances immune response. CU-3 competitively reduced the affinity of DGKα for ATP, but not diacylglycerol or phosphatidylserine. Moreover, this compound induced apoptosis in HepG2 hepatocellular carcinoma and HeLa cervical cancer cells while simultaneously enhancing the interleukin-2 production of Jurkat T cells.
26763253	Acute Myeloid Leukemia	TIGIT	Inhibit immunity (T cell function)	TIGIT contributes to functional T-cell impairment and associates with poor clinical outcome in AML.
26762740	Non-Small Cell Lung Carcinoma	CD274	Inhibit immunity (T cell function)	PD-L1 Is Upregulated by Simultaneous Amplification of?the PD-L1 and JAK2 Genes in Non-Small Cell Lung?Cancer.
26762740	Non-Small Cell Lung Carcinoma	JAK2	Inhibit immunity (T cell function)	PD-L1 Is Upregulated by Simultaneous Amplification of?the PD-L1 and JAK2 Genes in Non-Small Cell Lung?Cancer.
26759242	Triple-Negative Breast Carcinoma	EGFR	Inhibit immunity (T cell function)	Furthermore, we showed that one of these intermediates, fructose 1,6 bisphosphate (F1,6BP), directly binds to and enhances the activity of the EGFR, thereby increasing lactate excretion, which leads to inhibition of local cytotoxic T-cell activity.
26755531	Melanoma	IL18	Promote immunity	The results demonstrated that IL18 enhanced therapeutic effects of immune checkpoint blockade against peritoneal dissemination of carcinoma or tail vein injection metastasis of melanoma through accumulation of pre-mNK cells, memory-type CD8(+) T cells, and suppression of CD4(+)CD25(+)Foxp3(+) T cells.
26740106	Head and Neck Squamous Cell Carcinoma	SEMA4D	Inhibit immunity (T cell function)	Human Head and Neck Squamous Cell Carcinoma-Associated Semaphorin 4D Induces Expansion of Myeloid-Derived Suppressor Cells.
26740106	Head and Neck Squamous Cell Carcinoma	ARG1	Inhibit immunity (T cell function)	Similarly, knockdown of Sema4D in an HNSCC cell line resulted in a loss of MDSC function as shown by a decrease in the production of the immune-suppressive cytokines arginase-1, TGF-β, and IL-10 by MDSC, concomitant with recovery of T cell proliferation and IFN-γ production following stimulation of CD3/CD28.
26740106	Head and Neck Squamous Cell Carcinoma	TGFB1	Inhibit immunity (T cell function)	Similarly, knockdown of Sema4D in an HNSCC cell line resulted in a loss of MDSC function as shown by a decrease in the production of the immune-suppressive cytokines arginase-1, TGF-β, and IL-10 by MDSC, concomitant with recovery of T cell proliferation and IFN-γ production following stimulation of CD3/CD28.
26740106	Head and Neck Squamous Cell Carcinoma	IL10	Inhibit immunity (T cell function)	Similarly, knockdown of Sema4D in an HNSCC cell line resulted in a loss of MDSC function as shown by a decrease in the production of the immune-suppressive cytokines arginase-1, TGF-β, and IL-10 by MDSC, concomitant with recovery of T cell proliferation and IFN-γ production following stimulation of CD3/CD28.
26740106	Head and Neck Squamous Cell Carcinoma	IFNG	Promote immunity (T cell function)	Similarly, knockdown of Sema4D in an HNSCC cell line resulted in a loss of MDSC function as shown by a decrease in the production of the immune-suppressive cytokines arginase-1, TGF-β, and IL-10 by MDSC, concomitant with recovery of T cell proliferation and IFN-γ production following stimulation of CD3/CD28.
26734010	Melanoma	DKK3	Inhibit immunity (infiltration)	Increased CD8(+) T cell and reduced M2-type macrophages infiltration was observed in tumors inoculated together with DKK3-deficient MSCs.
26731475	Melanoma	BACH2	Inhibit immunity (T cell function)	The transcription factor BACH2 promotes tumor immunosuppression. Mechanistically, BACH2 promoted tumor immunosuppression through Treg-mediated inhibition of intratumoral CD8+ T cells and IFN-γ.
26731475	Melanoma	IFNG	Promote immunity (T cell function)	The transcription factor BACH2 promotes tumor immunosuppression. Mechanistically, BACH2 promoted tumor immunosuppression through Treg-mediated inhibition of intratumoral CD8+ T cells and IFN-γ.
26729864	Melanoma	TNFRSF4	Promote immunity (T cell function)	Combination OX40 agonism/CTLA-4 blockade with HER2 vaccination reverses T-cell anergy and promotes survival in tumor-bearing mice.
26729864	Melanoma	ERBB2	Inhibit immunity (T cell function)	Combination OX40 agonism/CTLA-4 blockade with HER2 vaccination reverses T-cell anergy and promotes survival in tumor-bearing mice.
26729864	Melanoma	IFNG	Promote immunity	Vaccination with combination therapy uniquely restricted Th2-cytokine production by CD4 cells, relative to combination therapy alone, and enhanced IFNγ production by CD8 and CD4 cells.
26729864	Melanoma	CCL3	Promote immunity	Vaccination with combination therapy uniquely restricted Th2-cytokine production by CD4 cells, relative to combination therapy alone, and enhanced IFNγ production by CD8 and CD4 cells. We observed an increase in MIP-1α (macrophage inflammatory protein-1α)/CCL3 [chemokine (C-C motif) ligand 3], MIP-1β/CCL4, RANTES (regulated on activation, normal T-cell expressed and excreted)/CCL5, and GM-CSF production by CD8 and CD4 T cells following treatment.
26729864	Melanoma	CCL4	Promote immunity	Vaccination with combination therapy uniquely restricted Th2-cytokine production by CD4 cells, relative to combination therapy alone, and enhanced IFNγ production by CD8 and CD4 cells. We observed an increase in MIP-1α (macrophage inflammatory protein-1α)/CCL3 [chemokine (C-C motif) ligand 3], MIP-1β/CCL4, RANTES (regulated on activation, normal T-cell expressed and excreted)/CCL5, and GM-CSF production by CD8 and CD4 T cells following treatment.
26729864	Melanoma	CCL5	Promote immunity	Vaccination with combination therapy uniquely restricted Th2-cytokine production by CD4 cells, relative to combination therapy alone, and enhanced IFNγ production by CD8 and CD4 cells. We observed an increase in MIP-1α (macrophage inflammatory protein-1α)/CCL3 [chemokine (C-C motif) ligand 3], MIP-1β/CCL4, RANTES (regulated on activation, normal T-cell expressed and excreted)/CCL5, and GM-CSF production by CD8 and CD4 T cells following treatment.
26729864	Melanoma	CSF2	Promote immunity	Vaccination with combination therapy uniquely restricted Th2-cytokine production by CD4 cells, relative to combination therapy alone, and enhanced IFNγ production by CD8 and CD4 cells. We observed an increase in MIP-1α (macrophage inflammatory protein-1α)/CCL3 [chemokine (C-C motif) ligand 3], MIP-1β/CCL4, RANTES (regulated on activation, normal T-cell expressed and excreted)/CCL5, and GM-CSF production by CD8 and CD4 T cells following treatment.
26721894	Leukemia	KLRC1	Inhibit immunity	Thus, this anti-NKG2A may exploit the anti-leukemic action of the wave of NKG2A(+) natural killer cells recovering after hematopoietic stem cell transplants or adoptive therapy with natural killer cell infusions from matched or mismatched family donors after chemotherapy for acute leukemia, without the need to search for a natural killer cell alloreactive donor.
26719528	Breast Carcinoma	STAT3	Inhibit immunity	STAT3 Establishes an Immunosuppressive Microenvironment during the Early Stages of Breast Carcinogenesis to Promote Tumor Growth and Metastasis.
26719346	Melanoma	CCL5	Promote immunity (infiltration)	Senescent melanoma cells secret CCL5, which promotes recruitment of TILs.
26719346	Melanoma	AURKA	Inhibit immunity (infiltration)	AURKAi and CDK4/6i promoted the recruitment of TILs by inducing CCL5 secretion in melanoma cells (P ≤ .005) in an NF-κB-dependent manner.
26719346	Melanoma	CDK6	Inhibit immunity (infiltration)	AURKAi and CDK4/6i promoted the recruitment of TILs by inducing CCL5 secretion in melanoma cells (P ≤ .005) in an NF-κB-dependent manner.
26719346	Melanoma	CDK4	Inhibit immunity (infiltration)	AURKAi and CDK4/6i promoted the recruitment of TILs by inducing CCL5 secretion in melanoma cells (P ≤ .005) in an NF-κB-dependent manner.
26719303	Colorectal Carcinoma	IL17A	Promote immunity (infiltration)	Indeed, owing to IL-17 secretion, CRC-derived Th17 triggered the release of protumorigenic factors by tumour and tumour-associated stroma. However, on the other hand, they favoured recruitment of beneficial neutrophils through IL-8 secretion and, most importantly, they drove highly cytotoxic CCR5+CCR6+CD8+ T cells into tumour tissue, through CCL5 and CCL20 release.
26719303	Colorectal Carcinoma	CXCL8	Promote immunity (infiltration)	Indeed, owing to IL-17 secretion, CRC-derived Th17 triggered the release of protumorigenic factors by tumour and tumour-associated stroma. However, on the other hand, they favoured recruitment of beneficial neutrophils through IL-8 secretion and, most importantly, they drove highly cytotoxic CCR5+CCR6+CD8+ T cells into tumour tissue, through CCL5 and CCL20 release.
26719303	Colorectal Carcinoma	CCL5	Promote immunity (infiltration)	Indeed, owing to IL-17 secretion, CRC-derived Th17 triggered the release of protumorigenic factors by tumour and tumour-associated stroma. However, on the other hand, they favoured recruitment of beneficial neutrophils through IL-8 secretion and, most importantly, they drove highly cytotoxic CCR5+CCR6+CD8+ T cells into tumour tissue, through CCL5 and CCL20 release.
26719303	Colorectal Carcinoma	CCL20	Promote immunity (infiltration)	Indeed, owing to IL-17 secretion, CRC-derived Th17 triggered the release of protumorigenic factors by tumour and tumour-associated stroma. However, on the other hand, they favoured recruitment of beneficial neutrophils through IL-8 secretion and, most importantly, they drove highly cytotoxic CCR5+CCR6+CD8+ T cells into tumour tissue, through CCL5 and CCL20 release.
26717410	Luminal A Breast Carcinoma	ELF5	Promote immunity (infiltration)	In the mouse mammary tumor virus-Polyoma Middle T (MMTV-PyMT) model of luminal breast cancer, induction of ELF5 levels increased leukocyte infiltration, angiogenesis, and blood vessel permeability in primary tumors and greatly increased the size and number of lung metastasis.
26715645	Pancreatic Carcinoma	BTK	Inhibit immunity	Here, we report that targeting Bruton tyrosine kinase (BTK), a key B-cell and macrophage kinase, restores T cell-dependent antitumor immune responses, thereby inhibiting PDAC growth and improving responsiveness to standard-of-care chemotherapy.
26714554	Melanoma	SIGLEC1	Promote immunity	The iPS-ML-IFNs increased the expression of CD169, a marker of M1 macrophages that can activate antitumor immunity.
26707870	Clear Cell Renal Cell Carcinoma	VHL	Promote immunity (T cell function)	Our work provides the first evidence that VHL mutations positively correlate with PD-L1 expression in ccRCC and may influence the response to ccRCC anti-PD-L1/PD-1 immunotherapy.
26707829	Melanoma	BRAF	Resistant to immunotherapy	The greatest survival improvement was observed with the combination of BRAF plus MEK inhibitors as well as with Programmed-death-1 (PD1) blockers with or without cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) blockers, respectively, with these two treatment strategies showing similar survival outcomes.
26707829	Melanoma	MAP2K1	Resistant to immunotherapy	The greatest survival improvement was observed with the combination of BRAF plus MEK inhibitors as well as with Programmed-death-1 (PD1) blockers with or without cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) blockers, respectively, with these two treatment strategies showing similar survival outcomes.
26704363	Lung Adenocarcinoma	HDAC5	Promote immunity (T cell function)	Taken together, targeting HDAC5 weakens suppressive function and de-novo induction of Tregs, but also reduces the ability of CD8(+) T cells to produce IFN-γ.
26676749	Head and Neck Squamous Cell Carcinoma	IFNG	Promote immunity (T cell function)	Interferon gamma (IFNγ) and the epidermal growth factor receptor (EGFR) utilize Janus kinase 2 (JAK2) as a common signaling node to transmit tumor cell-mediated extrinsic or intrinsic signals, respectively. Collectively, our findings suggest a novel role for JAK2/STAT1 in EGFR-mediated immune evasion, and therapies targeting this signaling axis may be beneficial to block PD-L1 upregulation found in a large subset of HNC tumors.
26676749	Head and Neck Squamous Cell Carcinoma	EGFR	Inhibit immunity (T cell function)	Interferon gamma (IFNγ) and the epidermal growth factor receptor (EGFR) utilize Janus kinase 2 (JAK2) as a common signaling node to transmit tumor cell-mediated extrinsic or intrinsic signals, respectively. Collectively, our findings suggest a novel role for JAK2/STAT1 in EGFR-mediated immune evasion, and therapies targeting this signaling axis may be beneficial to block PD-L1 upregulation found in a large subset of HNC tumors.
26676749	Head and Neck Squamous Cell Carcinoma	JAK2	Inhibit immunity (T cell function)	Interferon gamma (IFNγ) and the epidermal growth factor receptor (EGFR) utilize Janus kinase 2 (JAK2) as a common signaling node to transmit tumor cell-mediated extrinsic or intrinsic signals, respectively. Collectively, our findings suggest a novel role for JAK2/STAT1 in EGFR-mediated immune evasion, and therapies targeting this signaling axis may be beneficial to block PD-L1 upregulation found in a large subset of HNC tumors.
26676749	Head and Neck Squamous Cell Carcinoma	STAT1	Inhibit immunity (T cell function)	Interferon gamma (IFNγ) and the epidermal growth factor receptor (EGFR) utilize Janus kinase 2 (JAK2) as a common signaling node to transmit tumor cell-mediated extrinsic or intrinsic signals, respectively. Collectively, our findings suggest a novel role for JAK2/STAT1 in EGFR-mediated immune evasion, and therapies targeting this signaling axis may be beneficial to block PD-L1 upregulation found in a large subset of HNC tumors.
26647968	Melanoma	SIGLEC1	Inhibit immunity (T cell function)	CD169(-/-) mice had significantly enhanced in vivo cytotoxic T lymphocyte responses to antigen-pulsed ApoVs, indicating a suppressive role for CD169(+) macrophages to ApoV-associated antigen.
26645196	Melanoma	PTEN	Promote immunity (infiltration)	PTEN loss in tumor cells increased the expression of immunosuppressive cytokines, resulting in decreased T-cell infiltration in tumors, and inhibited autophagy, which decreased T cell-mediated cell death.
26645196	Melanoma	PIK3CB	Resistant to immunotherapy	Treatment with a selective PI3Kβ inhibitor improved the efficacy of both anti-PD-1 and anti-CTLA-4 antibodies in murine models.
26639061	Hepatocellular Carcinoma	LEP	Promote immunity (T cell function)	Hepatoma cell-derived leptin downregulates the immunosuppressive function of regulatory T-cells to enhance the anti-tumor activity of CD8+ T-cells.
26637667	Lung Carcinoma	AKT1	Inhibit immunity (T cell function)	AKT These data suggest that oncogenic activation of the AKT-mTOR pathway promotes immune escape by driving expression of PD-L1, which was confirmed in syngeneic and genetically engineered mouse models of lung cancer where an mTOR inhibitor combined with a PD-1 antibody decreased tumor growth, increased tumor-infiltrating T cells, and decreased regulatory T cells.
26637667	Lung Carcinoma	MTOR	Inhibit immunity (T cell function)	AKT These data suggest that oncogenic activation of the AKT-mTOR pathway promotes immune escape by driving expression of PD-L1, which was confirmed in syngeneic and genetically engineered mouse models of lung cancer where an mTOR inhibitor combined with a PD-1 antibody decreased tumor growth, increased tumor-infiltrating T cells, and decreased regulatory T cells.
26607445	Melanoma; Colon Carcinoma	TMEM173	Promote immunity (T cell function)	Here, we find that enforced activation of STING by intratumoral injection of cyclic dinucleotide GMP-AMP (cGAMP), potently enhanced antitumor CD8 T responses leading to growth control of injected and contralateral tumors in mouse models of melanoma and colon cancer.
26606967	Breast Carcinoma	ERBB2	Resistant to immunotherapy	We show that T-DM1 is particularly effective in eliciting antitumor immunity in patients with early breast cancer (WSG-ADAPT trial) and in a HER2-expressing orthotopic tumor model. In the latter, despite primary resistance to immunotherapy, combined treatment with T-DM1 and anti-CTLA-4/PD-1 (cytotoxic T lymphocyte-associated protein-4/programmed cell death protein-1) was curative because it triggered innate and adaptive immunity.
26603621	Melanoma	MIF	Inhibit immunity (T cell function)	These findings indicate that monocyte-derived MIF is centrally involved in human monocytic MDSC induction/immunosuppressive function and that therapeutic targeting of MIF may provide a novel means of inducing antitumor DC responses in late-stage melanoma patients.
26598503	Breast Carcinoma; Lung Carcinoma; Ovarian Carcinoma	HSPA4	Inhibit immunity (T cell function)	Exosomes, via heat shock protein 70 (HSP70) expressed in their membrane, are able to interact with the toll-like receptor 2 (TLR2) on myeloid-derived suppressive cells (MDSCs), thereby activating them.
26598503	Breast Carcinoma; Lung Carcinoma; Ovarian Carcinoma	TLR2	Inhibit immunity (T cell function)	Exosomes, via heat shock protein 70 (HSP70) expressed in their membrane, are able to interact with the toll-like receptor 2 (TLR2) on myeloid-derived suppressive cells (MDSCs), thereby activating them.
26595750	Neuroblastoma	HMOX1	Inhibit immunity (T cell function)	Importantly, HO-1 inhibition abrogated immune cell paralysis affecting CD4 and CD8 T-effector cells.
26577528	Non-Small Cell Lung Carcinoma	TP53	Promote immunity (T cell function)	We identified a novel mechanism by which tumor immune evasion is regulated by p53/miR-34/PDL1 axis.
26573793	Ovarian Carcinoma	NFKB1	Inhibit immunity (T cell function)	In summary, we found that chemotherapy induces local immune suppression in ovarian cancer through NF-κB-mediated PD-L1 upregulation.
26567141	Ovarian Carcinoma	PDCD1	Inhibit immunity	PD-1 Blunts the Function of Ovarian Tumor-Infiltrating Dendritic Cells by Inactivating NF-κB.
26567141	Ovarian Carcinoma	NFKB1	Promote immunity	PD-1 Blunts the Function of Ovarian Tumor-Infiltrating Dendritic Cells by Inactivating NF-κB.
26567139	Colon Carcinoma	EZH2	Inhibit immunity (infiltration)	We found that PRC2 components and demethylase JMJD3-mediated histone H3 lysine 27 trimethylation (H3K27me3) repress the expression and subsequent production of Th1-type chemokines CXCL9 and CXCL10, mediators of effector T-cell trafficking. Moreover, the expression levels of PRC2 components, including EZH2, SUZ12, and EED, were inversely associated with those of CD4, CD8, and Th1-type chemokines in human colon cancer tissue, and this expression pattern was significantly associated with patient survival.
26567139	Colon Carcinoma	SUZ12	Inhibit immunity (infiltration)	We found that PRC2 components and demethylase JMJD3-mediated histone H3 lysine 27 trimethylation (H3K27me3) repress the expression and subsequent production of Th1-type chemokines CXCL9 and CXCL10, mediators of effector T-cell trafficking. Moreover, the expression levels of PRC2 components, including EZH2, SUZ12, and EED, were inversely associated with those of CD4, CD8, and Th1-type chemokines in human colon cancer tissue, and this expression pattern was significantly associated with patient survival.
26567139	Colon Carcinoma	EED	Inhibit immunity (infiltration)	We found that PRC2 components and demethylase JMJD3-mediated histone H3 lysine 27 trimethylation (H3K27me3) repress the expression and subsequent production of Th1-type chemokines CXCL9 and CXCL10, mediators of effector T-cell trafficking. Moreover, the expression levels of PRC2 components, including EZH2, SUZ12, and EED, were inversely associated with those of CD4, CD8, and Th1-type chemokines in human colon cancer tissue, and this expression pattern was significantly associated with patient survival.
26567139	Colon Carcinoma	KDM6B	Inhibit immunity (infiltration)	We found that PRC2 components and demethylase JMJD3-mediated histone H3 lysine 27 trimethylation (H3K27me3) repress the expression and subsequent production of Th1-type chemokines CXCL9 and CXCL10, mediators of effector T-cell trafficking. Moreover, the expression levels of PRC2 components, including EZH2, SUZ12, and EED, were inversely associated with those of CD4, CD8, and Th1-type chemokines in human colon cancer tissue, and this expression pattern was significantly associated with patient survival.
26567139	Colon Carcinoma	CXCL9	Promote immunity (infiltration)	We found that PRC2 components and demethylase JMJD3-mediated histone H3 lysine 27 trimethylation (H3K27me3) repress the expression and subsequent production of Th1-type chemokines CXCL9 and CXCL10, mediators of effector T-cell trafficking. Moreover, the expression levels of PRC2 components, including EZH2, SUZ12, and EED, were inversely associated with those of CD4, CD8, and Th1-type chemokines in human colon cancer tissue, and this expression pattern was significantly associated with patient survival.
26567139	Colon Carcinoma	CXCL10	Promote immunity (infiltration)	We found that PRC2 components and demethylase JMJD3-mediated histone H3 lysine 27 trimethylation (H3K27me3) repress the expression and subsequent production of Th1-type chemokines CXCL9 and CXCL10, mediators of effector T-cell trafficking. Moreover, the expression levels of PRC2 components, including EZH2, SUZ12, and EED, were inversely associated with those of CD4, CD8, and Th1-type chemokines in human colon cancer tissue, and this expression pattern was significantly associated with patient survival.
26564005	Follicular Dendritic Cell Sarcoma	CD274	Inhibit immunity (T cell function)	Last, focal copy-number gain of chromosome 9p24 including the genes CD274 (PD-L1) and PDCD1LG2 (PD-L2) was noted in three cases, which represents a well-described mechanism of immune evasion in cancer.
26527801	Melanoma	CISH	Inhibit immunity (T cell function)	Genetic deletion of Cish in CD8(+) T cells enhances their expansion, functional avidity, and cytokine polyfunctionality, resulting in pronounced and durable regression of established tumors.
26523864	Ovarian Carcinoma	EZH2	Promote immunity (T cell function)	EZH2 activated the Notch pathway by suppressing Notch repressors Numb and Fbxw7 via trimethylation of histone H3 at Lys27 and, consequently, stimulated T cell polyfunctional cytokine expression and promoted their survival via Bcl-2 signaling.
26523864	Ovarian Carcinoma	NUMB	Inhibit immunity (T cell function)	EZH2 activated the Notch pathway by suppressing Notch repressors Numb and Fbxw7 via trimethylation of histone H3 at Lys27 and, consequently, stimulated T cell polyfunctional cytokine expression and promoted their survival via Bcl-2 signaling.
26523864	Ovarian Carcinoma	FBXW7	Inhibit immunity (T cell function)	EZH2 activated the Notch pathway by suppressing Notch repressors Numb and Fbxw7 via trimethylation of histone H3 at Lys27 and, consequently, stimulated T cell polyfunctional cytokine expression and promoted their survival via Bcl-2 signaling.
26523864	Ovarian Carcinoma	NOTCH1	Promote immunity (T cell function)	EZH2 activated the Notch pathway by suppressing Notch repressors Numb and Fbxw7 via trimethylation of histone H3 at Lys27 and, consequently, stimulated T cell polyfunctional cytokine expression and promoted their survival via Bcl-2 signaling.
26515496	Breast Carcinoma	MAP2K7	Biomarker of response to immunotherapy	Furthermore, Ras/MAPK activation and MHC expression may be predictive biomarkers of response to immune checkpoint inhibitors.
26511282	Melanoma; Colon Carcinoma	IL15	Promote immunity (T cell function)	IL15, a potent stimulant of CD8(+) T cells and natural killer (NK) cells, is a promising cancer immunotherapeutic.
26503055	Ovarian Carcinoma	EZH2	Inhibit immunity (infiltration)	Using human ovarian cancers as our model, here we show that enhancer of zeste homologue 2 (EZH2)-mediated histone H3 lysine 27 trimethylation (H3K27me3) and DNA methyltransferase 1 (DNMT1)-mediated DNA methylation repress the tumour production of T helper 1 (TH1)-type chemokines CXCL9 and CXCL10, and subsequently determine effector T-cell trafficking to the tumour microenvironment.
26503055	Ovarian Carcinoma	DNMT1	Inhibit immunity (infiltration)	Using human ovarian cancers as our model, here we show that enhancer of zeste homologue 2 (EZH2)-mediated histone H3 lysine 27 trimethylation (H3K27me3) and DNA methyltransferase 1 (DNMT1)-mediated DNA methylation repress the tumour production of T helper 1 (TH1)-type chemokines CXCL9 and CXCL10, and subsequently determine effector T-cell trafficking to the tumour microenvironment.
26503055	Ovarian Carcinoma	CXCL9	Promote immunity (infiltration)	Using human ovarian cancers as our model, here we show that enhancer of zeste homologue 2 (EZH2)-mediated histone H3 lysine 27 trimethylation (H3K27me3) and DNA methyltransferase 1 (DNMT1)-mediated DNA methylation repress the tumour production of T helper 1 (TH1)-type chemokines CXCL9 and CXCL10, and subsequently determine effector T-cell trafficking to the tumour microenvironment.
26503055	Ovarian Carcinoma	CXCL10	Promote immunity (infiltration)	Using human ovarian cancers as our model, here we show that enhancer of zeste homologue 2 (EZH2)-mediated histone H3 lysine 27 trimethylation (H3K27me3) and DNA methyltransferase 1 (DNMT1)-mediated DNA methylation repress the tumour production of T helper 1 (TH1)-type chemokines CXCL9 and CXCL10, and subsequently determine effector T-cell trafficking to the tumour microenvironment.
26500140	Diffuse Large B-Cell Lymphoma	FOXP1	Inhibit immunity	FOXP1 knockdown in ABC-DLBCL cells led to increased cell-surface expression of HLA-DRA and CD74. We propose that FOXP1 represents a novel regulator of genes targeted by the class II MHC transactivator CIITA (MHC II and CD74) and therapeutically targeting the FOXP1 pathway may improve antigen presentation and immune surveillance in high-risk DLBCL patients.
26500140	Diffuse Large B-Cell Lymphoma	HLA-DRA	Promote immunity	FOXP1 knockdown in ABC-DLBCL cells led to increased cell-surface expression of HLA-DRA and CD74. We propose that FOXP1 represents a novel regulator of genes targeted by the class II MHC transactivator CIITA (MHC II and CD74) and therapeutically targeting the FOXP1 pathway may improve antigen presentation and immune surveillance in high-risk DLBCL patients.
26500140	Diffuse Large B-Cell Lymphoma	CD74	Promote immunity	FOXP1 knockdown in ABC-DLBCL cells led to increased cell-surface expression of HLA-DRA and CD74. We propose that FOXP1 represents a novel regulator of genes targeted by the class II MHC transactivator CIITA (MHC II and CD74) and therapeutically targeting the FOXP1 pathway may improve antigen presentation and immune surveillance in high-risk DLBCL patients.
26493961	Melanoma	TNFRSF9	Inhibit immunity	Moreover, administration of systemic sFLT3L and local poly-ICLC enhanced DC-mediated cross-priming and synergized with anti-CD137- and anti-PD-1-mediated immunostimulation in tumor therapy against B16-ovalbumin-derived melanomas, whereas this function was lost in Batf3(-/-) mice.
26483205	Colon Carcinoma; Lung Carcinoma	TNFRSF1B	Inhibit immunity (T cell function)	Overall, our findings implicate TNFR2 in supporting MDSC-mediated immune suppression and metastasis in the liver, suggesting the use of TNFR2 inhibitors as a strategy to prevent metastatic progression to liver in colon, lung, and various other types of cancer.
26472927	Hepatocellular Carcinoma; Lung Adenocarcinoma; Cervical Carcinoma	NCR3LG1	Promote immunity (NK cell function)	Further studies showed that treatment of tumor cells with almost all standard tumor therapeutics, including chemotherapy (cisplatin, 5-fluorouracil), radiation therapy, non-lethal heat shock, and cytokine therapy (TNF-α), could up-regulate the expression of B7-H6 in tumor cells and enhance tumor sensitivity to NK cell cytolysis.
27076627	Ovarian Carcinoma	VEGFA	Inhibit immunity (NKT cell function)	We found that VEGF inhibition restores NKT-cell function in an in vitro ovarian cancer model.
27076449	Oral Cavity Carcinoma	MTOR	Inhibit immunity (T cell function); resistant to immunotherapy	Enhanced Tumor Control with Combination mTOR and PD-L1 Inhibition in Syngeneic Oral Cavity Cancers.
27070705	Colorectal Carcinoma	CXCL9	Promote immunity (infiltration)	While two distinct subsets of myeloid cells induce an influx of T cells into the invasive margin via CXCL9/CXCL10, CCL5 is produced by these T cells and stimulates pro-tumoral effects via CCR5.
27070705	Colorectal Carcinoma	CXCL10	Promote immunity (infiltration)	While two distinct subsets of myeloid cells induce an influx of T cells into the invasive margin via CXCL9/CXCL10, CCL5 is produced by these T cells and stimulates pro-tumoral effects via CCR5.
27070705	Colorectal Carcinoma	CCL5	Inhibit immunity (T cell function)	While two distinct subsets of myeloid cells induce an influx of T cells into the invasive margin via CXCL9/CXCL10, CCL5 is produced by these T cells and stimulates pro-tumoral effects via CCR5.
27070705	Colorectal Carcinoma	CCR5	Inhibit immunity (T cell function)	While two distinct subsets of myeloid cells induce an influx of T cells into the invasive margin via CXCL9/CXCL10, CCL5 is produced by these T cells and stimulates pro-tumoral effects via CCR5.
27049944	Pancreatic Ductal Adenocarcinoma	CXCL1	Inhibit immunity	Our work describes parallel networks of necroptosis-induced CXCL1 and Mincle signalling that promote macrophage-induced adaptive immune suppression and thereby enable PDA progression.
27049944	Pancreatic Ductal Adenocarcinoma	CLEC4E	Inhibit immunity	Our work describes parallel networks of necroptosis-induced CXCL1 and Mincle signalling that promote macrophage-induced adaptive immune suppression and thereby enable PDA progression.
27045006	Lung Carcinoma	DKK1	Inhibit immunity (T cell function)	Here, we demonstrate that stroma-derived Dickkopf-1 (Dkk1) targets β-catenin in MDSCs, thus exerting immune suppressive effects during tumor progression. Mice bearing extraskeletal tumors show significantly elevated levels of Dkk1 in bone microenvironment relative to tumor site. Strikingly, Dkk1 neutralization decreases tumor growth and MDSC numbers by rescuing β-catenin in these cells and restores T cell recruitment at the tumor site.
27045006	Lung Carcinoma	CTNNB1	Promote immunity (T cell function)	Here, we demonstrate that stroma-derived Dickkopf-1 (Dkk1) targets β-catenin in MDSCs, thus exerting immune suppressive effects during tumor progression. Mice bearing extraskeletal tumors show significantly elevated levels of Dkk1 in bone microenvironment relative to tumor site. Strikingly, Dkk1 neutralization decreases tumor growth and MDSC numbers by rescuing β-catenin in these cells and restores T cell recruitment at the tumor site.
27035983	Pancreatic Neuroendocrine Tumor	CD47	Inhibit immunity	We performed proteomic profiling of 332 antigens in two cell lines and four primary tumors, and showed that CD47, a cell-surface protein that acts as a "don't eat me" signal co-opted by cancers to evade innate immune surveillance, is ubiquitously expressed.
27030019	Renal Cell Carcinoma	ICAM1	Promote immunity (T cell function)	This study shows that overproduction of prostaglandin (PG) E2by metastatic murine renal carcinoma (Renca) cells inhibited direct priming of tumor-specific CTL responsesin vivoby preventing the IFNγ-dependent upregulation of ICAM-1 that is vital during the initial priming of na?ve CD8+T cells.
27022421	Melanoma	CXCL10	Promote immunity (infiltration)	Folate-modified Chitosan Nanoparticles Containing the IP-10 Gene Enhance Melanoma-specific Cytotoxic CD8(+)CD28(+) T Lymphocyte Responses. After treatment with combination therapy, the proportion of MDSCs and Tregs decreased, while the percentage of CXCR3(+)CD8(+) T cells increased.
27020860	E7+ tumor TC-1	CD27	Promote immunity (infiltration)	Combining CD27 agonism with CTLA-4 blockade improved vaccine-induced CTL priming and tumor infiltration, but only combination with PD-1 blockade was effective at eradicating tumors, thereby fully recapitulating the effect of CD4(+) T-cell help on vaccine efficacy.
27015306	Lung Carcinoma; Breast Carcinoma	SOX2	Inhibit immunity	LCC cells show stem-cell-like characteristics and express SOX2 and SOX9 transcription factors, which are essential for their survival in host organs under immune surveillance and for metastatic outgrowth under permissive conditions.
27015306	Lung Carcinoma; Breast Carcinoma	SOX9	Inhibit immunity	LCC cells show stem-cell-like characteristics and express SOX2 and SOX9 transcription factors, which are essential for their survival in host organs under immune surveillance and for metastatic outgrowth under permissive conditions.
27015306	Lung Carcinoma; Breast Carcinoma	DKK1	Inhibit immunity	Through expression of the WNT inhibitor DKK1, LCC cells self-impose a slow-cycling state with broad downregulation of ULBP ligands for NK cells and evasion of NK-cell-mediated clearance.
27006175	Glioblastoma	S100A8	Inhibit immunity (T cell function)	Elevated levels of polymorphonuclear myeloid-derived suppressor cells in patients with glioblastoma highly express S100A8/9 and arginase and suppress T cell function.
27006175	Glioblastoma	S100A9	Inhibit immunity (T cell function)	Elevated levels of polymorphonuclear myeloid-derived suppressor cells in patients with glioblastoma highly express S100A8/9 and arginase and suppress T cell function.
27001312	Glioma	IL6	Inhibit immunity (T cell function)	Mechanistically, glioma initiating CD133(+) cells and Mφs/microglia cointeraction activated expression of B7-H4 via IL6 and IL10 in both tumor cells and microenvironment supporting cells. IL6-activated STAT3 bound to the promoter of B7-H4 gene and enhanced B7-H4 expression. Furthermore, CD133(+) cells mediated immunosuppression through B7-H4 expression on Mφs/microglia by silencing of B7-H4 expression on these cells, which led to increased microenvironment T-cell function and tumor regression in the xenograft glioma mouse model.
27001312	Glioma	IL10	Inhibit immunity (T cell function)	Mechanistically, glioma initiating CD133(+) cells and Mφs/microglia cointeraction activated expression of B7-H4 via IL6 and IL10 in both tumor cells and microenvironment supporting cells. IL6-activated STAT3 bound to the promoter of B7-H4 gene and enhanced B7-H4 expression. Furthermore, CD133(+) cells mediated immunosuppression through B7-H4 expression on Mφs/microglia by silencing of B7-H4 expression on these cells, which led to increased microenvironment T-cell function and tumor regression in the xenograft glioma mouse model.
27001312	Glioma	STAT3	Inhibit immunity (T cell function)	Mechanistically, glioma initiating CD133(+) cells and Mφs/microglia cointeraction activated expression of B7-H4 via IL6 and IL10 in both tumor cells and microenvironment supporting cells. IL6-activated STAT3 bound to the promoter of B7-H4 gene and enhanced B7-H4 expression. Furthermore, CD133(+) cells mediated immunosuppression through B7-H4 expression on Mφs/microglia by silencing of B7-H4 expression on these cells, which led to increased microenvironment T-cell function and tumor regression in the xenograft glioma mouse model.
27001312	Glioma	VTCN1	Inhibit immunity (T cell function)	Mechanistically, glioma initiating CD133(+) cells and Mφs/microglia cointeraction activated expression of B7-H4 via IL6 and IL10 in both tumor cells and microenvironment supporting cells. IL6-activated STAT3 bound to the promoter of B7-H4 gene and enhanced B7-H4 expression. Furthermore, CD133(+) cells mediated immunosuppression through B7-H4 expression on Mφs/microglia by silencing of B7-H4 expression on these cells, which led to increased microenvironment T-cell function and tumor regression in the xenograft glioma mouse model.
26994345	Breast Carcinoma	IL10	Inhibit immunity	The delivery of let-7b could reactivate TAMs/TIDCs by acting as a TLR-7 agonist and suppressing IL-10 production in vitro. In a breast cancer mouse model, let-7b delivered by this system efficiently reprogrammed the functions of TAMs/TIDCs, reversed the suppressive tumor microenvironment, and inhibited tumor growth.
26994345	Breast Carcinoma	TLR7	Inhibit immunity	The delivery of let-7b could reactivate TAMs/TIDCs by acting as a TLR-7 agonist and suppressing IL-10 production in vitro. In a breast cancer mouse model, let-7b delivered by this system efficiently reprogrammed the functions of TAMs/TIDCs, reversed the suppressive tumor microenvironment, and inhibited tumor growth.
26982734	Melanoma	ACAT1	Inhibit immunity (T cell function)	ACAT1-deficient CD8(+) T cells were better than wild-type CD8(+) T cells at controlling melanoma growth and metastasis in mice.
26980767	Pancreatic Carcinoma	TGFB1	Inhibit immunity	TGFβ Signaling in the Pancreatic Tumor Microenvironment Promotes Fibrosis and Immune Evasion to Facilitate Tumorigenesis.
26979392	Melanoma; Breast Carcinoma	IDO1	Inhibit immunity	The addition of IDO blockade to radiotherapy + CpG decreased IDO activity, reduced tumor growth, and reduced immunosuppressive factors, such as regulatory T cells in the tumor microenvironment.
26977880	Colon Adenocarcinoma	TNFSF14	Resistant to immunotherapy	Our data indicate that targeting LIGHT might be a potent strategy to increase the responses to checkpoint blockades and other immunotherapies in non-T cell-inflamed tumors.
26966191	Leukemia; Lymphoma	MYC	Inhibit immunity (T cell function)	MYC inactivation in mouse tumors down-regulated CD47 and PD-L1 expression and enhanced the antitumor immune response.
26966191	Leukemia; Lymphoma	CD47	Inhibit immunity (T cell function)	MYC inactivation in mouse tumors down-regulated CD47 and PD-L1 expression and enhanced the antitumor immune response.
26966191	Leukemia; Lymphoma	CD274	Inhibit immunity (T cell function)	MYC inactivation in mouse tumors down-regulated CD47 and PD-L1 expression and enhanced the antitumor immune response.
26964621	Lung Carcinoma	TMEM173	Inhibit immunity (T cell function)	Here, we show that IDO activity induced by STING activity in the tumor microenvironment (TME) promoted the growth of Lewis lung carcinoma (LLC).
26964621	Lung Carcinoma	IDO1	Inhibit immunity (T cell function)	Here, we show that IDO activity induced by STING activity in the tumor microenvironment (TME) promoted the growth of Lewis lung carcinoma (LLC).
26957560	Neuroblastoma	CSF1R	Inhibit immunity	Our results demonstrate the essential role of CSF-1R signaling during the induction of suppressive myeloid cells and emphasize its clinical potential as an immunotherapy for human cancers.
26944201	Colon Carcinoma	MAP2K7	Inhibit immunity (T cell function), resistant to immunotherapy	Thus, despite the central importance of the MAP kinase pathway in some aspects of T cell function, MEK-targeted agents can be compatible with T-cell-dependent immunotherapy.
27246829	Follicular Lymphoma	ICOS	Inhibit immunity (T cell function)	These Tregs comprised activated ICOS(+) Tregs that were able to suppress not only conventional T cells, but also FL B cells.
27245613	Cervical Carcinoma	PRKACA	Inhibit immunity	PKA also stimulated the binding of the coactivator p300 to HIF-1α to enhance its transcriptional activity and counteracted the inhibitory effect of asparaginyl hydroxylation on the association of p300 with HIF-1α. Furthermore, increased cAMP concentrations enhanced the expression of HIF target genes encoding CD39 and CD73, which are enzymes that convert extracellular adenosine 5'-triphosphate to adenosine, a molecule that enhances tumor immunosuppression and reduces heart rate and contractility.
27245613	Cervical Carcinoma	HIF1A	Inhibit immunity	PKA also stimulated the binding of the coactivator p300 to HIF-1α to enhance its transcriptional activity and counteracted the inhibitory effect of asparaginyl hydroxylation on the association of p300 with HIF-1α. Furthermore, increased cAMP concentrations enhanced the expression of HIF target genes encoding CD39 and CD73, which are enzymes that convert extracellular adenosine 5'-triphosphate to adenosine, a molecule that enhances tumor immunosuppression and reduces heart rate and contractility.
27245613	Cervical Carcinoma	ENTPD1	Inhibit immunity	PKA also stimulated the binding of the coactivator p300 to HIF-1α to enhance its transcriptional activity and counteracted the inhibitory effect of asparaginyl hydroxylation on the association of p300 with HIF-1α. Furthermore, increased cAMP concentrations enhanced the expression of HIF target genes encoding CD39 and CD73, which are enzymes that convert extracellular adenosine 5'-triphosphate to adenosine, a molecule that enhances tumor immunosuppression and reduces heart rate and contractility.
27245613	Cervical Carcinoma	NT5E	Inhibit immunity	PKA also stimulated the binding of the coactivator p300 to HIF-1α to enhance its transcriptional activity and counteracted the inhibitory effect of asparaginyl hydroxylation on the association of p300 with HIF-1α. Furthermore, increased cAMP concentrations enhanced the expression of HIF target genes encoding CD39 and CD73, which are enzymes that convert extracellular adenosine 5'-triphosphate to adenosine, a molecule that enhances tumor immunosuppression and reduces heart rate and contractility.
27233495	Breast Carcinoma	APOBEC3B	Inhibit immunity	Analysis of breast cancers from METABRIC revealed breast cancers from APOBEC3B deletion carriers to have significantly higher abundance of tumour-infiltrating immune cells.
27226632	Melanoma	PLA2G2D	Inhibit immunity	Altogether, these results underscore a general role of sPLA2-IID as an immunosuppressive sPLA2 that allows the microenvironmental lipid balance toward an anti-inflammatory state, exerting beneficial or detrimental impact depending upon distinct pathophysiological contexts in inflammation and cancer.
27217585	Pancreatic Ductal Adenocarcinoma	CD40	Promote immunity (infiltration)	Agonistic CD40 mAb promotes stromal degradation and, in combination with chemotherapy, drives T cell infiltration and de novo responses against tumors, rendering resistant tumors susceptible to current immunotherapies.
27216180	Melanoma; Breast Carcinoma	ITGB3	Promote immunity (infiltration)	We hypothesized that integrin β3 could affect tumor immunity and evaluated tumors in mice with deletion of integrin β3 in macrophage lineage cells (β3KOM). β3KOM mice had increased melanoma and breast cancer growth with increased tumor-promoting M2 macrophages and decreased CD8(+) T cells.
27216177	Hepatocellular Carcinoma	FAP	Inhibit immunity (T cell function)	In a murine liver tumor model, we found that FAP(+)CAFs were a major source of CCL2 and that fibroblastic STAT3-CCL2 signaling in this setting promoted tumor growth by enhancing recruitment of myeloid-derived suppressor cells (MDSC).
27216177	Hepatocellular Carcinoma	STAT3	Inhibit immunity (T cell function)	In a murine liver tumor model, we found that FAP(+)CAFs were a major source of CCL2 and that fibroblastic STAT3-CCL2 signaling in this setting promoted tumor growth by enhancing recruitment of myeloid-derived suppressor cells (MDSC).
27216177	Hepatocellular Carcinoma	CCL2	Inhibit immunity (T cell function)	In a murine liver tumor model, we found that FAP(+)CAFs were a major source of CCL2 and that fibroblastic STAT3-CCL2 signaling in this setting promoted tumor growth by enhancing recruitment of myeloid-derived suppressor cells (MDSC).
27213690	Melanoma; Prostate Carcinoma; Breast Carcinoma	CISH	Inhibit immunity (NK cell function)	We identified cytokine-inducible SH2-containing protein (CIS, encoded by Cish) as a critical negative regulator of IL-15 signaling in NK cells. Cish was rapidly induced in response to IL-15, and deletion of Cish rendered NK cells hypersensitive to IL-15, as evidenced by enhanced proliferation, survival, IFN-γ production and cytotoxicity toward tumors.
27213690	Melanoma; Prostate Carcinoma; Breast Carcinoma	IL15	Inhibit immunity (NK cell function)	We identified cytokine-inducible SH2-containing protein (CIS, encoded by Cish) as a critical negative regulator of IL-15 signaling in NK cells. Cish was rapidly induced in response to IL-15, and deletion of Cish rendered NK cells hypersensitive to IL-15, as evidenced by enhanced proliferation, survival, IFN-γ production and cytotoxicity toward tumors.
27208904	Melanoma	ALCAM	Inhibit immunity (T cell function)	The cryo-induced ALCAM(+) cells including CD45(-) mesenchymal stem/stromal cells, CD11b(+)Gr1(+) myeloid-derived suppressor cells, and CD4(+)Foxp3(+) regulatory T cells significantly suppressed interferon γ production and cytotoxicity of tumour-specific CD8(+) T cells via ALCAM expressed in these cells.
27197181	Breast Carcinoma	LY6E	Inhibit immunity (T cell function)	Ly6E/K Signaling to TGFβ Promotes Breast Cancer Progression, Immune Escape, and Drug Resistance. Increased expression of Ly6K/E also correlated with increased expression of the immune checkpoint molecules PDL1 and CTLA4, increased tumor-infiltrating T regulatory cells, and decreased natural killer (NK) cell activation.
27197181	Breast Carcinoma	LY6K	Inhibit immunity (T cell function)	Ly6E/K Signaling to TGFβ Promotes Breast Cancer Progression, Immune Escape, and Drug Resistance. Increased expression of Ly6K/E also correlated with increased expression of the immune checkpoint molecules PDL1 and CTLA4, increased tumor-infiltrating T regulatory cells, and decreased natural killer (NK) cell activation.
27197181	Breast Carcinoma	TGFB1	Inhibit immunity (T cell function)	Ly6E/K Signaling to TGFβ Promotes Breast Cancer Progression, Immune Escape, and Drug Resistance. Increased expression of Ly6K/E also correlated with increased expression of the immune checkpoint molecules PDL1 and CTLA4, increased tumor-infiltrating T regulatory cells, and decreased natural killer (NK) cell activation.
27197153	Breast Carcinoma	SEMA3A	Promote immunity (T cell function)	In human breast cancer specimens, we found that immunohistochemical levels of SEMA3A correlated with the expression of genes characteristic of M1 macrophages, CD8(+) T cells, and NK cells, while inversely correlating with established characters of malignancy.
27197152	Breast Carcinoma	STAT3	Inhibit immunity (T cell function)	We suggest that targeting STAT3-NOTCH cross-talk between MDSC and CSC could offer a unique locus to improve cancer treatment, by coordinately targeting a coupled mechanism that enables cancer stemness and immune escape.
27197152	Breast Carcinoma	NOTCH1	Inhibit immunity (T cell function)	We suggest that targeting STAT3-NOTCH cross-talk between MDSC and CSC could offer a unique locus to improve cancer treatment, by coordinately targeting a coupled mechanism that enables cancer stemness and immune escape.
27193093	Breast Carcinoma	POSTN	Inhibit immunity (T cell function)	Here, we demonstrate that POSTN promotes the pulmonary accumulation of myeloid-derived suppressor cells (MDSCs) during the early stage of breast tumour metastasis.
27192578	Melanoma	SELPLG	Inhibit immunity (T cell function)	In models of melanoma cancer in which T cell dysfunction occurs, PSGL-1 deficiency led to PD-1 downregulation, improved T cell responses, and tumor control.
27185917	Melanoma	IKZF2	Inhibit immunity (T cell function)	Here we report that selective Helios deficiency within CD4 Tregs leads to enhanced antitumor immunity through induction of an unstable phenotype and conversion of intratumoral Tregs into T effector cells within the tumor microenvironment.
27162338	Pan-Cancer	NLRC5	Promote immunity (infiltration)	Strikingly, NLRC5 expression was significantly associated with the activation of CD8(+) cytotoxic T cells and patient survival in multiple cancer types.
27157615	Brain Neoplasm	MIF	Inhibit immunity	The inhibition of MIF signaling or its receptor CD74 promotes IFN-γ release and amplifies tumor death either through pharmacological inhibition or through siRNA-mediated knockdown.
27157615	Brain Neoplasm	CD74	Inhibit immunity	The inhibition of MIF signaling or its receptor CD74 promotes IFN-γ release and amplifies tumor death either through pharmacological inhibition or through siRNA-mediated knockdown.
27127303	Plasma Cell Myeloma	TNFSF13	Inhibit immunity	APRIL and BCMA promote human multiple myeloma growth and immunosuppression in the bone marrow microenvironment.
27127303	Plasma Cell Myeloma	TNFRSF17	Inhibit immunity	APRIL and BCMA promote human multiple myeloma growth and immunosuppression in the bone marrow microenvironment.
27116977	Glioma	ULBP1	Promote immunity (NK cell function)	IDH mutant glioma cells acquire resistance to NK cells through epigenetic silencing of NKG2D ligands ULBP1 and ULBP3.
27116977	Glioma	ULBP3	Promote immunity (NK cell function)	IDH mutant glioma cells acquire resistance to NK cells through epigenetic silencing of NKG2D ligands ULBP1 and ULBP3.
26939703	Hepatocellular Carcinoma	AR	Inhibit immunity (NK cell function)	Our results showed AR could suppress IL12A expression at the transcriptional level via direct binding to the IL12A promoter region that resulted in repressing efficacy of NK cell cytotoxicity against HCC, and sorafenib treatment could enhance IL12A signals via suppressing AR signals.
26939703	Hepatocellular Carcinoma	IL12A	Promote immunity (NK cell function)	Our results showed AR could suppress IL12A expression at the transcriptional level via direct binding to the IL12A promoter region that resulted in repressing efficacy of NK cell cytotoxicity against HCC, and sorafenib treatment could enhance IL12A signals via suppressing AR signals.
26936918	Glioblastoma	KMO	Promote immunity	Kynurenine that is not degraded by KMO or KYNU may bind to the aryl hydrocarbon receptor that recruits immune-suppressive T cells, leading to immune evasion.
26936918	Glioblastoma	KYNU	Inhibit immunity (T cell function)	Kynurenine that is not degraded by KMO or KYNU may bind to the aryl hydrocarbon receptor that recruits immune-suppressive T cells, leading to immune evasion.
26936880	Breast Carcinoma; Colon Carcinoma	NFE2L2	Inhibit immunity (T cell function)	Nrf2 enhanced MDSC suppressive activity by increasing MDSC production of H2O2, and it increased the quantity of tumor-infiltrating MDSC by reducing their oxidative stress and rate of apoptosis.
26928313	Hepatocellular Carcinoma	TLR4	Inhibit immunity (T cell function)	TLR4-mediated BCL6 upregulation was crucial for PD-1(hi) B-cell induction by HCC environmental factors, and that effect was abolished by IL4-elicited STAT6 phosphorylation. Importantly, upon encountering PD-L1(+) cells or undergoing PD-1 triggering, PD-1(hi) B cells acquired regulatory functions that suppressed tumor-specific T-cell immunity and promoted cancer growth via IL10 signals.
26928313	Hepatocellular Carcinoma	BCL6	Inhibit immunity (T cell function)	TLR4-mediated BCL6 upregulation was crucial for PD-1(hi) B-cell induction by HCC environmental factors, and that effect was abolished by IL4-elicited STAT6 phosphorylation. Importantly, upon encountering PD-L1(+) cells or undergoing PD-1 triggering, PD-1(hi) B cells acquired regulatory functions that suppressed tumor-specific T-cell immunity and promoted cancer growth via IL10 signals.
26928313	Hepatocellular Carcinoma	IL10	Inhibit immunity (T cell function)	TLR4-mediated BCL6 upregulation was crucial for PD-1(hi) B-cell induction by HCC environmental factors, and that effect was abolished by IL4-elicited STAT6 phosphorylation. Importantly, upon encountering PD-L1(+) cells or undergoing PD-1 triggering, PD-1(hi) B cells acquired regulatory functions that suppressed tumor-specific T-cell immunity and promoted cancer growth via IL10 signals.
26928313	Hepatocellular Carcinoma	IL4	Promote immunity (T cell function)	TLR4-mediated BCL6 upregulation was crucial for PD-1(hi) B-cell induction by HCC environmental factors, and that effect was abolished by IL4-elicited STAT6 phosphorylation. Importantly, upon encountering PD-L1(+) cells or undergoing PD-1 triggering, PD-1(hi) B cells acquired regulatory functions that suppressed tumor-specific T-cell immunity and promoted cancer growth via IL10 signals.
26928313	Hepatocellular Carcinoma	STAT6	Promote immunity (T cell function)	TLR4-mediated BCL6 upregulation was crucial for PD-1(hi) B-cell induction by HCC environmental factors, and that effect was abolished by IL4-elicited STAT6 phosphorylation. Importantly, upon encountering PD-L1(+) cells or undergoing PD-1 triggering, PD-1(hi) B cells acquired regulatory functions that suppressed tumor-specific T-cell immunity and promoted cancer growth via IL10 signals.
26924089	Hepatocellular Carcinoma	CCL2	Inhibit immunity (T cell function)	TAN-conditioned media, as well as recombinant CCL2 and CCL17, increased the migratory activity of the macrophages and T-regulatory (Treg) cells from patients or mice with HCC to a greater extent that PBN-conditioned media. Neutralizing antibodies against CCL2 and CCL17, or their receptors C-C chemokine receptor 2 and C-C chemokine receptor 4, reduced the migratory activities of macrophage and Treg cells.
26924089	Hepatocellular Carcinoma	CCL17	Inhibit immunity (T cell function)	TAN-conditioned media, as well as recombinant CCL2 and CCL17, increased the migratory activity of the macrophages and T-regulatory (Treg) cells from patients or mice with HCC to a greater extent that PBN-conditioned media. Neutralizing antibodies against CCL2 and CCL17, or their receptors C-C chemokine receptor 2 and C-C chemokine receptor 4, reduced the migratory activities of macrophage and Treg cells.
26921343	Lung Carcinoma	TGFB1	Promote immunity (infiltration, T cell function)	Here, we used viable human lung tumor slices and autologous tumor antigen-specific T-lymphocyte clones to provide evidence that CD103 is directly involved in T-lymphocyte recruitment within epithelial tumor islets and intratumoral early T-cell signaling. Mechanistic investigations revealed that TGFβ bound to its receptors (TGFBR), which promoted the recruitment and phosphorylation of integrin-linked kinase (ILK) by TGFBR1. We further show that ILK interacted with the CD103 intracellular domain, resulting in protein kinase B (PKB)/AKT activation, thereby initiating integrin inside-out signaling.
26921343	Lung Carcinoma	ILK	Promote immunity (infiltration, T cell function)	Here, we used viable human lung tumor slices and autologous tumor antigen-specific T-lymphocyte clones to provide evidence that CD103 is directly involved in T-lymphocyte recruitment within epithelial tumor islets and intratumoral early T-cell signaling. Mechanistic investigations revealed that TGFβ bound to its receptors (TGFBR), which promoted the recruitment and phosphorylation of integrin-linked kinase (ILK) by TGFBR1. We further show that ILK interacted with the CD103 intracellular domain, resulting in protein kinase B (PKB)/AKT activation, thereby initiating integrin inside-out signaling.
26921343	Lung Carcinoma	AKT1	Promote immunity (infiltration and T cell function)	Here, we used viable human lung tumor slices and autologous tumor antigen-specific T-lymphocyte clones to provide evidence that CD103 is directly involved in T-lymphocyte recruitment within epithelial tumor islets and intratumoral early T-cell signaling. Mechanistic investigations revealed that TGFβ bound to its receptors (TGFBR), which promoted the recruitment and phosphorylation of integrin-linked kinase (ILK) by TGFBR1. We further show that ILK interacted with the CD103 intracellular domain, resulting in protein kinase B (PKB)/AKT activation, thereby initiating integrin inside-out signaling.
26921343	Lung Carcinoma	ITGAE	Promote immunity (infiltration, T cell function)	Here, we used viable human lung tumor slices and autologous tumor antigen-specific T-lymphocyte clones to provide evidence that CD103 is directly involved in T-lymphocyte recruitment within epithelial tumor islets and intratumoral early T-cell signaling. Mechanistic investigations revealed that TGFβ bound to its receptors (TGFBR), which promoted the recruitment and phosphorylation of integrin-linked kinase (ILK) by TGFBR1. We further show that ILK interacted with the CD103 intracellular domain, resulting in protein kinase B (PKB)/AKT activation, thereby initiating integrin inside-out signaling.
26917236	Glioma	CD40	Promote immunity (infiltration)	In vitro, we demonstrated direct antitumor effects of an anti-CD40 agonistic monoclonal antibody (FGK45) against the cell lines. Increases in apoptosis and CD4(+) and CD8(+) T cell infiltration were observed in the bRiTs-G3 model after FGK45 treatment.
26903482	Melanoma	IKBKB	Promote immunity (T cell function)	We hypothesized that forcing T cell-intrinsic NF-κB activation might break this cycle and induce tumor elimination. NF-κB was activated in T cells by inducing the expression of a constitutively active form of the upstream activator IκB kinase β (IKKβ). T cell-restricted constitutively active IKKβ augmented the frequency of functional tumor-specific CD8(+) T cells and improved tumor control.
26903482	Melanoma	NFKB1	Promote immunity (T cell function)	We hypothesized that forcing T cell-intrinsic NF-κB activation might break this cycle and induce tumor elimination. NF-κB was activated in T cells by inducing the expression of a constitutively active form of the upstream activator IκB kinase β (IKKβ). T cell-restricted constitutively active IKKβ augmented the frequency of functional tumor-specific CD8(+) T cells and improved tumor control.
26896171	Melanoma	TNF	Inhibit immunity (T cell function)	In sharp contrast, DN-TNF treatment dramatically decreased IL1α and increased the essential immunoregulatory cytokines IL1β, IL12p70, and IL17 in the peripheral blood of MCA-injected mice. In addition, MDSC accumulation, STAT3 phosphorylation, and immunosuppression in MCA-injected mice were prevented by DN-TNF treatment, TNFR2-Fc treatment, and/or gene deletion of TNF or TNFR1, but not deletion of TNFR2.
26896171	Melanoma	TNFRSF1A	Inhibit immunity (T cell function)	In sharp contrast, DN-TNF treatment dramatically decreased IL1α and increased the essential immunoregulatory cytokines IL1β, IL12p70, and IL17 in the peripheral blood of MCA-injected mice. In addition, MDSC accumulation, STAT3 phosphorylation, and immunosuppression in MCA-injected mice were prevented by DN-TNF treatment, TNFR2-Fc treatment, and/or gene deletion of TNF or TNFR1, but not deletion of TNFR2.
26896171	Melanoma	TNFRSF1B	Inhibit immunity (T cell function)	In sharp contrast, DN-TNF treatment dramatically decreased IL1α and increased the essential immunoregulatory cytokines IL1β, IL12p70, and IL17 in the peripheral blood of MCA-injected mice. In addition, MDSC accumulation, STAT3 phosphorylation, and immunosuppression in MCA-injected mice were prevented by DN-TNF treatment, TNFR2-Fc treatment, and/or gene deletion of TNF or TNFR1, but not deletion of TNFR2.
26880800	Melanoma; Breast Carcinoma	BTK	Inhibit immunity (T cell function)	Ibrutinib treatment also resulted in a significant reduction of MDSCs in wild-type mice bearing B16F10 melanoma tumors, but not in X-linked immunodeficiency mice (XID) harboring a BTK mutation, suggesting that BTK inhibition plays an important role in the observed reduction of MDSCs in vivo
26880715	Lung Carcinoma	KRAS	Inhibit immunity (T cell function)	Overexpression of the mutant KRAS(G12V)gene in wild-type KRAS tumor cells led to regulatory T-cell (Treg) induction. We also demonstrate that mutant KRAS induces the secretion of IL10 and transforming growth factor-β1 (both required for Treg induction) by tumor cells through the activation of the MEK-ERK-AP1 pathway.
26880715	Lung Carcinoma	IL10	Inhibit immunity (T cell function)	Overexpression of the mutant KRAS(G12V)gene in wild-type KRAS tumor cells led to regulatory T-cell (Treg) induction. We also demonstrate that mutant KRAS induces the secretion of IL10 and transforming growth factor-β1 (both required for Treg induction) by tumor cells through the activation of the MEK-ERK-AP1 pathway.
26880715	Lung Carcinoma	TGFB1	Inhibit immunity (T cell function)	Overexpression of the mutant KRAS(G12V)gene in wild-type KRAS tumor cells led to regulatory T-cell (Treg) induction. We also demonstrate that mutant KRAS induces the secretion of IL10 and transforming growth factor-β1 (both required for Treg induction) by tumor cells through the activation of the MEK-ERK-AP1 pathway.
26880715	Lung Carcinoma	MAP2K1	Inhibit immunity (T cell function)	Overexpression of the mutant KRAS(G12V)gene in wild-type KRAS tumor cells led to regulatory T-cell (Treg) induction. We also demonstrate that mutant KRAS induces the secretion of IL10 and transforming growth factor-β1 (both required for Treg induction) by tumor cells through the activation of the MEK-ERK-AP1 pathway.
26880715	Lung Carcinoma	MAPK1	Inhibit immunity (T cell function)	Overexpression of the mutant KRAS(G12V)gene in wild-type KRAS tumor cells led to regulatory T-cell (Treg) induction. We also demonstrate that mutant KRAS induces the secretion of IL10 and transforming growth factor-β1 (both required for Treg induction) by tumor cells through the activation of the MEK-ERK-AP1 pathway.
26880715	Lung Carcinoma	JUN	Inhibit immunity (T cell function)	Overexpression of the mutant KRAS(G12V)gene in wild-type KRAS tumor cells led to regulatory T-cell (Treg) induction. We also demonstrate that mutant KRAS induces the secretion of IL10 and transforming growth factor-β1 (both required for Treg induction) by tumor cells through the activation of the MEK-ERK-AP1 pathway.
26879524	Melanoma	PLAUR	Inhibit immunity	Herein, we report the first antibody-recruiting small molecule (ARM) that is capable of recognizing the urokinase-type plasminogen activator receptor (uPAR), a uniquely overexpressed cancer cell-surface marker, and facilitating the immune-mediated destruction of cancer cells.
26872698	lung adenocarcinoma	TP53	Promote immunity	Here, using lung adenocarcinoma mouse models, including genetic models, we show that autochthonous tumors that lacked T cell infiltration and resisted current treatment options could be successfully sensitized to host antitumor T cell immunity when appropriately selected immunogenic drugs (e.g., oxaliplatin combined with cyclophosphamide for treatment against tumors expressing oncogenic Kras and lacking Trp53) were used.
26872698	lung adenocarcinoma	KRAS	Inhibit immunity (infiltration)	Here, using lung adenocarcinoma mouse models, including genetic models, we show that autochthonous tumors that lacked T cell infiltration and resisted current treatment options could be successfully sensitized to host antitumor T cell immunity when appropriately selected immunogenic drugs (e.g., oxaliplatin combined with cyclophosphamide for treatment against tumors expressing oncogenic Kras and lacking Trp53) were used.
26841680	Colorectal Carcinoma	TFF2	Promote immunity (T cell function)	TFF2 is important to the anti-inflammatory reflex arc and plays an essential role in arresting MDSC proliferation.
26837767	Hepatocellular Carcinoma	HIF1A	Inhibit immunity (T cell function)	Collectively, our findings suggest that the HIF-1α/CCL20/IDO axis in hepatocellular carcinoma is important for accelerating tumor metastasis through both the induction of EMT and the establishment of an immunosuppressive tumor microenvironment, warranting further investigation into the therapeutic effects of blocking specific nodes of this signaling network.
26837767	Hepatocellular Carcinoma	CCL20	Inhibit immunity (T cell function)	Collectively, our findings suggest that the HIF-1α/CCL20/IDO axis in hepatocellular carcinoma is important for accelerating tumor metastasis through both the induction of EMT and the establishment of an immunosuppressive tumor microenvironment, warranting further investigation into the therapeutic effects of blocking specific nodes of this signaling network.
26837767	Hepatocellular Carcinoma	IDO1	Inhibit immunity (T cell function)	Collectively, our findings suggest that the HIF-1α/CCL20/IDO axis in hepatocellular carcinoma is important for accelerating tumor metastasis through both the induction of EMT and the establishment of an immunosuppressive tumor microenvironment, warranting further investigation into the therapeutic effects of blocking specific nodes of this signaling network.
26833127	Lung Carcinoma	STK11	Promote immunity (infiltration)	STK11/LKB1 Deficiency Promotes Neutrophil Recruitment and Proinflammatory Cytokine Production to Suppress T-cell Activity in the Lung Tumor Microenvironment.
26831100	Colorectal Carcinoma	TLR5	Promote immunity	Toll-like receptor-5 agonist, entolimod, suppresses metastasis and induces immunity by stimulating an NK-dendritic-CD8+ T-cell axis.
26450924	Colon Carcinoma	TLR9	Promote immunity	In the present study, we aimed to boost anti-tumour immunity in a murine colon cancer model by synergizing DCs and iNKT cells using α-Galcer-loaded tumour cells (tumour-Gal) and the TLR9 agonist cytosine-phosphorothioate-guanine (CpG1826).
26432403	Melanoma	CCL22	Inhibit immunity (T cell function)	Suppression of intratumoral CCL22 by type i interferon inhibits migration of regulatory T cells and blocks cancer progression.
26423796	Lymphoma	IL15	Promote immunity (NK cell function)	ALT-803 is a superagonist IL-15 mutant and IL-15Rα-Fc fusion complex that activates the IL-15 receptor constitutively expressed on natural killer (NK) cells. ALT-803 augmented cytotoxicity and the expression of granzyme B and perforin, providing one potential mechanism for this enhanced functionality.
26423796	Lymphoma	GZMB	Promote immunity (NK cell function)	ALT-803 is a superagonist IL-15 mutant and IL-15Rα-Fc fusion complex that activates the IL-15 receptor constitutively expressed on natural killer (NK) cells. ALT-803 augmented cytotoxicity and the expression of granzyme B and perforin, providing one potential mechanism for this enhanced functionality.
26423796	Lymphoma	PRF1	Promote immunity (NK cell function)	ALT-803 is a superagonist IL-15 mutant and IL-15Rα-Fc fusion complex that activates the IL-15 receptor constitutively expressed on natural killer (NK) cells. ALT-803 augmented cytotoxicity and the expression of granzyme B and perforin, providing one potential mechanism for this enhanced functionality.
26423152	Colon Adenocarcinoma	TNFRSF18	Promote immunity (T cell function)	These results suggest that GITR signaling has stimulatory effects on effector T cells and inhibitory effects through Treg cells.
26408403	Laryngeal Squamous Cell Carcinoma	CD274	Inhibit immunity (T cell function)	Increased TILs density and PD-L1 levels are associated with better outcome in laryngeal squamous cell cancer. Assessment of TILs and PD-L1 expression could be useful to predict response to immune checkpoint inhibitors.
26406376	Squamous Cell Carcinoma	PTK2	Inhibit immunity (T cell function)	Mechanistically, nuclear FAK is associated with chromatin and exists in complex with transcription factors and their upstream regulators that control Ccl5 expression. Finally, we show that a small-molecule FAK kinase inhibitor, VS-4718, which is currently in clinical development, also drives depletion of Tregs and promotes a CD8(+) T cell-mediated anti-tumor response.
26406376	Squamous Cell Carcinoma	CCL5	Inhibit immunity (T cell function)	Mechanistically, nuclear FAK is associated with chromatin and exists in complex with transcription factors and their upstream regulators that control Ccl5 expression. Finally, we show that a small-molecule FAK kinase inhibitor, VS-4718, which is currently in clinical development, also drives depletion of Tregs and promotes a CD8(+) T cell-mediated anti-tumor response.
26404003	Lung Cacinoma	DLL1	Promote immunity (infiltration, T cell function)	Systemic DLL-1 administration increased T-cell infiltration into tumors and elevated numbers of CD44(+)CD62L(+)CD8(+) memory T cells while decreasing the number of regulatory T cells and limiting tumor vascularization. This treatment was associated with upregulation of Notch and its ligands in tumor-infiltrating T cells enhanced expression of T-bet and phosphorylation of Stat1/2.
26404003	Lung Cacinoma	TBX21	Promote immunity (infiltration)	Systemic DLL-1 administration increased T-cell infiltration into tumors and elevated numbers of CD44(+)CD62L(+)CD8(+) memory T cells while decreasing the number of regulatory T cells and limiting tumor vascularization. This treatment was associated with upregulation of Notch and its ligands in tumor-infiltrating T cells enhanced expression of T-bet and phosphorylation of Stat1/2.
26404003	Lung Cacinoma	STAT1	Promote immunity (infiltration)	Systemic DLL-1 administration increased T-cell infiltration into tumors and elevated numbers of CD44(+)CD62L(+)CD8(+) memory T cells while decreasing the number of regulatory T cells and limiting tumor vascularization. This treatment was associated with upregulation of Notch and its ligands in tumor-infiltrating T cells enhanced expression of T-bet and phosphorylation of Stat1/2.
26404003	Lung Cacinoma	STAT2	Promote immunity (infiltration)	Systemic DLL-1 administration increased T-cell infiltration into tumors and elevated numbers of CD44(+)CD62L(+)CD8(+) memory T cells while decreasing the number of regulatory T cells and limiting tumor vascularization. This treatment was associated with upregulation of Notch and its ligands in tumor-infiltrating T cells enhanced expression of T-bet and phosphorylation of Stat1/2.
26387540	Melanoma	NFATC2	Inhibit immunity	The relevance of NFATc2-dependent melanoma dedifferentiation for immune escape was shown by cytolytic T-cell assays.
26384545	Colorectal Carcinoma	NLRP3	Promote immunity (NK cell function)	Here, we show that mice deficient in Nlrp3 inflammasome components had exacerbated liver colorectal cancer metastatic growth, which was mediated by impaired interleukin-18 (IL-18) signaling. Control of tumor growth was independent of differential cancer cell colonization or proliferation, intestinal microbiota effects, or tumoricidal activity by the adaptive immune system.
26384545	Colorectal Carcinoma	IL18	Promote immunity (NK cell function)	Here, we show that mice deficient in Nlrp3 inflammasome components had exacerbated liver colorectal cancer metastatic growth, which was mediated by impaired interleukin-18 (IL-18) signaling. Control of tumor growth was independent of differential cancer cell colonization or proliferation, intestinal microbiota effects, or tumoricidal activity by the adaptive immune system.
26381407	Melanoma	TAPBP	Promote immunity	This treatment combined with tapasin reconstitution and IFN-γ stimulation restored the highest level of HLA class I expression and its ability to elicit cytotoxic T cell responses.
26381407	Melanoma	HLA-A	Promote immunity	This treatment combined with tapasin reconstitution and IFN-γ stimulation restored the highest level of HLA class I expression and its ability to elicit cytotoxic T cell responses.
26364607	Gastric Carcinoma	NCR3	Promote immunity (NK cell function)	In contrast, another cell line AGS expressing low levels of HLA-I with activated NKp30/MAPK/IL-12 (interleukin-12) or IL-2 (interleukin-2) pathway was susceptible to NK lysis. Treatment of tumor bearing mice with systemic administration of IL-12 in combination with intratumor injection of anti-HLA-I antibody significantly increased NK cell recruitment into xenograft tumors, which became sensitive to NK killing, resulting in reduced tumor progression.
26364607	Gastric Carcinoma	MAPK1	Promote immunity (NK cell function)	In contrast, another cell line AGS expressing low levels of HLA-I with activated NKp30/MAPK/IL-12 (interleukin-12) or IL-2 (interleukin-2) pathway was susceptible to NK lysis. Treatment of tumor bearing mice with systemic administration of IL-12 in combination with intratumor injection of anti-HLA-I antibody significantly increased NK cell recruitment into xenograft tumors, which became sensitive to NK killing, resulting in reduced tumor progression.
26364607	Gastric Carcinoma	IL12A	Promote immunity (NK cell function)	In contrast, another cell line AGS expressing low levels of HLA-I with activated NKp30/MAPK/IL-12 (interleukin-12) or IL-2 (interleukin-2) pathway was susceptible to NK lysis. Treatment of tumor bearing mice with systemic administration of IL-12 in combination with intratumor injection of anti-HLA-I antibody significantly increased NK cell recruitment into xenograft tumors, which became sensitive to NK killing, resulting in reduced tumor progression.
26364607	Gastric Carcinoma	IL2	Promote immunity (NK cell function)	In contrast, another cell line AGS expressing low levels of HLA-I with activated NKp30/MAPK/IL-12 (interleukin-12) or IL-2 (interleukin-2) pathway was susceptible to NK lysis. Treatment of tumor bearing mice with systemic administration of IL-12 in combination with intratumor injection of anti-HLA-I antibody significantly increased NK cell recruitment into xenograft tumors, which became sensitive to NK killing, resulting in reduced tumor progression.
26363007	Ovarian Carcinoma	NT5E	Inhibit immunity (T cell function)	Furthermore, high levels of CD73 expression in ovarian tumor cells abolished the good prognosis associated with intraepithelial CD8(+) cells.
26355571	AIDS-Related Diffuse Large B-cell Lymphoma	TP53	Inhibit immunity (T cell function)	When we examined the relationship between stromal immune cells and tumor molecular characteristics, stromal FOXP3+ Treg cells were found to be positively associated with tumor expression of p53 and cMYC, and inversely associated with BCL6.
26355571	AIDS-Related Diffuse Large B-cell Lymphoma	MYC	Inhibit immunity (T cell function)	When we examined the relationship between stromal immune cells and tumor molecular characteristics, stromal FOXP3+ Treg cells were found to be positively associated with tumor expression of p53 and cMYC, and inversely associated with BCL6.
26355571	AIDS-Related Diffuse Large B-cell Lymphoma	BCL6	Promote immunity (T cell function)	When we examined the relationship between stromal immune cells and tumor molecular characteristics, stromal FOXP3+ Treg cells were found to be positively associated with tumor expression of p53 and cMYC, and inversely associated with BCL6.
26343581	Melanoma	NRAS	Inhibit immunity	Genetic ablation of cyclooxygenases (COX) or prostaglandin E synthases in Braf(V600E) mouse melanoma cells, as well as in Nras(G12D) melanoma or in breast or colorectal cancer cells, renders them susceptible to immune control and provokes a shift in the tumor inflammatory profile toward classic anti-cancer immune pathways.
26343581	Melanoma	BRAF	Inhibit immunity	Genetic ablation of cyclooxygenases (COX) or prostaglandin E synthases in Braf(V600E) mouse melanoma cells, as well as in Nras(G12D) melanoma or in breast or colorectal cancer cells, renders them susceptible to immune control and provokes a shift in the tumor inflammatory profile toward classic anti-cancer immune pathways.
26334519	Melanoma	TNF	Promote immunity (T cell function)	In the tumor microenvironment, the combination therapy led to significantly downregulated levels of immunosuppressive factors, such as decreased numbers of myeloid-derived suppressor cells and regulatory T cells (Treg) cells and declined levels of interleukin-6 and chemokine ligand 2-in correlation with increased levels of proinflammatory cytokines, including tumor necrosis factor-α and IFN-γ as well as an elevation in the CD8(+) T-cell population.
26334519	Melanoma	IFNG	Promote immunity (T cell function)	In the tumor microenvironment, the combination therapy led to significantly downregulated levels of immunosuppressive factors, such as decreased numbers of myeloid-derived suppressor cells and regulatory T cells (Treg) cells and declined levels of interleukin-6 and chemokine ligand 2-in correlation with increased levels of proinflammatory cytokines, including tumor necrosis factor-α and IFN-γ as well as an elevation in the CD8(+) T-cell population.
26334519	Melanoma	IL6	Inhibit immunity (T cell function)	In the tumor microenvironment, the combination therapy led to significantly downregulated levels of immunosuppressive factors, such as decreased numbers of myeloid-derived suppressor cells and regulatory T cells (Treg) cells and declined levels of interleukin-6 and chemokine ligand 2-in correlation with increased levels of proinflammatory cytokines, including tumor necrosis factor-α and IFN-γ as well as an elevation in the CD8(+) T-cell population.
26334519	Melanoma	CCL2	Inhibit immunity (T cell function)	In the tumor microenvironment, the combination therapy led to significantly downregulated levels of immunosuppressive factors, such as decreased numbers of myeloid-derived suppressor cells and regulatory T cells (Treg) cells and declined levels of interleukin-6 and chemokine ligand 2-in correlation with increased levels of proinflammatory cytokines, including tumor necrosis factor-α and IFN-γ as well as an elevation in the CD8(+) T-cell population.
26330543	Breast Carcinoma; Ovarian Carcinoma	PCSK1	Inhibit immunity	A complete proteomic study of secretomes and intracellular proteins was undertaken and revealed that inhibition of proprotein convertase 1/3 orient macrophages toward an M1 activated phenotype.
26329536	Breast Carcinoma; Lung Carcinoma	CD81	Inhibit immunity (T cell function)	Tetraspanin CD81 Promotes Tumor Growth and Metastasis by Modulating the Functions of T Regulatory and Myeloid-Derived Suppressor Cells
26324768	Hepatocellular Carcinoma	FOXP3	Inhibit immunity (T cell function)	FOXP3/NFAT interaction is required to repress expression of IL-2, upregulate expression of the Treg markers CTLA4 and CD25, and confer suppressor function to Tregs.
26324768	Hepatocellular Carcinoma	NFATC2	Inhibit immunity (T cell function)	FOXP3/NFAT interaction is required to repress expression of IL-2, upregulate expression of the Treg markers CTLA4 and CD25, and confer suppressor function to Tregs.
26324768	Hepatocellular Carcinoma	IL2	Promote immunity (T cell function)	FOXP3/NFAT interaction is required to repress expression of IL-2, upregulate expression of the Treg markers CTLA4 and CD25, and confer suppressor function to Tregs.
26324768	Hepatocellular Carcinoma	CTLA4	Inhibit immunity (T cell function)	FOXP3/NFAT interaction is required to repress expression of IL-2, upregulate expression of the Treg markers CTLA4 and CD25, and confer suppressor function to Tregs.
26322579	Colon Adenocarcinoma	CD47	Inhibit immunity (T cell function)	Together, our findings indicate that CD47 blockade drives T cell-mediated elimination of immunogenic tumors.
26321681	Melanoma	PCK1	Promote immunity (T cell function)	Moreover, PCK1-overexpressing T cells restricted tumor growth and prolonged the survival of melanoma-bearing mice.
26289067	Melanoma	S100A8	Inhibit immunity (T cell function)	Moreover, in nonresponders, moMDSCs produced significantly more nitric oxide, and granulocytic MDSCs expressed higher levels of PD-L1 than these parameters at baseline and in responders, suggesting their enhanced immunosuppressive capacity. Upon the first ipilimumab infusion, nonresponders displayed elevated serum concentrations of S100A8/A9 and HMGB1 that attract and activate MDSCs.
26289067	Melanoma	S100A9	Inhibit immunity (T cell function)	Moreover, in nonresponders, moMDSCs produced significantly more nitric oxide, and granulocytic MDSCs expressed higher levels of PD-L1 than these parameters at baseline and in responders, suggesting their enhanced immunosuppressive capacity. Upon the first ipilimumab infusion, nonresponders displayed elevated serum concentrations of S100A8/A9 and HMGB1 that attract and activate MDSCs.
26289067	Melanoma	HMGB1	Inhibit immunity (T cell function)	Moreover, in nonresponders, moMDSCs produced significantly more nitric oxide, and granulocytic MDSCs expressed higher levels of PD-L1 than these parameters at baseline and in responders, suggesting their enhanced immunosuppressive capacity. Upon the first ipilimumab infusion, nonresponders displayed elevated serum concentrations of S100A8/A9 and HMGB1 that attract and activate MDSCs.
26249173	Breast Carcinoma	CCL5	Inhibit immunity	Thus, our findings showed that CCL5/CCR3 signaling promotes metastasis by inducing Th2 polarization of CD4? T cells, with implications for prognosis and immunotherapy of luminal breast cancer.
26249173	Breast Carcinoma	CCR3	Inhibit immunity	Thus, our findings showed that CCL5/CCR3 signaling promotes metastasis by inducing Th2 polarization of CD4? T cells, with implications for prognosis and immunotherapy of luminal breast cancer.
26239999	Renal Cell Carcinoma	TNFRSF18	Promote immunity (T cell function)	Furthermore, mechanistic investigation revealed that Sunitinib treatment reprograms tumor-associated macrophages toward classically activated or "M1" polarization upon GITR stimulation and consequently mounts an antitumor CD8(+) T and NK cell response via inhibiting STAT3 activity.
26239999	Renal Cell Carcinoma	STAT3	Inhibit immunity (T cell function)	Furthermore, mechanistic investigation revealed that Sunitinib treatment reprograms tumor-associated macrophages toward classically activated or "M1" polarization upon GITR stimulation and consequently mounts an antitumor CD8(+) T and NK cell response via inhibiting STAT3 activity.
26221040	Melanoma	GJA1	Promote immunity (NK cell function)	The Selective Degradation of Synaptic Connexin 43 Protein by Hypoxia-induced Autophagy Impairs Natural Killer Cell-mediated Tumor Cell Killing.
26216383	Ovarian Carcinoma	IL6	Inhibit immunity	Interleukin-6 is associated with chemoresistance and an immune-suppressive tumor microenvironment. Functional IL-6R blocking is feasible and safe in EOC patients treated with carboplatin/(pegylated liposomal)doxorubicin, using 8 mg/kg tocilizumab.
26216383	Ovarian Carcinoma	IL6R	Inhibit immunity	Interleukin-6 is associated with chemoresistance and an immune-suppressive tumor microenvironment. Functional IL-6R blocking is feasible and safe in EOC patients treated with carboplatin/(pegylated liposomal)doxorubicin, using 8 mg/kg tocilizumab.
26208907	Colorectal Carcinoma	STAT3	Inhibit immunity (infiltration)	As compared with Stat3-sufficient control tumors, Stat3(-/-) cancer cells exhibited an increased infiltration by dendritic cells and cytotoxic T lymphocytes after chemotherapy.
26194763	Mantle Cell Lymphoma	IL21	Promote immunity (T/NK cell function)	Together, these data indicate that IL-21 has potent antitumor activity against MCL cells via direct cytotoxic and indirect, immune-mediated effects.
26183926	Melanoma	HLA-DPA1	Inhibit immunity (T cell function)	Taken together, our results illustrate a novel immune escape mechanism that can be activated by aberrant expression of MHC class II molecules, which by attracting tumor-specific CD4(+) T cells elicit a local inflammatory response dominated by TNF that, in turn, inhibits cytotoxic CD8(+) T-cell responses.
26183926	Melanoma	HLA-DRA	Inhibit immunity (T cell function)	Taken together, our results illustrate a novel immune escape mechanism that can be activated by aberrant expression of MHC class II molecules, which by attracting tumor-specific CD4(+) T cells elicit a local inflammatory response dominated by TNF that, in turn, inhibits cytotoxic CD8(+) T-cell responses.
26183926	Melanoma	HLA-DQA1	Inhibit immunity (T cell function)	Taken together, our results illustrate a novel immune escape mechanism that can be activated by aberrant expression of MHC class II molecules, which by attracting tumor-specific CD4(+) T cells elicit a local inflammatory response dominated by TNF that, in turn, inhibits cytotoxic CD8(+) T-cell responses.
26183450	Lung Carcinoma	NPC2	Promote immunity	Stromal immature macrophage-lineage cells (IMCs) promote proliferation and transcriptional alterations suggestive of epithelial-mesenchymal transition in isolated premalignant lung tumour cells ex vivo, and are required for the maintenance of early-stage lung tumours in vivo. Together, these findings show that NPC2 secreted by premalignant lung tumours suppresses IMC recruitment to the microenvironment in a paracrine manner, thus identifying a novel target for the development of chemopreventive strategies in lung cancer.
26174883	Glioblastoma	IL15	Promote immunity (infiltration); increase the efficacy of immunotherapy	We show that an IL-15 superagonist complex ALT-803, as a single treatment as well as in combination with anti-PD-1 antibody or stereotactic radiosurgery, exhibits a robust antitumor immune response resulting in a prolonged survival including complete remission in tumor bearing mice.
26151313	Lymphoma	KLRK1	Promote immunity	Critical role of the NKG2D receptor for NK cell-mediated control and immune escape of B-cell lymphoma. This indicates that NK cells and the NKG2D receptor play a role for control of lymphomas and that selection for NKG2D-L loss mutants provides a mechanism of tumor escape.
26141620	Melanoma	CD40	Promote immunity (T cell function)	We found that the combination of agonistic anti-CD40 + IL2/anti-IL2 complexes (IL2cx) + IL12Fc was a distinctively effective treatment with respect to priming protective, tumor-specific immunity and eradicating tumors at advanced disease stage.
26141620	Melanoma	IL2	Promote immunity (T cell function)	We found that the combination of agonistic anti-CD40 + IL2/anti-IL2 complexes (IL2cx) + IL12Fc was a distinctively effective treatment with respect to priming protective, tumor-specific immunity and eradicating tumors at advanced disease stage.
26141620	Melanoma	IL12A	Promote immunity (T cell function)	We found that the combination of agonistic anti-CD40 + IL2/anti-IL2 complexes (IL2cx) + IL12Fc was a distinctively effective treatment with respect to priming protective, tumor-specific immunity and eradicating tumors at advanced disease stage.
26139534	Melanoma	TGFB1	Inhibit immunity (T cell function)	Therefore, the melanoma microenvironment contributes to skewing of CD8 T cell differentiation programs, in part by TGFβ/IL-6-mediated induction of Maf.
26139534	Melanoma	IL16	Inhibit immunity (T cell function)	Therefore, the melanoma microenvironment contributes to skewing of CD8 T cell differentiation programs, in part by TGFβ/IL-6-mediated induction of Maf.
26139534	Melanoma	MAF	Inhibit immunity (T cell function)	Therefore, the melanoma microenvironment contributes to skewing of CD8 T cell differentiation programs, in part by TGFβ/IL-6-mediated induction of Maf.
26138335	Breast Carcinoma	PARP1	Inhibit immunity	These results demonstrate that CTLA-4 blockade combined with PARP inhibition induces protective antitumor immunity and significant survival benefit in the BRCA1(-) tumor model, and support clinical testing of this regimen to improve outcomes for women with hereditary ovarian cancer.
26136424	Colon Carcinoma	FAS	Promote immunity (T cell function)	Using an orthotopic colon cancer mouse model, we demonstrated that tumor-infiltrating cytotoxic T lymphocytes are FasL(+) and that FasL-mediated cancer immune surveillance is essential for colon carcinoma growth control in vivo. Our findings determine that H3K9me3 of the FAS promoter is a dominant mechanism underlying FAS silencing and resultant colon carcinoma immune evasion and progression.
26122932	E7+ tumor TC-1	ISG15	Promote immunity (T cell function)	Ubiquitin-like Molecule ISG15 Acts as an Immune Adjuvant to Enhance Antigen-specific CD8 T-cell Tumor Immunity.
26116271	Pan-Cancer	CD47	Inhibit immunity (T cell function)	Blockade of the CD47:SIRP-α axis between tumor cells and innate immune cells (monocytes, macrophages, and dendritic cells) increases tumor cell phagocytosis in both solid tumors (including, but not limited to, bladder, breast, colon, lung, and pancreatic) and hematologic malignancies.
26112923	Ovarian Carcinoma	FSHR	Inhibit immunity (T cell function)	Receptor ligand-based anti-FSHR immunoreceptors were constructed that contained small binding fragments from the ligand for FSHR, FSH, fused to T-cell transmembrane and T-cell signaling domains. Human T cells transduced to express anti-FSHR immunoreceptors were specifically immunoreactive against FSHR-expressing human and mouse ovarian cancer cell lines in an MHC-nonrestricted manner and mediated effective lysis of FHSR-expressing tumor cells, but not FSHR-deficient targets, in vitro.
26109379	Melanoma	CXCR3	Promote immunity (infiltration)	These studies unexpectedly reveal a non-redundant requirement for the CXCR3-CXCL9/CXCL10 axis for CD8+ T cell trafficking within the intravascular space that could not be predicted from static profiling of intratumoral chemokines or their receptors on T cells.
26109379	Melanoma	CXCL9	Promote immunity (infiltration)	These studies unexpectedly reveal a non-redundant requirement for the CXCR3-CXCL9/CXCL10 axis for CD8+ T cell trafficking within the intravascular space that could not be predicted from static profiling of intratumoral chemokines or their receptors on T cells.
26109379	Melanoma	CXCL10	Promote immunity (infiltration)	These studies unexpectedly reveal a non-redundant requirement for the CXCR3-CXCL9/CXCL10 axis for CD8+ T cell trafficking within the intravascular space that could not be predicted from static profiling of intratumoral chemokines or their receptors on T cells.
26105028	Pancreatic Carcinoma	CD28	Promote immunity (T cell function)	Transduction of the PD-1-CD28 receptor constructs mediated enhanced cytokine release, T cell proliferation, and T cell-induced lysis of target tumor cells.
26091714	Lung Carcinoma	CREB1	Inhibit immunity (T cell function)	Ectopic expression of CREB enhanced the transcriptional activity of the 5′ flanking sequence of miR-9-1, and mutation of the binding site for CREB abolished the enhancive effect of CREB. In this study, we found that inhibition of microRNA (miR)-9 promoted the differentiation of MDSCs with significantly reduced immunosuppressive function whereas overexpression of miR-9 markedly enhanced the function of MDSCs.
26091714	Lung Carcinoma	RUNX1	Inhibit immunity	In this study, we found that inhibition of microRNA (miR)-9 promoted the differentiation of MDSCs with significantly reduced immunosuppressive function whereas overexpression of miR-9 markedly enhanced the function of MDSCs. Moreover, miR-9 regulated MDSCs differentiation by targeting the runt-related transcription factor 1, an essential transcription factor in regulating MDSC differentiation and function. Furthermore, the CREB was found to regulate miR-9 expression in MDSCs.
26081225	Esophageal Adenocarcinoma	IL4	Inhibit immunity (T cell function)	Because the progression from squamous esophagitis to Barrett's esophagus is accompanied by a transition from a TH1 to TH2 immune response, we hypothesized that the TH2 cytokines IL4/IL13 could contribute to PD-L2 induction. We confirmed that these cytokines can augment PD-L2 expression in esophageal adenocarcinoma cell lines.
26081225	Esophageal Adenocarcinoma	IL13	Inhibit immunity (T cell function)	Because the progression from squamous esophagitis to Barrett's esophagus is accompanied by a transition from a TH1 to TH2 immune response, we hypothesized that the TH2 cytokines IL4/IL13 could contribute to PD-L2 induction. We confirmed that these cytokines can augment PD-L2 expression in esophageal adenocarcinoma cell lines.
26081225	Esophageal Adenocarcinoma	PDCD1LG2	Inhibit immunity (T cell function)	Because the progression from squamous esophagitis to Barrett's esophagus is accompanied by a transition from a TH1 to TH2 immune response, we hypothesized that the TH2 cytokines IL4/IL13 could contribute to PD-L2 induction. We confirmed that these cytokines can augment PD-L2 expression in esophageal adenocarcinoma cell lines.
26075911	Melanoma	DPP4	Inhibit immunity (infiltration); decrease the efficacy of immunotherapy	Here we show that in vivo post-translational processing of chemokines by dipeptidylpeptidase 4 (DPP4, also known as CD26) limits lymphocyte migration to sites of inflammation and tumors.
26075911	Melanoma	CXCL10	Promote immunity (infiltration)	Inhibition of DPP4 enzymatic activity enhanced tumor rejection by preserving biologically active CXCL10 and increasing trafficking into the tumor by lymphocytes expressing the counter-receptor CXCR3. Furthermore, DPP4 inhibition improved adjuvant-based immunotherapy, adoptive T cell transfer and checkpoint blockade.
26075911	Melanoma	CXCR3	Promote immunity (infiltration)	Inhibition of DPP4 enzymatic activity enhanced tumor rejection by preserving biologically active CXCL10 and increasing trafficking into the tumor by lymphocytes expressing the counter-receptor CXCR3. Furthermore, DPP4 inhibition improved adjuvant-based immunotherapy, adoptive T cell transfer and checkpoint blockade.
26073941	Ovarian Carcinoma	XBP1	Inhibit immunity (T cell function)	Dendritic cells (DCs) are required to initiate and sustain T cell-dependent anti-cancer immunity. However, tumors often evade immune control by crippling normal DC function. Here we show that constitutive activation of XBP1 in tumor-associated DCs (tDCs) drives ovarian cancer (OvCa) progression by blunting anti-tumor immunity.
26062742	Renal Cell Carcinoma	HIF1A	Inhibit immunity (T cell function; infiltration)	Carbonic anhydrase (CA) IX is a surface-expressed protein that is upregulated by the hypoxia inducible factor (HIF) and represents a prototypic tumor-associated antigen that is overexpressed on renal cell carcinoma (RCC). We show that anti-CAIX mAbs are capable of mediating human immune response in vivo including tumor infiltration of NK cells and activation of T cells, resulting in inhibition of CAIX(+) tumor growth.
26062742	Renal Cell Carcinoma	CA9	Inhibit immunity (T cell function; infiltration)	We show that anti-CAIX mAbs are capable of mediating human immune response in vivo including tumor infiltration of NK cells and activation of T cells, resulting in inhibition of CAIX(+) tumor growth.
26056232	Breast Carcinoma	CCL2	Inhibit immunity	Pulmonary metastasis of breast cancer cells is promoted by a distinct population of macrophages, metastasis-associated macrophages (MAMs), which originate from inflammatory monocytes (IMs) recruited by the CC-chemokine ligand 2 (CCL2). We demonstrate here that, through activation of the CCL2 receptor CCR2, the recruited MAMs secrete another chemokine ligand CCL3. Genetic deletion of CCL3 or its receptor CCR1 in macrophages reduces the number of lung metastasis foci, as well as the number of MAMs accumulated in tumor-challenged lung in mice.
26056232	Breast Carcinoma	CCR2	Inhibit immunity	Pulmonary metastasis of breast cancer cells is promoted by a distinct population of macrophages, metastasis-associated macrophages (MAMs), which originate from inflammatory monocytes (IMs) recruited by the CC-chemokine ligand 2 (CCL2). We demonstrate here that, through activation of the CCL2 receptor CCR2, the recruited MAMs secrete another chemokine ligand CCL3. Genetic deletion of CCL3 or its receptor CCR1 in macrophages reduces the number of lung metastasis foci, as well as the number of MAMs accumulated in tumor-challenged lung in mice.
26056232	Breast Carcinoma	CCL3	Promote immunity	Pulmonary metastasis of breast cancer cells is promoted by a distinct population of macrophages, metastasis-associated macrophages (MAMs), which originate from inflammatory monocytes (IMs) recruited by the CC-chemokine ligand 2 (CCL2). We demonstrate here that, through activation of the CCL2 receptor CCR2, the recruited MAMs secrete another chemokine ligand CCL3. Genetic deletion of CCL3 or its receptor CCR1 in macrophages reduces the number of lung metastasis foci, as well as the number of MAMs accumulated in tumor-challenged lung in mice.
26056232	Breast Carcinoma	CCR1	Inhibit immunity	Pulmonary metastasis of breast cancer cells is promoted by a distinct population of macrophages, metastasis-associated macrophages (MAMs), which originate from inflammatory monocytes (IMs) recruited by the CC-chemokine ligand 2 (CCL2). We demonstrate here that, through activation of the CCL2 receptor CCR2, the recruited MAMs secrete another chemokine ligand CCL3. Genetic deletion of CCL3 or its receptor CCR1 in macrophages reduces the number of lung metastasis foci, as well as the number of MAMs accumulated in tumor-challenged lung in mice.
26055519	Cervical Carcinoma	IFRD1	Inhibit immunity	These results suggest that IFRD1 may also play a role in suppressing the response of cancer cells to immune stimuli such as IFN-γ and TNF-α.
26055519	Cervical Carcinoma	EGFR	Inhibit immunity	Thus, our study reveals an EGFR-IFRD1-mediated viral immune evasion mechanism, which can also be exploited by cancer cells.
26054597	Neuroblastoma	ARG2	Inhibit immunity (T cell function)	Neuroblastoma Arginase Activity Creates an Immunosuppressive Microenvironment That Impairs Autologous and Engineered Immunity.
26041736	Melanoma	PORCN	Inhibit immunity (T cell function)	We further show that the genetic silencing of the PORCN membrane-bound O-acyl transferase, which is necessary for melanoma Wnt ligand secretion, enhances antitumor T-cell immunity, and that the pharmacologic inhibition of this enzyme synergistically suppresses melanoma progression when combined with anti-CTLA-4 antibody therapy.
26041736	Melanoma	WNT5A	Inhibit immunity (T cell function)	Melanoma-Derived Wnt5a Promotes Local Dendritic-Cell Expression of IDO and Immunotolerance: Opportunities for Pharmacologic Enhancement of Immunotherapy.
26041736	Melanoma	CTNNB1	Inhibit immunity (T cell function)	This work demonstrates that melanoma-derived Wnt5a ligand upregulates the durable expression and activity of the indoleamine 2,3-dioxygenase-1 (IDO) enzyme by local DCs in a manner that depends upon the β-catenin signaling pathway.
26041736	Melanoma	IDO1	Inhibit immunity (T cell function)	This work demonstrates that melanoma-derived Wnt5a ligand upregulates the durable expression and activity of the indoleamine 2,3-dioxygenase-1 (IDO) enzyme by local DCs in a manner that depends upon the β-catenin signaling pathway.
26041735	Sarcoma	SSX2	Promote immunity (T cell function)	We previously reported that a DNA vaccine encoding the cancer-testis antigen SSX2, modified to encode altered epitopes with increased MHC class I affinity, elicited a greater frequency of cytolytic, multifunctional CD8(+) T cells in non-tumor-bearing mice.
26034288	Melanoma	TNFRSF9	Promote immunity (T cell function)	Focusing and sustaining the antitumor CTL effector killer response by agonist anti-CD137 mAb.
26025380	Melanoma; Lung Carcinoma	STAT3	Inhibit immunity (T cell function)	Together, our study reveals a negative regulation by STAT3 signaling in T cells on cross-talk between myeloid cells and T cells through IFNγ/CXCR3/CXCL10, which is important for CD8(+) T cells homing to tumors.
26025380	Melanoma; Lung Carcinoma	IFNG	Promote immunity (T cell function)	Together, our study reveals a negative regulation by STAT3 signaling in T cells on cross-talk between myeloid cells and T cells through IFNγ/CXCR3/CXCL10, which is important for CD8(+) T cells homing to tumors.
26025380	Melanoma; Lung Carcinoma	CXCR3	Promote immunity (T cell function)	Together, our study reveals a negative regulation by STAT3 signaling in T cells on cross-talk between myeloid cells and T cells through IFNγ/CXCR3/CXCL10, which is important for CD8(+) T cells homing to tumors.
26025380	Melanoma; Lung Carcinoma	CXCL10	Promote immunity (infiltration)	Together, our study reveals a negative regulation by STAT3 signaling in T cells on cross-talk between myeloid cells and T cells through IFNγ/CXCR3/CXCL10, which is important for CD8(+) T cells homing to tumors.
26019274	Melanoma	IFNG	Promote immunity (T cell function)	Immunization in the presence of TPCS2a significantly increased activation of CD8 T cells compared with immunization without TPCS2a and as measured by CD8 T cell proliferation, production of proinflammatory IFN-γ, TNF-α, and IL-2, and prevention of tumor growth.
26019274	Melanoma	TNF	Promote immunity (T cell function)	Immunization in the presence of TPCS2a significantly increased activation of CD8 T cells compared with immunization without TPCS2a and as measured by CD8 T cell proliferation, production of proinflammatory IFN-γ, TNF-α, and IL-2, and prevention of tumor growth.
26019274	Melanoma	IL2	Promote immunity (T cell function)	Immunization in the presence of TPCS2a significantly increased activation of CD8 T cells compared with immunization without TPCS2a and as measured by CD8 T cell proliferation, production of proinflammatory IFN-γ, TNF-α, and IL-2, and prevention of tumor growth.
26014096	Lung Carcinoma	JAK3	Inhibit immunity (T cell function)	We discovered activating somatic and germline amino acid variants in JAK3 that promoted PD-L1 induction in lung cancer cells and in the tumor immune microenvironment.
25984582	Colon Carcinoma	SLC5A8	Inhibit immunity (T cell function)	Slc5a8-null DCs do not induce IDO1 and Aldh1A2 and do not generate Tregs or suppress IFN-γ-producing T-cells in response to butyrate.
25984582	Colon Carcinoma	IDO1	Inhibit immunity (T cell function)	We found that DCs exposed to butyrate express the immunosuppressive enzymes indoleamine 2,3-dioxygenase 1 (IDO1) and aldehyde dehydrogenase 1A2 (Aldh1A2), promote conversion of naive T-cells into immunosuppressive forkhead box P3(+) (FoxP3(+)) Tregs (regulatory T-cells) and suppress conversion of naive T-cells into pro-inflammatory interferon (IFN)-γ-producing cells.
25984582	Colon Carcinoma	ALDH1A2	Inhibit immunity (T cell function)	We found that DCs exposed to butyrate express the immunosuppressive enzymes indoleamine 2,3-dioxygenase 1 (IDO1) and aldehyde dehydrogenase 1A2 (Aldh1A2), promote conversion of naive T-cells into immunosuppressive forkhead box P3(+) (FoxP3(+)) Tregs (regulatory T-cells) and suppress conversion of naive T-cells into pro-inflammatory interferon (IFN)-γ-producing cells.
25977337	Melanoma	TNFRSF1A	Inhibit immunity (infiltration)	Collectively, our observations indicate that TNF-R1-dependent TNF signaling impairs tumor-infiltrating CD8(+) T-cell accumulation and may serve as a putative target to favor CD8(+) T-cell-dependent immune response in melanoma.
25977337	Melanoma	TNF	Inhibit immunity (infiltration)	Collectively, our observations indicate that TNF-R1-dependent TNF signaling impairs tumor-infiltrating CD8(+) T-cell accumulation and may serve as a putative target to favor CD8(+) T-cell-dependent immune response in melanoma.
25972070	Head and Neck Squamous Cell Carcinoma	EGFR	Inhibit immunity	EGFR induces HLA downregulation through SHP-2/STAT1 suppression. Abrogating EGFR-induced immune escape mechanisms and restoring STAT1 signaling to reverse HLA downregulation using cetuximab should be combined with strategies to enhance adaptive cellular immunity.
25972070	Head and Neck Squamous Cell Carcinoma	PTPN11	Promote immunity	EGFR induces HLA downregulation through SHP-2/STAT1 suppression. Abrogating EGFR-induced immune escape mechanisms and restoring STAT1 signaling to reverse HLA downregulation using cetuximab should be combined with strategies to enhance adaptive cellular immunity.
25972070	Head and Neck Squamous Cell Carcinoma	STAT1	Promote immunity	EGFR induces HLA downregulation through SHP-2/STAT1 suppression. Abrogating EGFR-induced immune escape mechanisms and restoring STAT1 signaling to reverse HLA downregulation using cetuximab should be combined with strategies to enhance adaptive cellular immunity.
25972070	Head and Neck Squamous Cell Carcinoma	HLA-B	Promote immunity	EGFR induces HLA downregulation through SHP-2/STAT1 suppression. Abrogating EGFR-induced immune escape mechanisms and restoring STAT1 signaling to reverse HLA downregulation using cetuximab should be combined with strategies to enhance adaptive cellular immunity.
25972070	Head and Neck Squamous Cell Carcinoma	HLA-C	Promote immunity	EGFR induces HLA downregulation through SHP-2/STAT1 suppression. Abrogating EGFR-induced immune escape mechanisms and restoring STAT1 signaling to reverse HLA downregulation using cetuximab should be combined with strategies to enhance adaptive cellular immunity.
25971300	Glioblastoma	FGL2	Inhibit immunity (T cell function)	FGL2 augments glioma immunosuppression by increasing the expression levels of PD-1 and CD39, expanding the frequency of tumor-supportive M2 macrophages via the FcγRIIB pathway, and enhancing the number of MDSCs and CD39(+) regulatory T cells.
25971300	Glioblastoma	ENTPD1	Inhibit immunity (T cell function)	FGL2 augments glioma immunosuppression by increasing the expression levels of PD-1 and CD39, expanding the frequency of tumor-supportive M2 macrophages via the FcγRIIB pathway, and enhancing the number of MDSCs and CD39(+) regulatory T cells.
25967142	Prostate Carcinoma	TLR9	Promote immunity	TLR9-Targeted STAT3 Silencing Abrogates Immunosuppressive Activity of Myeloid-Derived Suppressor Cells from Prostate Cancer Patients
25967142	Prostate Carcinoma	STAT3	Inhibit immunity (T cell function)	TLR9-Targeted STAT3 Silencing Abrogates Immunosuppressive Activity of Myeloid-Derived Suppressor Cells from Prostate Cancer Patients
25967142	Prostate Carcinoma	ARG1	Inhibit immunity (T cell function)	TLR9-Targeted STAT3 Silencing Abrogates Immunosuppressive Activity of Myeloid-Derived Suppressor Cells from Prostate Cancer Patients. These effects depended on reduced expression and enzymatic activity of Arginase-1, a downstream STAT3 target gene and a potent T cell inhibitor.
25964334	Colon Carcinoma	C10orf54	Inhibit immunity (T cell function)	A combinatorial blockade using monoclonal antibodies specific for VISTA and PD-L1 achieved optimal tumor-clearing therapeutic efficacy.
25952647	Pancreatic Carcinoma	CSF2	Inhibit immunity (T cell function)	GM-CSF production was significantly enhanced in various PDAC cell lines or PDAC tumor tissues from patients after treatment with chemotherapy, which induced the differentiation of monocytes into myeloid-derived suppressor cells (MDSC). Furthermore, blockade of GM-CSF with monoclonal antibodies helped to restore T-cell proliferation when cocultured with monocytes stimulated with tumor supernatants.
25944800	Melanoma	IL10	Inhibit immunity (T cell function)	Functional studies demonstrated that some factors, including IL10 and IL32-gamma, induced PD-L1 expression on monocytes but not tumor cells.
25944800	Melanoma	IL32	Inhibit immunity (T cell function)	Functional studies demonstrated that some factors, including IL10 and IL32-gamma, induced PD-L1 expression on monocytes but not tumor cells.
25943534	Colorectal Carcinoma	CD274	Inhibit immunity (T cell function)	Taken together, our results demonstrate that inhibition of PD-L1 function can have potent antitumor activity when used as monotherapy or in combination in preclinical models, and suggest it may be a promising therapeutic approach for the treatment of cancer.
25924227	Melanoma	TGFB1	Inhibit immunity (T cell function)	Here we demonstrate that upregulation of the Inhibitor of Differentiation 1 (Id1), in response to tumour-derived factors, such as TGFβ, is responsible for the switch from dendritic cell (DC) differentiation to myeloid-derived suppressor cell expansion during tumour progression.
25924227	Melanoma	ID1	Inhibit immunity (T cell function)	Here we demonstrate that upregulation of the Inhibitor of Differentiation 1 (Id1), in response to tumour-derived factors, such as TGFβ, is responsible for the switch from dendritic cell (DC) differentiation to myeloid-derived suppressor cell expansion during tumour progression.
25924065	Prostate Carcinoma	IL10	Inhibit immunity (T cell function)	The crucial immunosuppressive B cells are plasmocytes that express IgA, interleukin (IL)-10 and programmed death ligand 1 (PD-L1), the appearance of which depends on TGFβ receptor signalling. Elimination of these cells, which also infiltrate human-therapy-resistant prostate cancer, allows CTL-dependent eradication of oxaliplatin-treated tumours.
25924065	Prostate Carcinoma	TGFBR1	Inhibit immunity (T cell function)	The crucial immunosuppressive B cells are plasmocytes that express IgA, interleukin (IL)-10 and programmed death ligand 1 (PD-L1), the appearance of which depends on TGFβ receptor signalling. Elimination of these cells, which also infiltrate human-therapy-resistant prostate cancer, allows CTL-dependent eradication of oxaliplatin-treated tumours.
25893601	Plasma Cell Myeloma	CD226	Promote immunity (T cell function)	In this study using this unique mouse model of multiple myeloma (MM), we demonstrate the importance of NK and CD8+ T cells in MM immunosurveillance and response to treatment in vivo through CD226 and CD155 interactions.
25893601	Plasma Cell Myeloma	PVR	Promote immunity (T cell function)	In this study using this unique mouse model of multiple myeloma (MM), we demonstrate the importance of NK and CD8+ T cells in MM immunosurveillance and response to treatment in vivo through CD226 and CD155 interactions.
25893601	Plasma Cell Myeloma	TNFRSF9	Promote immunity (T cell function)	Activation of costimulatory receptor CD137 with mAb (4-1BB) exerted strong antimyeloma activity, while inhibition of coinhibitory receptors PD-1 and CTLA-4 had no effect.
25851535	Melanoma	FYB	Inhibit immunity (T cell function)	Together, we propose that targeting the unrecognized ADAP-SKAP55-NFATc1-PD-1 pathway might increase efficacy of anti-tumor immunotherapy.
25851535	Melanoma	SKAP1	Inhibit immunity (T cell function)	Together, we propose that targeting the unrecognized ADAP-SKAP55-NFATc1-PD-1 pathway might increase efficacy of anti-tumor immunotherapy.
25851535	Melanoma	NFATC1	Inhibit immunity (T cell function)	Together, we propose that targeting the unrecognized ADAP-SKAP55-NFATc1-PD-1 pathway might increase efficacy of anti-tumor immunotherapy.
25851535	Melanoma	PDCD1	Inhibit immunity (T cell function)	Together, we propose that targeting the unrecognized ADAP-SKAP55-NFATc1-PD-1 pathway might increase efficacy of anti-tumor immunotherapy.
25849134	Breast Carcinoma; Neuroblastoma	HPSE	Promote immunity (T cell function; infiltration)	Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes.
25825448	Non-Small Cell Lung Carcinoma	TLR7	Promote immunity (T cell function)	The ability of TLR7/8 agonists to reverse mMDSC-mediated immune suppression suggests that they might be useful adjuncts for tumor immunotherapy.
25825448	Non-Small Cell Lung Carcinoma	TLR8	Promote immunity (T cell function)	The ability of TLR7/8 agonists to reverse mMDSC-mediated immune suppression suggests that they might be useful adjuncts for tumor immunotherapy.
25814664	Thymoma	GSK3B	Promote immunity (T cell function)	Taken together, DC-based immune response mediated by interferon-γ-induced IDO expression via GSK-3β activity not only regulates CD8(+) T-cell proliferation and cytotoxic T lymphocyte activity but also modulates OVA-pulsed DC vaccination against EG7 thymoma.
25814664	Thymoma	IFNG	Promote immunity (T cell function)	Taken together, DC-based immune response mediated by interferon-γ-induced IDO expression via GSK-3β activity not only regulates CD8(+) T-cell proliferation and cytotoxic T lymphocyte activity but also modulates OVA-pulsed DC vaccination against EG7 thymoma.
25814664	Thymoma	IDO1	Inhibit immunity (T cell function)	Taken together, DC-based immune response mediated by interferon-γ-induced IDO expression via GSK-3β activity not only regulates CD8(+) T-cell proliferation and cytotoxic T lymphocyte activity but also modulates OVA-pulsed DC vaccination against EG7 thymoma.
25795007	Melanoma	BRAF	Inhibit immunity (T cell function)	Collectively, these data suggest that oncogenic activation of BRAF allows tumor cells to co-opt an evolutionarily conserved MHC-I trafficking pathway as a strategy to facilitate immune evasion.
25787767	Melanoma	BRAF	Inhibit immunity (T cell function)	Our findings support the testing of triple combination therapy of BRAF and MEK inhibitors with immunotherapy in patients with BRAF(V600E) mutant metastatic melanoma.
25787767	Melanoma	MAP2K7	Inhibit immunity (T cell function)	Our findings support the testing of triple combination therapy of BRAF and MEK inhibitors with immunotherapy in patients with BRAF(V600E) mutant metastatic melanoma.
25765738	Melanoma	TLR2	Promote immunity (infiltration)	TLR2/6 agonists and interferon-gamma induce human melanoma cells to produce CXCL10. CXCL10 has been implicated as a critical chemokine supporting T-cell infiltration into the TME.
25765738	Melanoma	TLR6	Promote immunity (infiltration)	TLR2/6 agonists and interferon-gamma induce human melanoma cells to produce CXCL10. CXCL10 has been implicated as a critical chemokine supporting T-cell infiltration into the TME.
25765738	Melanoma	IFNG	Promote immunity (infiltration)	TLR2/6 agonists and interferon-gamma induce human melanoma cells to produce CXCL10. CXCL10 has been implicated as a critical chemokine supporting T-cell infiltration into the TME.
25765738	Melanoma	CXCL10	Promote immunity (infiltration)	TLR2/6 agonists and interferon-gamma induce human melanoma cells to produce CXCL10. CXCL10 has been implicated as a critical chemokine supporting T-cell infiltration into the TME.
25754875	Colorectal Carcinoma	CXCL9	Promote immunity (infiltration)	We also demonstrate a selective increase of the chemokines CXCL9 and CXCL10 in Treg-cell-depleted tumors, which were accompanied by accumulation of CXCR3(+) T cells, and increased IFN-γ mRNA expression.
25754875	Colorectal Carcinoma	CXCL10	Promote immunity (infiltration)	We also demonstrate a selective increase of the chemokines CXCL9 and CXCL10 in Treg-cell-depleted tumors, which were accompanied by accumulation of CXCR3(+) T cells, and increased IFN-γ mRNA expression.
25744203	Glioblastoma	TNFRSF4	Promote immunity	Moreover, compared with systemic intraperitoneal injection, the subcutaneous injection of the OX40 agonist antibody together with glioma cell lysates elicited stronger antitumor immunity and prolonged the survival of mice bearing glioma or glioma-initiating cell-like cells.
25744203	Glioblastoma	TNFSF4	Inhibit immunity (T cell function)	Taken together, these results suggest that glioblastoma may cooperate with Treg cells via OX40L, thereby enhancing IL-10 production. IL-10 in turn generates the immunosuppressive microenvironment. Such pro-tumor effects caused by Treg cells may be enhanced under hypoxic conditions.
25744203	Glioblastoma	IL10	Inhibit immunity (T cell function)	Taken together, these results suggest that glioblastoma may cooperate with Treg cells via OX40L, thereby enhancing IL-10 production. IL-10 in turn generates the immunosuppressive microenvironment. Such pro-tumor effects caused by Treg cells may be enhanced under hypoxic conditions.
25745066	Lymphoma; Acute Myeloid Leukemia	ULBP1	Promote immunity (NK cell function)	In contrast, we show that in mice, a shed form of MULT1, a high-affinity NKG2D ligand, causes NK cell activation and tumor rejection.
25744719	Lung Carcinoma	TGFB1	Inhibit immunity (T cell function)	We conclude that pulmonary exposure to SWCNT favors the formation of a niche that supports ingrowth of lung carcinoma in vivo via activation of TGFβ production by SWCNT-attracted and -presensitized MDSC.
25744717	Melanoma	CEACAM1	Promote immunity (NK cell function)	CEACAM1-3S Drives Melanoma Cells into NK Cell-Mediated Cytolysis and Enhances Patient Survival.
25744717	Melanoma	CEACAM1	Inhibit immunity (NK cell function)	Conversely, CEACAM1-4L downregulated cell surface levels of the NKG2D ligands MICA and ULBP2 by enhanced shedding, thereby promoting malignant character.
25744717	Melanoma	MICA	Promote immunity (NK cell function)	Finally, we provide strong evidences that CEACAM1-3S triggers melanoma cells for NK cell-mediated cytolysis by upregulating cell surface expression of MICA and ULBP2, whereas CEACAM1-4L causes the contrary effect due to enhanced shedding of both NKG2D ligands (NKG2DLs).
25744717	Melanoma	ULBP2	Promote immunity (NK cell function)	Finally, we provide strong evidences that CEACAM1-3S triggers melanoma cells for NK cell-mediated cytolysis by upregulating cell surface expression of MICA and ULBP2, whereas CEACAM1-4L causes the contrary effect due to enhanced shedding of both NKG2D ligands (NKG2DLs).
25720800	Melanoma	IL10	Inhibit immunity (T cell function)	IL10 and PD-1 Cooperate to Limit the Activity of Tumor-Specific CD8+ T Cells. Collectively, our findings offer a rationale to block both IL10 and PD-1 to strengthen the counteraction of T-cell immunosuppression and to enhance the activity of TA-specific CD8(+) T cell in advanced melanoma patients.
25720800	Melanoma	PDCD1	Inhibit immunity (T cell function)	IL10 and PD-1 Cooperate to Limit the Activity of Tumor-Specific CD8+ T Cells. Collectively, our findings offer a rationale to block both IL10 and PD-1 to strengthen the counteraction of T-cell immunosuppression and to enhance the activity of TA-specific CD8(+) T cell in advanced melanoma patients.
25713363	Follicular Lymphoma	CREBBP	Promote immunity	These observations therefore implicate CREBBP mutation as an early event in FL evolution that contributes to immune evasion via decreased antigen presentation.
25697354	Lung Carcinoma	THBS1	Promote immunity	Exogenous treatment of TSP-1 may be able to suppress the CD47-mediated tumor immune escape by disrupting the CD47-SIRP-a interaction. With the increasing surface expression of CD47, this suppression effect may be even more obvious in immune-selected cells. These findings prove that the TSP-1/CD47/SIRP-α signal axis is important to the evolution of tumor cells in the microenvironment of immunotherapy and identify thrombospondin-1 as a key signal with therapeutic benefits in overcoming long term relapse, providing new evidence for the clinical promise of cancer vaccination.
25697354	Lung Carcinoma	CD47	Inhibit immunity	Exogenous treatment of TSP-1 may be able to suppress the CD47-mediated tumor immune escape by disrupting the CD47-SIRP-a interaction. With the increasing surface expression of CD47, this suppression effect may be even more obvious in immune-selected cells. These findings prove that the TSP-1/CD47/SIRP-α signal axis is important to the evolution of tumor cells in the microenvironment of immunotherapy and identify thrombospondin-1 as a key signal with therapeutic benefits in overcoming long term relapse, providing new evidence for the clinical promise of cancer vaccination.
25697354	Lung Carcinoma	SIRPA	Inhibit immunity	Exogenous treatment of TSP-1 may be able to suppress the CD47-mediated tumor immune escape by disrupting the CD47-SIRP-a interaction. With the increasing surface expression of CD47, this suppression effect may be even more obvious in immune-selected cells. These findings prove that the TSP-1/CD47/SIRP-α signal axis is important to the evolution of tumor cells in the microenvironment of immunotherapy and identify thrombospondin-1 as a key signal with therapeutic benefits in overcoming long term relapse, providing new evidence for the clinical promise of cancer vaccination.
25691366	Breast Carcinoma	CCR9	Inhibit immunity (T cell function)	Unlike PDL1, which inhibits TCR signaling, CCR9 regulates STAT signaling in T cells, resulting in reduced T-helper-1 cytokine secretion and reduced cytotoxic capacity. Moreover, inhibition of CCR9 expression on tumor cells facilitated immunotherapy of human tumors by tumor-specific T cells in vivo.
25691328	Malignant Neoplasms of the Mouse Mammary Gland	LGALS3	Inhibit immunity (T cell function)	Galectin-3 Shapes Antitumor Immune Responses by Suppressing CD8+ T Cells via LAG-3 and Inhibiting Expansion of Plasmacytoid Dendritic Cells.
25691328	Malignant Neoplasms of the Mouse Mammary Gland	LAG3	Inhibit immunity (T cell function)	Galectin-3 Shapes Antitumor Immune Responses by Suppressing CD8+ T Cells via LAG-3 and Inhibiting Expansion of Plasmacytoid Dendritic Cells.
25680274	Colorectal Carcinoma	TIGIT	Inhibit immunity (NK cell function)	We have further demonstrated that tumor-infiltrating lymphocytes expressed TIGIT and that T cell activities were also inhibited by F. nucleatum via Fap2.
25658629	Non-Small Cell Lung Carcinoma	EGFR	Inhibit immunity (T cell function)	EGFR activation upregulated PD-L1 through p-ERK1/2/p-c-Jun but not through p-AKT/p-S6 pathway. PD-L1 mediated by EGFR activation could induce the apoptosis of T cells through PD-L1/PD-1 axis in tumor cells and peripheral blood mononuclear cells coculture system.
25658629	Non-Small Cell Lung Carcinoma	MAPK1	Inhibit immunity (T cell function)	EGFR activation upregulated PD-L1 through p-ERK1/2/p-c-Jun but not through p-AKT/p-S6 pathway. PD-L1 mediated by EGFR activation could induce the apoptosis of T cells through PD-L1/PD-1 axis in tumor cells and peripheral blood mononuclear cells coculture system.
25658629	Non-Small Cell Lung Carcinoma	MAPK3	Inhibit immunity (T cell function)	EGFR activation upregulated PD-L1 through p-ERK1/2/p-c-Jun but not through p-AKT/p-S6 pathway. PD-L1 mediated by EGFR activation could induce the apoptosis of T cells through PD-L1/PD-1 axis in tumor cells and peripheral blood mononuclear cells coculture system.
25658629	Non-Small Cell Lung Carcinoma	JUN	Inhibit immunity (T cell function)	EGFR activation upregulated PD-L1 through p-ERK1/2/p-c-Jun but not through p-AKT/p-S6 pathway. PD-L1 mediated by EGFR activation could induce the apoptosis of T cells through PD-L1/PD-1 axis in tumor cells and peripheral blood mononuclear cells coculture system.
25646304	Melanoma; Pancreatic Carcinoma; Prostate Carcinoma	TLR3	Promote immunity	The combination of ISCOMATRIX adjuvant and TLR agonists induces regression of established solid tumors in vivo.
25646304	Melanoma; Pancreatic Carcinoma; Prostate Carcinoma	TLR9	Promote immunity	The combination of ISCOMATRIX adjuvant and TLR agonists induces regression of established solid tumors in vivo.
25624500	Breast Carcinoma	CSF3	Inhibit immunity	These results demonstrate that prolonged G-CSF may be responsible for both the development and activity of immunosuppressive neutrophils in cancer.
25614966	Melanoma	IL27	Inhibit immunity (T cell function)	Thus, our data identify an IL-27/NFIL3 signalling axis as a key regulator of effector T-cell responses via induction of Tim-3, IL-10 and T-cell dysfunction.
25614966	Melanoma	NFIL3	Inhibit immunity (T cell function)	Thus, our data identify an IL-27/NFIL3 signalling axis as a key regulator of effector T-cell responses via induction of Tim-3, IL-10 and T-cell dysfunction.
25614966	Melanoma	HAVCR2	Inhibit immunity (T cell function)	Thus, our data identify an IL-27/NFIL3 signalling axis as a key regulator of effector T-cell responses via induction of Tim-3, IL-10 and T-cell dysfunction.
25614966	Melanoma	IL10	Inhibit immunity (T cell function)	Thus, our data identify an IL-27/NFIL3 signalling axis as a key regulator of effector T-cell responses via induction of Tim-3, IL-10 and T-cell dysfunction.
25614511	Colon Carcinoma	SEMA4D	Inhibit immunity (infiltration)	Antibody Blockade of Semaphorin 4D Promotes Immune Infiltration into Tumor and Enhances Response to Other Immunomodulatory Therapies.
25601928	Colon Adenocarcinoma	TNFRSF9	Promote immunity (T cell function)	In vivo 4-1BB deficiency in myeloid cells enhances peripheral T cell proliferation by increasing IL-15.
25601928	Colon Adenocarcinoma	IL15	Promote immunity (T cell function)	In vivo 4-1BB deficiency in myeloid cells enhances peripheral T cell proliferation by increasing IL-15.
25601652	Colon Carcinoma	VEGFA	Inhibit immunity (T cell function)	We report in the present work that VEGF-A produced in the tumor microenvironment enhances expression of PD-1 and other inhibitory checkpoints involved in CD8(+) T cell exhaustion, which could be reverted by anti-angiogenic agents targeting VEGF-A-VEGFR.
25600646	Hepatocellular Carcinoma	TLR2	Promote immunity (T cell function)	TLR2 limits development of hepatocellular carcinoma by reducing IL18-mediated immunosuppression.
25600646	Hepatocellular Carcinoma	CASP8	Inhibit immunity (T cell function)	TLR2 limits development of hepatocellular carcinoma by reducing IL18-mediated immunosuppression. IL18 production was mediated by caspase-8 insofar as the decrease in its silencing was sufficient to attenuate levels of mature IL18 in Tlr2(-/-) mice.
25600646	Hepatocellular Carcinoma	IL18	Inhibit immunity (T cell function)	TLR2 limits development of hepatocellular carcinoma by reducing IL18-mediated immunosuppression. IL18 production was mediated by caspase-8 insofar as the decrease in its silencing was sufficient to attenuate levels of mature IL18 in Tlr2(-/-) mice.
25600437	Melanoma	ITGA4	Promote immunity (infiltration)	Importantly, we found that the α4(S988A) mice exhibited a marked increase in T-cell entry into and reduced growth of B16 melanomas, consistent with antitumor roles of infiltrating T cells and progrowth functions of tumor-associated macrophages.
25597412	Non-Small Cell Lung Carcinoma	CKS1B	Inhibit immunity (T cell function)	Our discoveries suggest that the miR-197/CKS1B/STAT3-mediated network can drive tumor PD-L1 expression as a biomarker of this cascade, and miR-197 replacement therapy may be a potential treatment strategy for chemoresistant NSCLC.
25597412	Non-Small Cell Lung Carcinoma	STAT3	Inhibit immunity (T cell function)	Our discoveries suggest that the miR-197/CKS1B/STAT3-mediated network can drive tumor PD-L1 expression as a biomarker of this cascade, and miR-197 replacement therapy may be a potential treatment strategy for chemoresistant NSCLC.
25597412	Non-Small Cell Lung Carcinoma	CD274	Inhibit immunity (T cell function)	Our discoveries suggest that the miR-197/CKS1B/STAT3-mediated network can drive tumor PD-L1 expression as a biomarker of this cascade, and miR-197 replacement therapy may be a potential treatment strategy for chemoresistant NSCLC.
25592150	Cervix Carcinoma; Medulloblastoma; Lymphoma; Melanoma	ERAP1	Inhibit immunity (NK cell function)	Notably, ERAP1 inhibition enhanced the ability of NK cells to kill freshly established human lymphoblastoid cell lines from autologous or allogeneic sources, thereby promoting NK cytotoxic activity against target cells that would not be expected because of KIR-KIR ligand matching.
25589622	E7+ tumor TC-1	HIF1A	Inhibit immunity (T cell function)	Gain of HIF-1α under normoxia in cancer mediates immune adaptation through the AKT/ERK and VEGFA axes. We found that tumor cells gain HIF-1α in the course of immune selection under normoxia and that HIF-1α renders tumor cells resistant to lysis by tumor-specific cytotoxic T lymphocytes (CTL) in culture and in mice.
25589622	E7+ tumor TC-1	AKT1	Inhibit immunity (T cell function)	Gain of HIF-1α under normoxia in cancer mediates immune adaptation through the AKT/ERK and VEGFA axes. We found that tumor cells gain HIF-1α in the course of immune selection under normoxia and that HIF-1α renders tumor cells resistant to lysis by tumor-specific cytotoxic T lymphocytes (CTL) in culture and in mice.
25589622	E7+ tumor TC-1	MAPK1	Inhibit immunity (T cell function)	Gain of HIF-1α under normoxia in cancer mediates immune adaptation through the AKT/ERK and VEGFA axes. We found that tumor cells gain HIF-1α in the course of immune selection under normoxia and that HIF-1α renders tumor cells resistant to lysis by tumor-specific cytotoxic T lymphocytes (CTL) in culture and in mice.
25589622	E7+ tumor TC-1	VEGFA	Inhibit immunity (T cell function)	Gain of HIF-1α under normoxia in cancer mediates immune adaptation through the AKT/ERK and VEGFA axes. We found that tumor cells gain HIF-1α in the course of immune selection under normoxia and that HIF-1α renders tumor cells resistant to lysis by tumor-specific cytotoxic T lymphocytes (CTL) in culture and in mice.
25582824	Lymphoma	CD40LG	Promote immunity (T cell function)	Enhancing antitumor efficacy of chimeric antigen receptor T cells through constitutive CD40L expression.
25582080	Sarcoma; Colon Carcinoma	IL2	Promote immunity	Here, we show that neutralization of IL-2 or blocking the α and β subunits of the IL-2 receptor (CD25 and CD122, respectively) abolished the antitumor effects and the accompanying improvement of the ratio of intratumoral T effector versus regulatory cells (Tregs), which were otherwise induced by CTLA-4 blockade in preclinical mouse models.
25582080	Sarcoma; Colon Carcinoma	IL2RA	Inhibit immunity (T cell function); resistant to immunotherapy	Here, we show that neutralization of IL-2 or blocking the α and β subunits of the IL-2 receptor (CD25 and CD122, respectively) abolished the antitumor effects and the accompanying improvement of the ratio of intratumoral T effector versus regulatory cells (Tregs), which were otherwise induced by CTLA-4 blockade in preclinical mouse models.
25582080	Sarcoma; Colon Carcinoma	IL2RB	Inhibit immunity (T cell function); resistant to immunotherapy	Here, we show that neutralization of IL-2 or blocking the α and β subunits of the IL-2 receptor (CD25 and CD122, respectively) abolished the antitumor effects and the accompanying improvement of the ratio of intratumoral T effector versus regulatory cells (Tregs), which were otherwise induced by CTLA-4 blockade in preclinical mouse models.
25577439	Melanoma	SMAD4	Promote immunity (T cell function)	Here we have demonstrated an essential role for Smad4 in promoting T cell function during autoimmunity and anti-tumor immunity.
25568183	Melanoma	CTNNB1	Inhibit immunity (T cell function)	Hence, β-catenin/TCF4 signaling induces local regulatory DC and regulatory T-cell phenotypes via the RA pathway, identifying this pathway as an important target for anticancer immunotherapy.
25568183	Melanoma	TCF4	Inhibit immunity (T cell function)	Hence, β-catenin/TCF4 signaling induces local regulatory DC and regulatory T-cell phenotypes via the RA pathway, identifying this pathway as an important target for anticancer immunotherapy.
25564570	Head and Neck Squamous Cell Carcinoma	PDE5A	Inhibit immunity (T cell function)	This study demonstrates that a PDE5 inhibitor, tadalafil, can reverse tumor-specific immune suppression in patients with head and neck cancer, with potential for therapeutic application.
25548153	Melanoma	AKT1	Promote immunity (T cell function)	Expression of constitutively active Stat5a recapitulated the survival advantages conferred by miR-155, whereas constitutive Akt activation promoted sustained effector functions. Our results indicate that overexpression of miR-155 in tumor-specific T cells can be used to increase the effectiveness of adoptive immunotherapies in a cell-intrinsic manner without the need for life-threatening, lymphodepleting maneuvers.
25545618	Breast Carcinoma	IL10	Inhibit immunity (T cell function)	Depletion of IL-10 in B-cell adoptive transfers significantly increased CTLs and B-cell activity of PBMCs
25545618	Breast Carcinoma	FASLG	Promote immunity	Activated TDLN B cells express Fas ligand, which was further enhanced by coculture of these TDLN B cells with 4T1 tumor cells.
25542861	Melanoma	P2RX7	Promote immunity	Overall, our results showed that host P2X7R expression was critical to support an antitumor immune response, and to restrict tumor growth and metastatic diffusion.
25542861	Melanoma	IL1B	Promote immunity (infiltration)	In P2X7R-deficient mice, tumor growth and metastatic spreading were accelerated strongly, compared with wild-type (wt) mice. Intratumoral IL-1β and VEGF release were drastically reduced, and inflammatory cell infiltration was abrogated nearly completely.
25533286	Breast Carcinoma	IRF5	Promote immunity (infiltration)	IRF5 is a novel regulator of CXCL13 expression in breast cancer that regulates CXCR5(+) B- and T-cell trafficking to tumor-conditioned media.
25533286	Breast Carcinoma	CXCL13	Promote immunity (infiltration)	IRF5 is a novel regulator of CXCL13 expression in breast cancer that regulates CXCR5(+) B- and T-cell trafficking to tumor-conditioned media.
25533286	Breast Carcinoma	CXCR5	Promote immunity (infiltration)	IRF5 is a novel regulator of CXCL13 expression in breast cancer that regulates CXCR5(+) B- and T-cell trafficking to tumor-conditioned media.
25529917	Hepatocellular Carcinoma	CXCR4	Inhibit immunity (T cell function); resistant to immunotherapy	CXCR4 inhibition in tumor microenvironment facilitates anti-programmed death receptor-1 immunotherapy in sorafenib-treated hepatocellular carcinoma in mice.
25527358	Hepatocellular Carcinoma	TLR9	Promote immunity (T cell function)	The combination of TLR9 stimulation with RFA resulted in a potentiated antitumour T cell response and cytotoxicity in the VX2 tumour model.
25505237	Nasopharyngeal Carcinoma	CCL20	Inhibit immunity (T cell function)	CCL20 allowed the intratumoral recruitment of human Treg.
25492101	Cervical Carcinoma	HMGB1	Inhibit immunity (T cell function)	HMGB1 secretion during cervical carcinogenesis promotes the acquisition of a tolerogenic functionality by plasmacytoid dendritic cells.
25480946	Head and Neck Squamous Cell Carcinoma	PDCD1	Inhibit immunity (T cell function)	SHP-2 activation by fusaruside suppresses p-STAT1/T-bet and production of Th1 cytokines. Overall, these results defined a PD-1/SHP-2/STAT1/T-bet signaling axis mediating the suppressive effects of PD-1 on Th1 immunity at tumor sites. Our findings argue that PD-1 or SHP-2 blockade will be sufficient to restore robust Th1 immunity and T-cell activation and thereby reverse immunosuppression in the tumor microenvironment.
25480946	Head and Neck Squamous Cell Carcinoma	PTPN11	Inhibit immunity (T cell function)	SHP-2 activation by fusaruside suppresses p-STAT1/T-bet and production of Th1 cytokines. Overall, these results defined a PD-1/SHP-2/STAT1/T-bet signaling axis mediating the suppressive effects of PD-1 on Th1 immunity at tumor sites. Our findings argue that PD-1 or SHP-2 blockade will be sufficient to restore robust Th1 immunity and T-cell activation and thereby reverse immunosuppression in the tumor microenvironment.
25480946	Head and Neck Squamous Cell Carcinoma	STAT1	Promote immunity (T cell function)	SHP-2 activation by fusaruside suppresses p-STAT1/T-bet and production of Th1 cytokines. Overall, these results defined a PD-1/SHP-2/STAT1/T-bet signaling axis mediating the suppressive effects of PD-1 on Th1 immunity at tumor sites. Our findings argue that PD-1 or SHP-2 blockade will be sufficient to restore robust Th1 immunity and T-cell activation and thereby reverse immunosuppression in the tumor microenvironment.
25480946	Head and Neck Squamous Cell Carcinoma	TBX21	Promote immunity (T cell function)	SHP-2 activation by fusaruside suppresses p-STAT1/T-bet and production of Th1 cytokines. Overall, these results defined a PD-1/SHP-2/STAT1/T-bet signaling axis mediating the suppressive effects of PD-1 on Th1 immunity at tumor sites. Our findings argue that PD-1 or SHP-2 blockade will be sufficient to restore robust Th1 immunity and T-cell activation and thereby reverse immunosuppression in the tumor microenvironment.
25472998	Melanoma	TNFRSF9	Promote immunity (infiltration)	We found that addition of an agonistic anti-4-1BB antibody could activate 4-1BB signaling within early cultured tumor fragments and accelerated the rate of memory CD8(+) TIL outgrowth that were highly enriched for melanoma antigen specificity.
25468715	Hepatocellular Carcinoma	TNFRSF14	Inhibit immunity (infiltration)	Furthermore, HVEM status was inversely correlated with tumour-infiltrating CD4(+), CD8(+) and CD45RO(+) lymphocytes. In addition, it was also associated with reduced expression of perforin, granzyme B and interferon-γ (IFN-γ). Taken together, tumour-expressing HVEM plays a functionally important role in HCC.
25446897	Melanoma	IRF8	Promote immunity	Within these, CD103(+) DCs are extremely sparse and yet remarkably capable CTL stimulators. These are uniquely dependent on IRF8, Zbtb46, and Batf3 transcription factors and are generated by GM-CSF and FLT3L cytokines. Regressing tumors have higher proportions of these cells, T-cell-dependent immune clearance relies on them, and abundance of their transcripts in human tumors correlates with clinical outcome.
25446897	Melanoma	ZBTB46	Promote immunity	Within these, CD103(+) DCs are extremely sparse and yet remarkably capable CTL stimulators. These are uniquely dependent on IRF8, Zbtb46, and Batf3 transcription factors and are generated by GM-CSF and FLT3L cytokines. Regressing tumors have higher proportions of these cells, T-cell-dependent immune clearance relies on them, and abundance of their transcripts in human tumors correlates with clinical outcome.
25446897	Melanoma	BATF3	Promote immunity	Within these, CD103(+) DCs are extremely sparse and yet remarkably capable CTL stimulators. These are uniquely dependent on IRF8, Zbtb46, and Batf3 transcription factors and are generated by GM-CSF and FLT3L cytokines. Regressing tumors have higher proportions of these cells, T-cell-dependent immune clearance relies on them, and abundance of their transcripts in human tumors correlates with clinical outcome.
25432172	Melanoma	AKT1	Inhibit immunity (T cell function)	Consequently, Akt inhibition results in enhanced persistence of TIL after adoptive transfer into an immunodeficient animal model and augments antitumor immunity of CD8 T cells in a mouse model of cell-based immunotherapy.
25429071	Melanoma	IL33	Promote immunity (T cell function)	Mechanistically, IL-33 increased numbers and IFN-γ production by CD8(+) T and NK cells in tumor tissues, thereby inducing a tumor microenvironment favoring tumor eradication.
25428504	Melanoma	CD274	Inhibit immunity (T cell function)	Together, these data suggest that MPDL3280A is most effective in patients in which pre-existing immunity is suppressed by PD-L1, and is re-invigorated on antibody treatment.
25428504	Melanoma	CX3CL1	Inhibit immunity (T cell function); resistant to immunotherapy	Furthermore, responses were associated with T-helper type 1 (TH1) gene expression, CTLA4 expression and the absence of fractalkine (CX3CL1) in baseline tumour specimens.
25403716	Melanoma	ENTPD1	Inhibit immunity (T cell function)	The generation of adenosine via the CD39/CD73 pathway is recognized as a major mechanism of regulatory T cell (Treg) immunosuppressive function. Blockade of CD39 increases CTL- and NK cell–mediated killing.
25403716	Melanoma	NT5E	Inhibit immunity (T cell function)	The generation of adenosine via the CD39/CD73 pathway is recognized as a major mechanism of regulatory T cell (Treg) immunosuppressive function. Blockade of CD39 increases CTL- and NK cell–mediated killing.
25403209	Melanoma	IL15	Promote immunity (T cell function)	Interleukin-15 (IL-15) has significant potential in cancer immunotherapy as an activator of antitumor CD8 T and natural killer (NK) cells.
25398437	Melanoma	AURKA	Inhibit immunity	Here we show how combining a senescence-inducing inhibitor of the mitotic kinase Aurora A (AURKA) with an MDM2 antagonist activates p53 in senescent tumors harboring wildtype 53. In the model studied, this effect is accompanied proliferation arrest, mitochondrial depolarization, apoptosis and immune clearance of cancer cells by antitumor leukocytes in a manner reliant upon CCL5, CCL1 and CXCL9.
25398437	Melanoma	MDM2	Inhibit immunity	Here we show how combining a senescence-inducing inhibitor of the mitotic kinase Aurora A (AURKA) with an MDM2 antagonist activates p53 in senescent tumors harboring wildtype 53. In the model studied, this effect is accompanied proliferation arrest, mitochondrial depolarization, apoptosis and immune clearance of cancer cells by antitumor leukocytes in a manner reliant upon CCL5, CCL1 and CXCL9.
25398437	Melanoma	TP53	Promote immunity	Here we show how combining a senescence-inducing inhibitor of the mitotic kinase Aurora A (AURKA) with an MDM2 antagonist activates p53 in senescent tumors harboring wildtype 53. In the model studied, this effect is accompanied proliferation arrest, mitochondrial depolarization, apoptosis and immune clearance of cancer cells by antitumor leukocytes in a manner reliant upon CCL5, CCL1 and CXCL9.
25398437	Melanoma	CCL5	Promote immunity	Here we show how combining a senescence-inducing inhibitor of the mitotic kinase Aurora A (AURKA) with an MDM2 antagonist activates p53 in senescent tumors harboring wildtype 53. In the model studied, this effect is accompanied proliferation arrest, mitochondrial depolarization, apoptosis and immune clearance of cancer cells by antitumor leukocytes in a manner reliant upon CCL5, CCL1 and CXCL9.
25398437	Melanoma	CCL1	Promote immunity	Here we show how combining a senescence-inducing inhibitor of the mitotic kinase Aurora A (AURKA) with an MDM2 antagonist activates p53 in senescent tumors harboring wildtype 53. In the model studied, this effect is accompanied proliferation arrest, mitochondrial depolarization, apoptosis and immune clearance of cancer cells by antitumor leukocytes in a manner reliant upon CCL5, CCL1 and CXCL9.
25398437	Melanoma	CXCL9	Promote immunity	Here we show how combining a senescence-inducing inhibitor of the mitotic kinase Aurora A (AURKA) with an MDM2 antagonist activates p53 in senescent tumors harboring wildtype 53. In the model studied, this effect is accompanied proliferation arrest, mitochondrial depolarization, apoptosis and immune clearance of cancer cells by antitumor leukocytes in a manner reliant upon CCL5, CCL1 and CXCL9.
25393367	Hepatocellular Carcinoma	STAT3	Inhibit immunity (NK cell function)	SAHA downregulated the miR-17-92 cluster by abolishing tyrosine phosphorylation of STAT3 and decreased MCM7 transcription through localised histone deacetylation. SAHA upregulates the transcription of MICA/B by promoting MICA-associated histone acetylation while suppressing the MICA/B-targeting miRNAs miR-20a, miR-93 and miR-106b. In addition to the immediate effects on the tumour cell growth, HDACi upregulates the expression of MHC class I-related chain molecules A and B (MICA and MICB), resulting in an enhanced susceptibility of tumour cells to natural killer cell-mediated lysis.
25393367	Hepatocellular Carcinoma	MCM7	Inhibit immunity (NK cell function)	SAHA downregulated the miR-17-92 cluster by abolishing tyrosine phosphorylation of STAT3 and decreased MCM7 transcription through localised histone deacetylation. SAHA upregulates the transcription of MICA/B by promoting MICA-associated histone acetylation while suppressing the MICA/B-targeting miRNAs miR-20a, miR-93 and miR-106b. In addition to the immediate effects on the tumour cell growth, HDACi upregulates the expression of MHC class I-related chain molecules A and B (MICA and MICB), resulting in an enhanced susceptibility of tumour cells to natural killer cell-mediated lysis.
25387892	Melanoma	TNFRSF9	Promote immunity (T cell function)	Combination of 4-1BB agonist and PD-1 antagonist promotes antitumor effector/memory CD8 T cells in a poorly immunogenic tumor model.
25387892	Melanoma	PDCD1	Inhibit immunity (T cell function)	Combination of 4-1BB agonist and PD-1 antagonist promotes antitumor effector/memory CD8 T cells in a poorly immunogenic tumor model.
25385820	Melanoma	TMEM173	Promote immunity (T cell function)	DCs are shown to depend on STING function in vivo to efficiently prime IFN-dependent CD8(+) T cell responses to tumor Ags.
25381437	Glioblastoma	KIR2DS2	Promote immunity (NK cell function)	NK cells with KIR2DS2 immunogenotype have a functional activation advantage to efficiently kill glioblastoma and prolong animal survival.
25377469	Melanoma	ADORA2A	Inhibit immunity (T and NK cell function)	Myeloid expression of adenosine A2A receptor suppresses T and NK cell responses in the solid tumor microenvironment.
25363763	Colorectal Carcinoma	CEACAM1	Inhibit immunity (T cell function)	Co-blockade of CEACAM1 and TIM-3 leads to enhancement of anti-tumour immune responses with improved elimination of tumours in mouse colorectal cancer models.
25363763	Colorectal Carcinoma	HAVCR2	Inhibit immunity (T cell function)	Co-blockade of CEACAM1 and TIM-3 leads to enhancement of anti-tumour immune responses with improved elimination of tumours in mouse colorectal cancer models.
25363661	Glioblastoma	IL10	Inhibit immunity	While a number of key immunosuppressive cytokines were overexpressed in the treated cells, including IL-10, IL-6 and GM-CSF, suppression could be alleviated in a number of treated GBM lines by inhibition of prostaglandin E2.
25363661	Glioblastoma	IL6	Inhibit immunity	While a number of key immunosuppressive cytokines were overexpressed in the treated cells, including IL-10, IL-6 and GM-CSF, suppression could be alleviated in a number of treated GBM lines by inhibition of prostaglandin E2.
25363661	Glioblastoma	CSF2	Inhibit immunity	While a number of key immunosuppressive cytokines were overexpressed in the treated cells, including IL-10, IL-6 and GM-CSF, suppression could be alleviated in a number of treated GBM lines by inhibition of prostaglandin E2.
25362180	Melanoma	IL18	Inhibit immunity (T cell function)	IL-18 enhances immunosuppressive responses by promoting differentiation into monocytic myeloid-derived suppressor cells.
25351848	Colon Carcinoma	CD40	Inhibit immunity (T cell function)	In addition, we demonstrated that the CD40:CD40L cross-talk between the two cell populations is responsible for the instauration of a proinflammatory microenvironment and for the increase in the production of mediators that can further support MDSC mobilization and tumor growth.
25351848	Colon Carcinoma	CD40LG	Inhibit immunity (T cell function)	In addition, we demonstrated that the CD40:CD40L cross-talk between the two cell populations is responsible for the instauration of a proinflammatory microenvironment and for the increase in the production of mediators that can further support MDSC mobilization and tumor growth.
25351767	Breast Carcinoma	TP53	Promote immunity	The association of lymphocytic invasion of ER-negative breast tumors with the retention of wild-type TP53 implies a novel protective connection between TP53 function and tumor immunosurveillance.
25349304	Non-Small Cell Lung Carcinoma	CXCL1	Inhibit immunity (T cell function)	miR141-CXCL1-CXCR2 signaling-induced Treg recruitment regulates metastases and survival of non-small cell lung cancer. Mechanistically, decreased expressions of miR141, associated with the survival of patients with NSCLC with MPE, resulted in the increased production of CXCL1 and recruitment of Tregs to promote immune escape of tumor.
25349304	Non-Small Cell Lung Carcinoma	CXCR2	Inhibit immunity (T cell function)	miR141-CXCL1-CXCR2 signaling-induced Treg recruitment regulates metastases and survival of non-small cell lung cancer. Mechanistically, decreased expressions of miR141, associated with the survival of patients with NSCLC with MPE, resulted in the increased production of CXCL1 and recruitment of Tregs to promote immune escape of tumor.
25348003	Lung Carcinoma	ZEB1	Inhibit immunity (T cell function)	We show that microRNA-200 (miR-200), a cell-autonomous suppressor of EMT and metastasis, targets PD-L1. Moreover, ZEB1, an EMT activator and transcriptional repressor of miR-200, relieves miR-200 repression of PD-L1 on tumour cells, leading to CD8(+) T-cell immunosuppression and metastasis.
25348003	Lung Carcinoma	CD274	Inhibit immunity (T cell function)	We show that microRNA-200 (miR-200), a cell-autonomous suppressor of EMT and metastasis, targets PD-L1. Moreover, ZEB1, an EMT activator and transcriptional repressor of miR-200, relieves miR-200 repression of PD-L1 on tumour cells, leading to CD8(+) T-cell immunosuppression and metastasis.
25347474	Lung Carcinoma	PRDM1	Promote immunity (T cell function)	We determined that tumor-derived TGF-β directly suppresses CTL immune function by elevating miR-23a and downregulating BLIMP-1. Functional blocking of miR-23a in human CTLs enhanced granzyme B expression, and in mice with established tumors, immunotherapy with just a small number of tumor-specific CTLs in which miR-23a was inhibited robustly hindered tumor progression.
25347474	Lung Carcinoma	TGFB1	Inhibit immunity (T cell function)	We determined that tumor-derived TGF-β directly suppresses CTL immune function by elevating miR-23a and downregulating BLIMP-1. Functional blocking of miR-23a in human CTLs enhanced granzyme B expression, and in mice with established tumors, immunotherapy with just a small number of tumor-specific CTLs in which miR-23a was inhibited robustly hindered tumor progression.
25336630	Plasma Cell Myeloma	AKT1	Inhibit immunity (T cell function)	Akt Inhibition of Akt signaling promotes the generation of superior tumor-reactive T cells for adoptive immunotherapy.
25336190	Melanoma	IKBKB	Promote immunity	Myeloid IKKβ promotes antitumor immunity by modulating CCL11 and the innate immune response.
25336190	Melanoma	CCL11	Inhibit immunity	In a BRAF(V600E/PTEN(-/-)) allograft model, IKKβ loss in macrophages reduced recruitment of myeloid cells into the tumor, lowered expression of MHC class II molecules, and enhanced production of the chemokine CCL11, thereby negatively regulating dendritic-cell maturation.
25329698	Lymphoma	IL12A	Promote immunity (NK cell function)	Here, we found that treatments with IL-12 and IL-18 or with a mutant form of IL-2 (the "superkine" called H9) provided substantial therapeutic benefit for mice specifically bearing MHC class I-deficient tumors, but these treatments were ineffective for mice with matched MHC class I+ tumors. Cytokine efficacy was linked to the reversal of the anergic state of NK cells that specifically occurred in MHC class I-deficient tumors, but not MHC class I+ tumors.
25329698	Lymphoma	IL18	Promote immunity (NK cell function)	Here, we found that treatments with IL-12 and IL-18 or with a mutant form of IL-2 (the "superkine" called H9) provided substantial therapeutic benefit for mice specifically bearing MHC class I-deficient tumors, but these treatments were ineffective for mice with matched MHC class I+ tumors. Cytokine efficacy was linked to the reversal of the anergic state of NK cells that specifically occurred in MHC class I-deficient tumors, but not MHC class I+ tumors.
25320361	Head and Neck Squamous Cell Carcinoma	PDE5A	Inhibit immunity (T cell function)	PDE5 inhibitor tadalafil reduces myeloid-derived suppressor cells and regulatory T cells and promotes tumor immunity in patients with head and neck squamous cell carcinoma.
25320277	Ovarian Carcinoma	CXCL12	Inhibit immunity (T cell function)	CXCL12/CXCR4 blockade by oncolytic virotherapy inhibits ovarian cancer growth by decreasing immunosuppression and targeting cancer-initiating cells.
25320277	Ovarian Carcinoma	CXCR4	Inhibit immunity (T cell function)	CXCL12/CXCR4 blockade by oncolytic virotherapy inhibits ovarian cancer growth by decreasing immunosuppression and targeting cancer-initiating cells.
25315772	Colorectal Carcinoma; Prostate Carcinoma	LGALS3BP	Inhibit immunity	These findings suggest a novel immunoinhibitory function for LGALS3BP that might be important for immune evasion of tumor cells during cancer progression.
25300859	Glioma	TMEM173	Promote immunity	STING contributes to antiglioma immunity via triggering type I IFN signals in the tumor microenvironment.
25300859	Glioma	CXCL10	Promote immunity	STING contributes to antiglioma immunity via triggering type I IFN signals in the tumor microenvironment. Finally, intratumoral administration of a STING agonist (cyclic diguanylate monophosphate; c-di-GMP) improved the survival of glioma-bearing mice associated with enhanced type I IFN signaling, Cxcl10 and Ccl5, and T-cell migration into the brain.
25300859	Glioma	CCL5	Promote immunity	STING contributes to antiglioma immunity via triggering type I IFN signals in the tumor microenvironment. Finally, intratumoral administration of a STING agonist (cyclic diguanylate monophosphate; c-di-GMP) improved the survival of glioma-bearing mice associated with enhanced type I IFN signaling, Cxcl10 and Ccl5, and T-cell migration into the brain.
25297635	Breast Carcinoma; Colon Carcinoma	IL9	Inhibit immunity (T cell function)	Our results show the ability of IL9 to function as an inhibitor of adaptive immunity that prevents the formation of immunologic memory to a growing tumor, highlighting the potential for IL9 neutralization as a unique tool for cancer immunotherapy.
25297630	Melanoma	CD47	Inhibit immunity	Correspondingly, an inverse correlation between CD8(+) T-cell infiltration and CD47 expression was observed in human melanomas. Our findings establish that blocking CD47 in the context of radiotherapy enhances antitumor immunity by directly stimulating CD8(+) cytotoxic T cells, with the potential to increase curative responses.
25294906	Thyroid Gland Papillary Carcinoma	HLA-A	Promote immunity (infiltration)	Both MHC class I and β2-microglobulin expression was reduced or absent in 76% of PTC specimens and was associated with reduced tumor-infiltrating immune cells, including effector (CD3(+), CD8(+), CD16(+)) and suppressor (FoxP3(+)) populations.
25294906	Thyroid Gland Papillary Carcinoma	HLA-B	Promote immunity (infiltration)	Both MHC class I and β2-microglobulin expression was reduced or absent in 76% of PTC specimens and was associated with reduced tumor-infiltrating immune cells, including effector (CD3(+), CD8(+), CD16(+)) and suppressor (FoxP3(+)) populations.
25294906	Thyroid Gland Papillary Carcinoma	HLA-C	Promote immunity (infiltration)	Both MHC class I and β2-microglobulin expression was reduced or absent in 76% of PTC specimens and was associated with reduced tumor-infiltrating immune cells, including effector (CD3(+), CD8(+), CD16(+)) and suppressor (FoxP3(+)) populations.
25294906	Thyroid Gland Papillary Carcinoma	B2M	Promote immunity (infiltration)	Both MHC class I and β2-microglobulin expression was reduced or absent in 76% of PTC specimens and was associated with reduced tumor-infiltrating immune cells, including effector (CD3(+), CD8(+), CD16(+)) and suppressor (FoxP3(+)) populations.
25294906	Thyroid Gland Papillary Carcinoma	MAP2K1	Inhibit immunity (infiltration)	Treatment of PTC cell lines with the MEK1/2 inhibitor selumetinib or IFN increased HLA-ABC expression. Both MHC class I and β2-microglobulin expression was reduced or absent in 76% of PTC specimens and was associated with reduced tumor-infiltrating immune cells, including effector (CD3(+), CD8(+), CD16(+)) and suppressor (FoxP3(+)) populations.
25294906	Thyroid Gland Papillary Carcinoma	MAP2K2	Inhibit immunity (infiltration)	Treatment of PTC cell lines with the MEK1/2 inhibitor selumetinib or IFN increased HLA-ABC expression. Both MHC class I and β2-microglobulin expression was reduced or absent in 76% of PTC specimens and was associated with reduced tumor-infiltrating immune cells, including effector (CD3(+), CD8(+), CD16(+)) and suppressor (FoxP3(+)) populations.
25294906	Thyroid Gland Papillary Carcinoma	IFNA1	Promote immunity (infiltration)	Treatment of PTC cell lines with the MEK1/2 inhibitor selumetinib or IFN increased HLA-ABC expression. Both MHC class I and β2-microglobulin expression was reduced or absent in 76% of PTC specimens and was associated with reduced tumor-infiltrating immune cells, including effector (CD3(+), CD8(+), CD16(+)) and suppressor (FoxP3(+)) populations.
25273090	Colon Carcinoma	SPP1	Inhibit immunity (T cell function)	Tumor-derived osteopontin suppresses antitumor immunity by promoting extramedullary myelopoiesis. In this study, we found that osteopontin expressed by tumor cells enhances extramedullary myelopoiesis in a CD44-dependent manner through the Erk1/2-MAPK pathway.
25273090	Colon Carcinoma	MAPK3	Inhibit immunity (T cell function)	Tumor-derived osteopontin suppresses antitumor immunity by promoting extramedullary myelopoiesis. In this study, we found that osteopontin expressed by tumor cells enhances extramedullary myelopoiesis in a CD44-dependent manner through the Erk1/2-MAPK pathway.
25273090	Colon Carcinoma	MAPK1	Inhibit immunity (T cell function)	Tumor-derived osteopontin suppresses antitumor immunity by promoting extramedullary myelopoiesis. In this study, we found that osteopontin expressed by tumor cells enhances extramedullary myelopoiesis in a CD44-dependent manner through the Erk1/2-MAPK pathway.
25267631	Melanoma	C10orf54	Inhibit immunity (T cell function)	Taken together, our data suggest that VISTA is a negative checkpoint regulator whose loss of function lowers the threshold for T-cell activation, allowing for an enhanced proinflammatory phenotype and an increase in the frequency and intensity of autoimmunity under susceptible conditions.
25261236	Breast Carcinoma	ADIPOR1	Inhibit immunity	In this study, we show that DCs isolated from patients with metastatic or locally advanced breast cancer express high levels of the adiponectin receptors AdipoR1 and AdipoR2, which are sufficient to blunt antitumor immunity.
25261236	Breast Carcinoma	ADIPOR2	Inhibit immunity	In this study, we show that DCs isolated from patients with metastatic or locally advanced breast cancer express high levels of the adiponectin receptors AdipoR1 and AdipoR2, which are sufficient to blunt antitumor immunity.
25261236	Breast Carcinoma	PRKAA1	Inhibit immunity	In this study, we show that DCs isolated from patients with metastatic or locally advanced breast cancer express high levels of the adiponectin receptors AdipoR1 and AdipoR2, which are sufficient to blunt antitumor immunity. AdipoR1 stimulated IL10 production by activating the AMPK and MAPKp38 pathways, whereas AdipoR2 modified inflammatory processes by activating the COX-2 and PPARγ pathways.
25261236	Breast Carcinoma	MAPK1	Inhibit immunity	In this study, we show that DCs isolated from patients with metastatic or locally advanced breast cancer express high levels of the adiponectin receptors AdipoR1 and AdipoR2, which are sufficient to blunt antitumor immunity. AdipoR1 stimulated IL10 production by activating the AMPK and MAPKp38 pathways, whereas AdipoR2 modified inflammatory processes by activating the COX-2 and PPARγ pathways.
25261236	Breast Carcinoma	IL10	Inhibit immunity	In this study, we show that DCs isolated from patients with metastatic or locally advanced breast cancer express high levels of the adiponectin receptors AdipoR1 and AdipoR2, which are sufficient to blunt antitumor immunity. AdipoR1 stimulated IL10 production by activating the AMPK and MAPKp38 pathways, whereas AdipoR2 modified inflammatory processes by activating the COX-2 and PPARγ pathways.
25261236	Breast Carcinoma	PTGS2	Inhibit immunity	In this study, we show that DCs isolated from patients with metastatic or locally advanced breast cancer express high levels of the adiponectin receptors AdipoR1 and AdipoR2, which are sufficient to blunt antitumor immunity. AdipoR1 stimulated IL10 production by activating the AMPK and MAPKp38 pathways, whereas AdipoR2 modified inflammatory processes by activating the COX-2 and PPARγ pathways.
25261236	Breast Carcinoma	PPARG	Inhibit immunity	In this study, we show that DCs isolated from patients with metastatic or locally advanced breast cancer express high levels of the adiponectin receptors AdipoR1 and AdipoR2, which are sufficient to blunt antitumor immunity. AdipoR1 stimulated IL10 production by activating the AMPK and MAPKp38 pathways, whereas AdipoR2 modified inflammatory processes by activating the COX-2 and PPARγ pathways. Stimulation of these pathways was sufficient to block activation of NF-κB in DC, thereby attenuating their ability to stimulate antigen-specific T-cell responses.
25256739	Glioblastoma	MTOR	Inhibit immunity (T cell function)	Blockade of mTOR signaling via rapamycin combined with immunotherapy augments antiglioma cytotoxic and memory T-cell functions.
22728650	Lymphoma	STAT3	Inhibit immunity (T cell function)	Here, we show that genetic or pharmacologic disruption of Stat3 in malignant B cells augments their immunogenicity leading to better activation of antigen-specific CD4(+) T cells and restoration of responsiveness of tolerized T cells.
22710190	Gastric Carcinoma	IL6	Promote immunity (T cell function)	CD8(+) T cells that produce interleukin (IL)-17 (Tc17 cells) promote inflammation and have been identified in tumors. Tumor-activated monocytes secreted IL-6, IL-1β, and IL-23, which promoted development of Tc17 cell populations.
22710190	Gastric Carcinoma	IL1B	Promote immunity (T cell function)	CD8(+) T cells that produce interleukin (IL)-17 (Tc17 cells) promote inflammation and have been identified in tumors. Tumor-activated monocytes secreted IL-6, IL-1β, and IL-23, which promoted development of Tc17 cell populations.
22710190	Gastric Carcinoma	IL23A	Promote immunity (T cell function)	CD8(+) T cells that produce interleukin (IL)-17 (Tc17 cells) promote inflammation and have been identified in tumors. Tumor-activated monocytes secreted IL-6, IL-1β, and IL-23, which promoted development of Tc17 cell populations.
22710190	Gastric Carcinoma	CXCL12	Inhibit immunity (T cell function)	Supernatants from cultured Tc17 cells induced production of the chemokine CXCL12 by tumor cells; this promoted CXCR4-dependent migration of MDSCs and impaired functions of anti-tumor CD8(+) cytotoxic T cells via a cell contact-dependent mechanism.
22706089	Melanoma	IFNA1	Promote immunity (T cell function)	Autocrine IFN-γ promotes naive CD8 T cell differentiation and synergizes with IFN-α to stimulate strong function.
22706089	Melanoma	IFNG	Promote immunity (T cell function)	Autocrine IFN-γ promotes naive CD8 T cell differentiation and synergizes with IFN-α to stimulate strong function.
22704448	Renal Cell Carcinoma	IL2	Promote immunity	Radio frequency ablation of the primary tumor combined with interleukin-2 induces a systemic antitumor immune response to renal cell carcinoma, which is much stronger than that of interleukin-2 monotherapy.
22698406	Pancreatic Carcinoma	CSF2	Inhibit immunity	In humans, PDA tumor cells prominently expressed GM-CSF in vivo. Thus, tumor-derived GM-CSF is an important regulator of inflammation and immune suppression within the tumor microenvironment.
22693252	Melanoma	BRAF	Inhibit immunity	BRAF inhibitor vemurafenib improves the antitumor activity of adoptive cell immunotherapy.
22678912	Melanoma	HLA-G	Inhibit immunity	These data emphasize the impact of HLA-G conformation on its efficiency at inhibiting the antitumor response and thus favoring tumor progression.
22678911	Breast Carcinoma	S1PR4	Inhibit immunity (T cell function)	Immunosuppression via Treg cells was transferable and required the release of sphingosine-1-phosphate (S1P) from apoptotic cells, acting via S1P receptor 4 on DCs to induce IL-27 secretion. We propose that CD69 expression on CD39(+) Treg cells enables them to interact with CD73-expressing CD8(+) T cells to generate adenosine, thereby suppressing cytotoxicity.
22678911	Breast Carcinoma	IL27	Inhibit immunity (T cell function)	Immunosuppression via Treg cells was transferable and required the release of sphingosine-1-phosphate (S1P) from apoptotic cells, acting via S1P receptor 4 on DCs to induce IL-27 secretion. We propose that CD69 expression on CD39(+) Treg cells enables them to interact with CD73-expressing CD8(+) T cells to generate adenosine, thereby suppressing cytotoxicity.
22653638	Melanoma	IL6	Inhibit immunity	High amounts of IL-6, a key cytokine of immunosuppres-sion and decreased quality of life in tumor-bearing hosts. To block IL-6-signaling in vivo, tumor-bearing mice wereadministered with anti-IL-6R mAb. Anti-IL-6 receptor mAb eliminates myeloid-derived suppressor cells and inhibits tumor growth by enhancing T-cell responses.
22653638	Melanoma	IL6R	Inhibit immunity	High amounts of IL-6, a key cytokine of immunosuppres-sion and decreased quality of life in tumor-bearing hosts. To block IL-6-signaling in vivo, tumor-bearing mice wereadministered with anti-IL-6R mAb. Anti-IL-6 receptor mAb eliminates myeloid-derived suppressor cells and inhibits tumor growth by enhancing T-cell responses.
22615204	Hepatocellular Carcinoma	TGFB1	Inhibit immunity (T cell function)	Suppression of CD8(+) T cells by CCR4(+)CCR6(+)Th17 cells was partially dependent on TGF-β, because neutralization of TGF-β in cocultures reversed their suppressor function.
22588558	Nasopharyngeal Carcinoma	MYC	Inhibit immunity	These findings raise the possibility that c-Myc activation in nasopharyngeal carcinoma (NPC) might antagonise the effect of LMP1 on HLA class I expression thus contributing to immune escape of tumour cells.
22588558	Nasopharyngeal Carcinoma	PDLIM7	Promote immunity	These findings raise the possibility that c-Myc activation in nasopharyngeal carcinoma (NPC) might antagonise the effect of LMP1 on HLA class I expression thus contributing to immune escape of tumour cells.
22588558	Nasopharyngeal Carcinoma	IL6	Inhibit immunity	In epithelial cells, LMP1 up-regulated HLA class I APM. This effect could be counteracted by c-Myc, which itself was up-regulated by LMP1 apparently through IL6 induction and Jak3/STAT3 activation. These findings raise the possibility that c-Myc activation in nasopharyngeal carcinoma (NPC) might antagonise the effect of LMP1 on HLA class I expression thus contributing to immune escape of tumour cells.
22588558	Nasopharyngeal Carcinoma	JAK3	Inhibit immunity	In epithelial cells, LMP1 up-regulated HLA class I APM. This effect could be counteracted by c-Myc, which itself was up-regulated by LMP1 apparently through IL6 induction and Jak3/STAT3 activation. These findings raise the possibility that c-Myc activation in nasopharyngeal carcinoma (NPC) might antagonise the effect of LMP1 on HLA class I expression thus contributing to immune escape of tumour cells.
22588558	Nasopharyngeal Carcinoma	STAT3	Inhibit immunity	In epithelial cells, LMP1 up-regulated HLA class I APM. This effect could be counteracted by c-Myc, which itself was up-regulated by LMP1 apparently through IL6 induction and Jak3/STAT3 activation. These findings raise the possibility that c-Myc activation in nasopharyngeal carcinoma (NPC) might antagonise the effect of LMP1 on HLA class I expression thus contributing to immune escape of tumour cells.
22585684	Melanoma	IL15	Promote immunity (NK cell function)	Analysis of different NK-cell-activating cytokines indicated that IL-15 can partially overcome this novel tumor escape mechanism suggesting that IL-15, rather than IL-2, may be eligible for NK-cell-based immunotherapy.
22584123	Mesothelioma	CTLA4	Inhibit immunity (T cell function; infiltration)	Blockade of CTLA-4 signaling showed effective anticancer effect, correlating with inhibiting cancer cell repopulation between cycles of chemotherapy and upregulating tumor-infiltrating T lymphocytes, cytokines, and cytolytic enzymes in a murine mesothelioma model.
22583829	Oral Cavity Squamous Cell Carcinoma	TLR4	Inhibit immunity	Role of toll-like receptor 4 on the immune escape of human oral squamous cell carcinoma and resistance of cisplatin-induced apoptosis.
22581824	Squamous Cell Carcinoma	IL10	Promote immunity (T cell function)	Together, our findings indicate that IL-10 activates CD8(+) T-cell-mediated tumor control and suggest that IL-10 may represent a potential tumor immunotherapy in human patients with cancer.
22569001	Gastric Carcinoma	FOXP3	Inhibit immunity (T cell function)	Our findings suggested that FoxP3 expression by tumour cells might have important roles in immune escape of gastric carcinoma, and be associated with the malignant potential of scirrhous gastric carcinoma. Indoleamine-2,3-dioxygenase and galectin-1, key effectors of Treg-mediated immunosuppression, were downregulated by FoxP3 knockdown.
22569001	Gastric Carcinoma	IDO1	Inhibit immunity (T cell function)	Our findings suggested that FoxP3 expression by tumour cells might have important roles in immune escape of gastric carcinoma, and be associated with the malignant potential of scirrhous gastric carcinoma. Indoleamine-2,3-dioxygenase and galectin-1, key effectors of Treg-mediated immunosuppression, were downregulated by FoxP3 knockdown.
22569001	Gastric Carcinoma	LGALS1	Inhibit immunity (T cell function)	Our findings suggested that FoxP3 expression by tumour cells might have important roles in immune escape of gastric carcinoma, and be associated with the malignant potential of scirrhous gastric carcinoma. Indoleamine-2,3-dioxygenase and galectin-1, key effectors of Treg-mediated immunosuppression, were downregulated by FoxP3 knockdown.
22565311	Neuroblastoma	IL15	Promote immunity (T cell function)	Thus, tumor-induced chemokine production in hypoxic TAMs and consequent chemoattraction and inhibition of NKT cells represents a mechanism of immune escape that can be reversed by adoptive immunotherapy with IL-15-transduced NKT cells.
22547582	Chronic Lymphocytic Leukemia	CD200	Inhibit immunity	In the present study, we show via functional screening assays that CD200, CD270, CD274, and CD276 are coopted by CLL cells to induce impaired actin synapse formation in both allogeneic and autologous T cells.
22547582	Chronic Lymphocytic Leukemia	TNFRSF14	Inhibit immunity	In the present study, we show via functional screening assays that CD200, CD270, CD274, and CD276 are coopted by CLL cells to induce impaired actin synapse formation in both allogeneic and autologous T cells.
22547582	Chronic Lymphocytic Leukemia	CD274	Inhibit immunity	In the present study, we show via functional screening assays that CD200, CD270, CD274, and CD276 are coopted by CLL cells to induce impaired actin synapse formation in both allogeneic and autologous T cells.
22547582	Chronic Lymphocytic Leukemia	CD276	Inhibit immunity	In the present study, we show via functional screening assays that CD200, CD270, CD274, and CD276 are coopted by CLL cells to induce impaired actin synapse formation in both allogeneic and autologous T cells.
22544698	Lymphoma	EOMES	Promote immunity (NK cell function)	Rapid development of exhaustion and down-regulation of eomesodermin limit the antitumor activity of adoptively transferred murine natural killer cells.
22535639	Adenocarcinoma	FCAR	Promote immunity	This supports the idea that stimulation of neutrophil FcαRI, but not FcγR, initiates cross-talk between neutrophils and endothelial cells, leading to enhanced neutrophil migration towards tumour colonies and subsequent tumour killing.
22532287	Small Cell Lung Carcinoma	IL15	Inhibit immunity	Our data suggest that IL-15 and Treg cells are potential new therapeutic targets to improve immune response and patient survival in SCLC.
22531721	Endometrial Serous Adenocarcinoma	CD55	Inhibit immunity	Downregulation of membrane complement inhibitors CD55 and CD59 by siRNA sensitises uterine serous carcinoma overexpressing Her2/neu to complement and antibody-dependent cell cytotoxicity in vitro: implications for trastuzumab-based immunotherapy.
22531721	Endometrial Serous Adenocarcinoma	CD59	Inhibit immunity	Downregulation of membrane complement inhibitors CD55 and CD59 by siRNA sensitises uterine serous carcinoma overexpressing Her2/neu to complement and antibody-dependent cell cytotoxicity in vitro: implications for trastuzumab-based immunotherapy.
22529296	Melanoma	NOS2	Inhibit immunity (T cell function)	These data suggest a critical role for tumor-expressed iNOS in the recruitment and induction of functional MDSC by modulation of tumor VEGF secretion and upregulation of STAT3 and ROS in MDSC.
22529296	Melanoma	STAT3	Inhibit immunity (T cell function)	These data suggest a critical role for tumor-expressed iNOS in the recruitment and induction of functional MDSC by modulation of tumor VEGF secretion and upregulation of STAT3 and ROS in MDSC.
22529296	Melanoma	VEGFA	Inhibit immunity (T cell function)	These data suggest a critical role for tumor-expressed iNOS in the recruitment and induction of functional MDSC by modulation of tumor VEGF secretion and upregulation of STAT3 and ROS in MDSC.
22511579	Breast Carcinoma	TNFSF14	Promote immunity	LIGHT delivery to tumors by mesenchymal stem cells mobilizes an effective antitumor immune response.
22505239	Hepatocellular Carcinoma	HAVCR2	Inhibit immunity (T cell function)	Tim-3/galectin-9 signaling pathway mediates T-cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma.
22505239	Hepatocellular Carcinoma	LGALS9	Inhibit immunity (T cell function)	Tim-3/galectin-9 signaling pathway mediates T-cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma.
22474386	Prostate Carcinoma	IL15	Promote immunity	Combining the immune stimulatory properties of IL-15 with simultaneous removal of two critical immune inhibitory checkpoints, we showed enhancement of immune responses, leading to increased antitumor activity.
22474024	Colon Carcinoma	FKBP5	Inhibit immunity (T cell function)	Functional changes in myeloid-derived suppressor cells (MDSCs) during tumor growth: FKBP51 contributes to the regulation of the immunosuppressive function of MDSCs.
22474024	Colon Carcinoma	NOS2	Inhibit immunity (T cell function)	Experiments using small interfering RNA and a chemical inhibitor of FKBP51 revealed that FKBP51 contributes to the regulation of the suppressive function of MDSCs by increasing inducible NO synthase, arginase-1, and reactive oxygen species levels and enhancing NF-κB activity.
22474024	Colon Carcinoma	ARG1	Inhibit immunity (T cell function)	Experiments using small interfering RNA and a chemical inhibitor of FKBP51 revealed that FKBP51 contributes to the regulation of the suppressive function of MDSCs by increasing inducible NO synthase, arginase-1, and reactive oxygen species levels and enhancing NF-κB activity.
22474024	Colon Carcinoma	NFKB1	Inhibit immunity (T cell function)	Experiments using small interfering RNA and a chemical inhibitor of FKBP51 revealed that FKBP51 contributes to the regulation of the suppressive function of MDSCs by increasing inducible NO synthase, arginase-1, and reactive oxygen species levels and enhancing NF-κB activity.
22472122	Hepatocellular Carcinoma	IL2	Promote immunity	In an advanced murine metastatic liver tumor model, IL-2 inhibited tumor growth in a dose-dependent fashion. Taken together, our findings provide a novel clinical strategy to enhance the efficacy of HDIL-2 immunotherapy for patients with cancer.
29379494	Chronic Lymphocytic Leukemia	STAT3	Inhibit immunity	The CXCR4-STAT3-IL-10 Pathway Controls the Immunoregulatory Function of Chronic Lymphocytic Leukemia and Is Modulated by Lenalidomide. Knockdown of STAT3 significantly impaired the ability of CLL cells to produce IL-10.
29379494	Chronic Lymphocytic Leukemia	IL10	Inhibit immunity	The CXCR4-STAT3-IL-10 Pathway Controls the Immunoregulatory Function of Chronic Lymphocytic Leukemia and Is Modulated by Lenalidomide. Lenalidomide also suppressed IL-10-induced Y705-STAT3 phosphorylation in healthy T cells, thus reversing CLL-induced T-cell dysfunction.
29375567	Ovarian Carcinoma	ENTPD1	Inhibit immunity	Metformin-induced reduction of CD39 and CD73 blocks myeloid-derived suppressor cell activity in patients with ovarian cancer. Metformin triggered activation of AMP-activated protein kinase α (AMPKα) and subsequently suppressed hypoxia-inducible factor-α (HIF-1α), which was critical for induction of CD39/CD73 expression in MDSC.
29375567	Ovarian Carcinoma	NT5E	Inhibit immunity	Metformin-induced reduction of CD39 and CD73 blocks myeloid-derived suppressor cell activity in patients with ovarian cancer. Metformin triggered activation of AMP-activated protein kinase α (AMPKα) and subsequently suppressed hypoxia-inducible factor-α (HIF-1α), which was critical for induction of CD39/CD73 expression in MDSC.
29370526	Melanoma	BRAF	Inhibit immunity (infiltration); Resistant to immunotherapy	Nanoparticle-Mediated Trapping of Wnt Family Member 5A in Tumor Microenvironments Enhances Immunotherapy for B-Raf Proto-Oncogene Mutant Melanoma. Approximately 50% of human melanoma is driven by B-Raf proto-oncogene mutation (BRAF mutant). Tumors with such mutation are desmoplastic, highly immunosuppressive, and often resistant to immune checkpoint therapies. Wnt family member 5A (Wnt5a), a signaling protein highly produced by BRAF mutant melanoma cells, has been implicated in inducing dendritic cell tolerance and tumor fibrosis, thus hindering effective antigen presentation and T-cell infiltration.
29370526	Melanoma	WNT5A	Inhibit immunity (infiltration); Resistant to immunotherapy	Nanoparticle-Mediated Trapping of Wnt Family Member 5A in Tumor Microenvironments Enhances Immunotherapy for B-Raf Proto-Oncogene Mutant Melanoma. Wnt family member 5A (Wnt5a), a signaling protein highly produced by BRAF mutant melanoma cells, has been implicated in inducing dendritic cell tolerance and tumor fibrosis, thus hindering effective antigen presentation and T-cell infiltration. We hypothesized that Wnt5a is a key molecule controlling the immunosuppressive tumor microenvironment in metastatic melanoma. Our findings indicated that efficient local Wnt5a trapping significantly remodeled the immunosuppressive tumor microenvironment to facilitate immunogenic cell-death-mediated immunotherapy.
10706715	Lung Carcinoma	FAS	Promote immunity	The finding of up-regulated CD95 expression on tumor cells placed in vivo suggests that a CD95-based mechanism plays a role in tumor immunity at early stages of tumor growth. Consequently, the progressive down-regulation of CD95 expression during tumor progression may indeed be an escape mechanism as previously reported.
10706701	Colorectal adenocarcinoma	CXCL10	Promote immunity	Injection of AdCMVIP-10 into s.c. tumor nodules derived from the CT26 murine colorectal adenocarcinoma cell line displayed some antitumor activity but it was not curative in most cases. Importantly, intratumoral gene transfer with IL-12 and IP-10 generated a powerful tumor-specific CTL response in a synergistic fashion, while both CD4 and CD8 T cells appeared in the infiltrate of regressing tumors.
10706701	Colorectal adenocarcinoma	IL12A	Promote immunity	Injection of AdCMVIP-10 into s.c. tumor nodules derived from the CT26 murine colorectal adenocarcinoma cell line displayed some antitumor activity but it was not curative in most cases. Importantly, intratumoral gene transfer with IL-12 and IP-10 generated a powerful tumor-specific CTL response in a synergistic fashion, while both CD4 and CD8 T cells appeared in the infiltrate of regressing tumors.
29363545	Lung carcinoma	VAMP3	Promote immunity	Tumor conditioned DC exhibited downregulation of the SNARE VAMP3, a regulator of endosomes trafficking we found to be required for cross-presentation of tumor antigens and DC-mediated tumor rejection.
29361135	Non-Small Cell Lung Carcinoma	CD274	Inhibit immunity	Expression of PD-L1 in tumor cells and tumor-infiltrating immune cells has been associated with improved efficacy to anti-PD-1/PD-L1 inhibitors in patients with advanced-stage non-small-cell lung cancer (NSCLC) and emerged as a potential biomarker for the selection of patients to cancer immunotherapies.
29360818	EBV-positive malignancies	PDLIM7	Promote immunity (T cell function); Essential for immunotherapy	Both human CD8 and CD4 T-cells expressing the LMP1-TCR provoked high levels of cytokine secretion and cytolytic activity towards peptide-pulsed and LMP1-expressing tumour cells.
29358173	Pancreatic ductal adenocarcinoma	WT1	Promote immunity	We assessed WT1-specific immune responses via delayed-type hypersensitivity (DTH) to the WT1 peptide and a tetramer assay to detect WT1-specific cytotoxic T lymphocytes (WT1-CTL). These clinical effects were associated with the induction of WT1-specific immune responses.
29355622	Melanoma	IDO1	Inhibit immunity; immunotherapy target	We here successfully developed indoleamine 2, 3-dioxygenase (IDO) siRNA nanoparticle-coated and tyrosinase-related protein 2 (Trp2)-displayed recombinant Saccharomyces cerevisiae (YCP).
10699956	Melanoma	MAGEC2	Promote immunity	A serological survey identified 2 melanoma patients with anti-CT10 antibody, demonstrating the immunogenicity of CT10 in humans.
10699951	Uveal melanoma	HLA-A	Promote immunity	In OMM-1 cells, IFN-alpha and -gamma increased the expression of HLA-A but did not induce expression of the 2 B alleles, indicating an HLA-B locus-specific loss. The lack of HLA expression may explain why uveal melanoma cells escape immune surveillance by cytotoxic T cells and complicate the development of immunotherapy in uveal melanoma.
10697273	Central nervous system lymphoma	BCL2	Inhibit immunity	Overexpression of BCL-2, BCL-X, and BAX in primary central nervous system lymphomas that occur in immunosuppressed patients.
10697273	Central nervous system lymphoma	BCL2L1	Inhibit immunity	Overexpression of BCL-2, BCL-X, and BAX in primary central nervous system lymphomas that occur in immunosuppressed patients.
10697273	Central nervous system lymphoma	BAX	Inhibit immunity	Overexpression of BCL-2, BCL-X, and BAX in primary central nervous system lymphomas that occur in immunosuppressed patients.
10702232	Cervical carcinoma	IRF1	Promote immunity	Inactivation of interferon regulatory factor-1 tumor suppressor protein by HPV E7 oncoprotein. Implication for the E7-mediated immune evasion mechanism in cervical carcinogenesis. Transient co-expression of E7 significantly inhibits the IRF-1-mediated activation of IFN-beta promoter in NIH-3T3 cells. These results suggest that HPV E7 interferes with the transactivation function of IRF-1 by recruiting HDAC to the promoter.
10688838	Chronic myelogenous leukemia, BRC-ABL1 positive	BCR	Promote immunity	Vaccination of patients with chronic myelogenous leukemia with bcr-abl oncogene breakpoint fusion peptides generates specific immune responses.
10667570	Melanoma	DCT	Promote immunity	To further explore the linkage between immunotherapy and autoimmunity, we studied the response to vaccination with a related antigen, TRP-2. i.m. inoculation of plasmid DNA encoding murine trp-2 elicited antigen-specific CTLs that recognized the B16 mouse melanoma and protected the mice from challenge with tumor cells.
10657650	Colon carcinoma	BCL2	Inhibit immunity	Establishment of an immune response against cancer may depend on the capacity of dendritic cells to transfer tumor Ags into T cell-rich areas. Fluorescence-labeled mononuclear cells with a phenotype of MHC class II+ dendritic cells are also found in the T cell areas of the draining lymph nodes. Interestingly, no fluorescent cell can be found in lymph nodes after a s.c. injection of Bcl2-transfected apoptosis-resistant tumor cells that yielded progressive tumors.
27777574	Colorectal carcinoma	FCGR3A	Promote immunity	CRC-NK cells displayed underexpression of CD16, NKG2D, DNAM-1, CD161, NKp46, and NKp30 activating receptors, while inhibitory receptors CD85j and NKG2A were overexpressed. This inhibited phenotype affected cytotoxic functionality against CRC cells and interferon-γ production.
27777574	Colorectal carcinoma	KLRK1	Promote immunity (NK cell function)	CRC-NK cells displayed underexpression of CD16, NKG2D, DNAM-1, CD161, NKp46, and NKp30 activating receptors, while inhibitory receptors CD85j and NKG2A were overexpressed. This inhibited phenotype affected cytotoxic functionality against CRC cells and interferon-γ production.
27777574	Colorectal carcinoma	CD226	Promote immunity	CRC-NK cells displayed underexpression of CD16, NKG2D, DNAM-1, CD161, NKp46, and NKp30 activating receptors, while inhibitory receptors CD85j and NKG2A were overexpressed. This inhibited phenotype affected cytotoxic functionality against CRC cells and interferon-γ production.
27777574	Colorectal carcinoma	KLRB1	Promote immunity	CRC-NK cells displayed underexpression of CD16, NKG2D, DNAM-1, CD161, NKp46, and NKp30 activating receptors, while inhibitory receptors CD85j and NKG2A were overexpressed. This inhibited phenotype affected cytotoxic functionality against CRC cells and interferon-γ production.
27777574	Colorectal carcinoma	NCR1	Promote immunity	CRC-NK cells displayed underexpression of CD16, NKG2D, DNAM-1, CD161, NKp46, and NKp30 activating receptors, while inhibitory receptors CD85j and NKG2A were overexpressed. This inhibited phenotype affected cytotoxic functionality against CRC cells and interferon-γ production.
27777574	Colorectal carcinoma	NCR3	Promote immunity	CRC-NK cells displayed underexpression of CD16, NKG2D, DNAM-1, CD161, NKp46, and NKp30 activating receptors, while inhibitory receptors CD85j and NKG2A were overexpressed. This inhibited phenotype affected cytotoxic functionality against CRC cells and interferon-γ production.
27777574	Colorectal carcinoma	LILRB1	Inhibit immunity	CRC-NK cells displayed underexpression of CD16, NKG2D, DNAM-1, CD161, NKp46, and NKp30 activating receptors, while inhibitory receptors CD85j and NKG2A were overexpressed. This inhibited phenotype affected cytotoxic functionality against CRC cells and interferon-γ production.
27777574	Colorectal carcinoma	KLRC1	Inhibit immunity	CRC-NK cells displayed underexpression of CD16, NKG2D, DNAM-1, CD161, NKp46, and NKp30 activating receptors, while inhibitory receptors CD85j and NKG2A were overexpressed. This inhibited phenotype affected cytotoxic functionality against CRC cells and interferon-γ production.
27777574	Colorectal carcinoma	IL2	Promote immunity	IL-2 and IL-15 in combination with cetuximab stimulated NK cell, improving cytotoxicity.
27777574	Colorectal carcinoma	IL15	Promote immunity	IL-2 and IL-15 in combination with cetuximab stimulated NK cell, improving cytotoxicity.
27775550	Acute myeloid leukemia	TBX21	Promote immunity	Indeed, NK cells from leukemic mice and humans with AML showed lower levels of TBET and EOMES, transcription factors that are critical for terminal NK cell differentiation.
27775550	Acute myeloid leukemia	EOMES	Promote immunity	Indeed, NK cells from leukemic mice and humans with AML showed lower levels of TBET and EOMES, transcription factors that are critical for terminal NK cell differentiation.
27569584	Ovarian Carcinoma	CD47	Inhibit immunity	The CD47 "don't eat me signal" is highly expressed in human ovarian cancer. The CD47 "don't eat me" signal allows tumor immune evasion. This demonstrates that while CD47 may be an immunologic shield that may be considered for targeted therapies, it is likely that it operates in concert with other mechanisms of immune evasion.
27568346	Lung adenocarcinoma	CD274	Inhibit immunity	PD-L1 expression was associated with abundant CD8+ and/or T-bet+ tumor-infiltrating lymphocytes and EGFR wild-type, significant smoking history, and aggressive pathologic features. PD-L1 expression was significantly associated with decreased progression-free and overall survival rates by univariate analysis, but not by multivariate analysis.
27566188	Non-Small Cell Lung Carcinoma	EGF	Promote immunity; Essential for immunotherapy	Abnormalities in the epidermal growth factor (EGF) and EGFR pathway promote progression of NSCLC. This concept of pathway targeted immunotherapy (PTI) was validated in vitro by dose-related suppression of EGFR, Akt, and Erk1/2 phosphorylation in cell lines with different mutations.
27769244	Bladder carcinoma	IL2	Promote immunity	NK cells from healthy donors upon activation with IL-2 and IL-15 kills indiscriminately both stem-like and differentiated tumor cells via stress ligand recognition.
27769244	Bladder carcinoma	IL15	Promote immunity	NK cells from healthy donors upon activation with IL-2 and IL-15 kills indiscriminately both stem-like and differentiated tumor cells via stress ligand recognition.
27765535	Non-Small Cell Lung Carcinoma	EGFR	Promote immunity; Essential for immunotherapy	In the three included studies that compared immune checkpoint inhibitors (nivolumab [n = 292], pembrolizumab [n = 691], and atezolizumab [n =144]) against docetaxel (n = 776), immune checkpoint inhibitors significantly prolonged OS over that with docetaxel overall (n = 1903, HR = 0.68, 95% CI: 0.61-0.77, p < 0.0001) and in the EGFR wild-type subgroup (n = 1362, HR = 0.66, 95% CI: 0.58-0.76, p < 0.0001) but not in the EGFR-mutant subgroup (n = 186, HR = 1.05, 95% CI: 0.70-1.55, p < 0.81; treatment-mutation interaction p = 0.03). In EGFR-mutant advanced NSCLC, immune checkpoint inhibitors do not improve OS over that with docetaxel.
27513300	Chronic myeloid leukemia	CD1D	Promote immunity	Indeed, flow cytometry and confocal microscopy revealed that cell surface expression of CD1d was downregulated in CML mDCs, relative to healthy donor (HD) controls. In vitro treatment of CML mDCs with the Rho-associated protein kinase (ROCK) inhibitor Y-27632 partially restored both cell surface CD1d expression and CD1d-mediated antigen presentation, whereas it had no effect on HD mDCs. Our data support the conclusion that BCR-ABL-dependent ROCK, but not TK, is involved in CD1d downregulation.
27513300	Chronic myeloid leukemia	ROCK1	Inhibit immunity	In vitro treatment of CML mDCs with the Rho-associated protein kinase (ROCK) inhibitor Y-27632 partially restored both cell surface CD1d expression and CD1d-mediated antigen presentation, whereas it had no effect on HD mDCs. Our data support the conclusion that BCR-ABL-dependent ROCK, but not TK, is involved in CD1d downregulation.
27654852	Acute myeloid leukemia; chronic myeloid leukemia; myelodysplastic syndrome	TMEM37	Promote immunity	In conclusion, PR1 peptide vaccine induces specific immunity that correlates with clinical responses, including molecular remission, in AML, CML and MDS patients.
27733359	Lymphoma	HDAC3	Inhibit immunity	HDAC3 loss-of-function rescued repression of these enhancers and corresponding genes, including MHC class II, and more profoundly suppressed CREBBP-mutant lymphomas in vitro and in vivo.
27733359	Lymphoma	CREBBP	Promote immunity	Hence, CREBBP loss-of-function contributes to lymphomagenesis by enabling unopposed suppression of enhancers by BCL6/SMRT/HDAC3 complexes, suggesting HDAC3-targeted therapy as a precision approach for CREBBP-mutant lymphomas.
26452628	Hepatocellular carcinoma	CCL2	Inhibit immunity (T cell function); immunotherapy target	Targeting of tumour-infiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma. CCL2 is overexpressed in human liver cancers and is prognostic for patients with HCC. Blockade of CCL2/CCR2 signalling with knockout of CCR2 or with a CCR2 antagonist inhibits malignant growth and metastasis, reduces postsurgical recurrence, and enhances survival. Further, therapeutic blocking of the CCL2/CCR2 axis inhibits the recruitment of inflammatory monocytes, infiltration and M2-polarisation of TAMs, resulting in reversal of the immunosuppression status of the tumour microenvironment and activation of an antitumorous CD8+ T cell response. The results demonstrate the translational potential of CCL2/CCR2 blockade for treatment of HCCs.
27707838	Breast Carcinoma	CXCL10	Promote immunity (infiltration)	We found that DDRD breast tumors were associated with CD4+ and CD8+ lymphocytic infiltration (Fisher's exact test P < .001) and that DDRD cells expressed the chemokines CXCL10 and CCL5 3.5- to 11.9-fold more than DNA damage response-proficient cells (P < .01).
27707838	Breast Carcinoma	CCL5	Promote immunity (infiltration)	We found that DDRD breast tumors were associated with CD4+ and CD8+ lymphocytic infiltration (Fisher's exact test P < .001) and that DDRD cells expressed the chemokines CXCL10 and CCL5 3.5- to 11.9-fold more than DNA damage response-proficient cells (P < .01).
27697766	Acute Myeloid Leukemia	EPCAM	Inhibit immunity; immunotherapy target	In this study, we compared gene expression patterns of acute myeloid leukemia (AML) and normal bone marrow samples and found that epithelial cell adhesion molecule (EpCAM) is frequently overexpressed in patients with AML, with EpCAM+leukemic cells exhibiting enhanced chemoresistance and oncogenesis. Finally, EpCAM antibody treatment depleted AML in subcutaneous, disseminated, and intramedullary engrafted mice. In summary, EpCAM exhibits promise as a novel target for the treatment of leukemia.
27697578	Penile Carcinoma	CD274	Inhibit immunity	Compared to PD-L1 negative tumors, the PD-L1 expression patterns had different prognostic values in the whole cohort as well as in the high risk HPV negative subgroup. On multivariable analyses a marginal expression pattern was associated with absent lymph node metastases (OR 0.4) while diffuse expression was associated with poor survival (HR 2.58).
27693350	Diffuse Large B-Cell Lymphoma Germinal Center B-Cell Type	TNFRSF14	Promote immunity	Loss of the HVEM Tumor Suppressor in Lymphoma and Restoration by Modified CAR-T Cells. The HVEM (TNFRSF14) receptor gene is among the most frequently mutated genes in germinal center lymphomas.
27693350	Diffuse Large B-Cell Lymphoma Germinal Center B-Cell Type	CD19	Promote immunity	To deliver solHVEM to lymphomas in vivo, we engineered CD19-targeted chimeric antigen receptor (CAR) T cells that produce solHVEM locally and continuously. These modified CAR-T cells show enhanced therapeutic activity against xenografted lymphomas.
27692344	Lung Carcinoma	CD274	Inhibit immunity	Chemoresistance is a major challenge in lung cancer treatment. This induction correlated with reduction in expression of drug resistance genes MDR1, MRP1, ABCG2 and ABCC2 along with decreased expression of PD-L1 which is associated with severe dysfunction of tumor specific CD8+ T cells.
27687306	Lung adenocarcinoma	STK11	Promote immunity (infiltration)	Analysis of immunophenotypes revealed that LUADs with STK11 mutations exhibited relatively low levels of infiltrating CD4+/CD8+?T-cells indicative of a muted immune response.
27687306	Lung adenocarcinoma	TP53	Promote immunity	Tumoral PD-L1 was significantly elevated in TP53 mutant LUADs whereas PIK3CA mutant LUADs exhibited markedly down-regulated PD-L1 expression.
27687306	Lung adenocarcinoma	PIK3CA	Inhibit immunity	Tumoral PD-L1 was significantly elevated in TP53 mutant LUADs whereas PIK3CA mutant LUADs exhibited markedly down-regulated PD-L1 expression.
27687306	Lung adenocarcinoma	KEAP1	Inhibit immunity (infiltration)	LUADs with TP53 or KEAP1 mutations displayed relatively increased CD57 and Granzyme B levels indicative of augmented natural killer (NK) cell infiltration.
27687306	Lung adenocarcinoma	TP53	Promote immunity	LUADs with TP53 or KEAP1 mutations displayed relatively increased CD57 and Granzyme B levels indicative of augmented natural killer (NK) cell infiltration.
27687006	Colorectal Carcinoma	FABP1	Inhibit immunity (infiltration)	Fatty acid-binding protein 1 is preferentially lost in microsatellite instable colorectal carcinomas and is immune modulated via the interferon γ pathway. Previously, we compared expression of colonic epithelium genes in a subset of microsatellite instable (MSI) colorectal carcinomas (medullary carcinomas) to normal colonic mucosa and found that FABP1 expression was markedly decreased in the tumors. FABP1 was preferentially lost in MSI carcinomas (123/133, 93%) compared with microsatellite stable carcinomas (240/562, 43%, P<0.0001). In addition, higher numbers of tumor-infiltrating lymphocytes were present in tumors with loss of FABP1 (P<0.0001). Decreased expression of the fatty acid storage and glucose regulator, PPARγ, was associated with the loss of FABP1 (P<0.0001).
27685836	Lung Carcinoma	GSN	Promote immunity (T cell function); essential for immunotherapy	It is therefore essential to engineer therapeutic interventions by which T cell reactivity against tumor cells is selectively enhanced (i.e., "focused cancer immunotherapy") based on tumor antigens that are specifically expressed in the tumor of a certain cancer and in many patients with this cancer. This analysis indicated that gelsolin and inter-alpha-trypsin inhibitor heavy chains were specifically and frequently detected (at a frequency higher than 80%), and that phosphoproteins (VENTX, VCIP135) were also specifically present in the ICs of lung cancer patients.
27685836	Lung Carcinoma	ITIH1	Promote immunity (T cell function); essential for immunotherapy	It is therefore essential to engineer therapeutic interventions by which T cell reactivity against tumor cells is selectively enhanced (i.e., "focused cancer immunotherapy") based on tumor antigens that are specifically expressed in the tumor of a certain cancer and in many patients with this cancer. This analysis indicated that gelsolin and inter-alpha-trypsin inhibitor heavy chains were specifically and frequently detected (at a frequency higher than 80%), and that phosphoproteins (VENTX, VCIP135) were also specifically present in the ICs of lung cancer patients.
27685836	Lung Carcinoma	VENTX	Promote immunity (T cell function); essential for immunotherapy	It is therefore essential to engineer therapeutic interventions by which T cell reactivity against tumor cells is selectively enhanced (i.e., "focused cancer immunotherapy") based on tumor antigens that are specifically expressed in the tumor of a certain cancer and in many patients with this cancer. This analysis indicated that gelsolin and inter-alpha-trypsin inhibitor heavy chains were specifically and frequently detected (at a frequency higher than 80%), and that phosphoproteins (VENTX, VCIP135) were also specifically present in the ICs of lung cancer patients.
27678219	Melanoma	ID2	Promote immunity (T cell function)	Vaccination with ID2-GM-DCs slowed the progression of melanoma tumors and enhanced animal survival, which was associated with an increased abundance of tumor-infiltrating interferon-γ-positive CD4(+) effector and CD8(+) cytotoxic T cells and a decreased number of tumor-infiltrating regulatory CD4(+) T cells. The efficacy of the ID2-GM-DC vaccine was improved by combinatorial treatment with a blocking antibody to programmed cell death protein-1 (PD-1), a current immunotherapy that overcomes suppressive immune checkpoint signaling. Collectively, our data reveal a previously unrecognized STAT3-mediated immunosuppressive mechanism in DCs and indicate that DC-intrinsic ID2 promotes tumor immunity by modulating tumor-associated CD4(+) T cell responses. Thus, inhibiting STAT3 or overexpressing ID2 selectively in DCs may improve the efficiency of DC vaccines in cancer therapy.
27678219	Melanoma	STAT3	Inhibit immunity	Collectively, our data reveal a previously unrecognized STAT3-mediated immunosuppressive mechanism in DCs and indicate that DC-intrinsic ID2 promotes tumor immunity by modulating tumor-associated CD4(+) T cell responses. Thus, inhibiting STAT3 or overexpressing ID2 selectively in DCs may improve the efficiency of DC vaccines in cancer therapy.
27678219	Melanoma	PDCD1	Inhibit immunity; immunotherapy target	The efficacy of the ID2-GM-DC vaccine was improved by combinatorial treatment with a blocking antibody to programmed cell death protein-1 (PD-1), a current immunotherapy that overcomes suppressive immune checkpoint signaling.
27656909	Melanoma; Breast Carcinoma	MAP2K1	Inhibit immunity; immunotherapy target	The combinations of nanoscale MEK- and PI3K-targeting supramolecular therapeutics with checkpoint PDL1 and PD1 inhibitors exert enhanced antitumor outcome in melanoma and breast cancers in vivo, respectively.
27656909	Melanoma; Breast Carcinoma	PIK3CD	Inhibit immunity; immunotherapy target	The combinations of nanoscale MEK- and PI3K-targeting supramolecular therapeutics with checkpoint PDL1 and PD1 inhibitors exert enhanced antitumor outcome in melanoma and breast cancers in vivo, respectively.
27656909	Melanoma; Breast Carcinoma	CD274	Inhibit immunity; immunotherapy target	The combinations of nanoscale MEK- and PI3K-targeting supramolecular therapeutics with checkpoint PDL1 and PD1 inhibitors exert enhanced antitumor outcome in melanoma and breast cancers in vivo, respectively.
27656909	Melanoma; Breast Carcinoma	PDCD1	Inhibit immunity; immunotherapy target	The combinations of nanoscale MEK- and PI3K-targeting supramolecular therapeutics with checkpoint PDL1 and PD1 inhibitors exert enhanced antitumor outcome in melanoma and breast cancers in vivo, respectively.
27655849	Acute Myeloid Leukemia	IL12A	Promote immunity; Essential for immunotherapy	Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. Cytokine-induced memory-like NK cells differentiate after a brief preactivation with interleukin-12 (IL-12), IL-15, and IL-18 and exhibit enhanced responses to cytokine or activating receptor restimulation for weeks to months after preactivation.
27655849	Acute Myeloid Leukemia	IL15	Promote immunity; Essential for immunotherapy	Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. Cytokine-induced memory-like NK cells differentiate after a brief preactivation with interleukin-12 (IL-12), IL-15, and IL-18 and exhibit enhanced responses to cytokine or activating receptor restimulation for weeks to months after preactivation.
27655849	Acute Myeloid Leukemia	IL18	Promote immunity; Essential for immunotherapy	Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. Cytokine-induced memory-like NK cells differentiate after a brief preactivation with interleukin-12 (IL-12), IL-15, and IL-18 and exhibit enhanced responses to cytokine or activating receptor restimulation for weeks to months after preactivation.
27641098	Melanoma	LDHA	Inhibit immunity (T cell function)	Elevated lactate dehydrogenase A (LDHA) expression is associated with poor outcome in tumor patients. Database analyses revealed negative correlations between LDHA expression and T cell activation markers in human melanoma patients.
27623354	Clear Cell Renal Cell Carcinoma	CD274	Inhibit immunity (T cell function); immunotherapy target	Clear cell renal cell carcinoma (ccRCC) is an aggressive tumor that is characterized in most cases by inactivation of the tumor suppressor gene VHL. PD-L1 expression was observed in 69 ccRCC (70.4%) and the corresponding patients had a worse prognosis, with a median specific survival of 52 months (p?=?0.03). PD-L1 expression was significantly associated with poor prognostic factors such as a higher ISUP nucleolar grade (p?=?0.01), metastases at diagnosis (p?=?0.01), a sarcomatoid component (p?=?0.04), overexpression of VEGF (p?=?0.006), and cytoplasmic PAR-3 expression (p?=?0.01). Interestingly, all wild-type VHL tumors (no VHL gene alteration, 11.2%) expressed PD-L1. In this study, we found PD-L1 expression to be associated with noninactivated VHL tumors and in particular wild-type VHL ccRCC, which may benefit from therapies inhibiting PD-L1/PD-1.
27622997	Melanoma	PDCD1	Inhibit immunity (T cell function); immunotherapy target	Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Results from phase 2 and 3 trials in patients with advanced melanoma have shown significant improvements in the proportion of patients achieving an objective response and prolonged progression-free survival with the combination of nivolumab (an anti-PD-1 antibody) plus ipilimumab (an anti-CTLA-4 antibody) compared with ipilimumab alone.
27622997	Melanoma	CTLA4	Inhibit immunity (T cell function); immunotherapy target	Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Results from phase 2 and 3 trials in patients with advanced melanoma have shown significant improvements in the proportion of patients achieving an objective response and prolonged progression-free survival with the combination of nivolumab (an anti-PD-1 antibody) plus ipilimumab (an anti-CTLA-4 antibody) compared with ipilimumab alone.
27622331	Colorectal Carcinoma	NOS2	Promote immunity (T cell function)	These myeloid cells are phenotypically similar to inducible nitric oxide synthase (NOS2)- and tumor necrosis factor (TNF)-producing dendritic cells (DC), or Tip-DCs. Tumor elimination via NOS2 required the CD40-CD40L pathway. We also uncovered a strong correlation between survival of colorectal cancer patients and NOS2, CD40, and TNF expression in their tumors.
27622331	Colorectal Carcinoma	CD40	Promote immunity (T cell function)	These myeloid cells are phenotypically similar to inducible nitric oxide synthase (NOS2)- and tumor necrosis factor (TNF)-producing dendritic cells (DC), or Tip-DCs. Tumor elimination via NOS2 required the CD40-CD40L pathway. We also uncovered a strong correlation between survival of colorectal cancer patients and NOS2, CD40, and TNF expression in their tumors.
27622331	Colorectal Carcinoma	TNF	Promote immunity (T cell function)	These myeloid cells are phenotypically similar to inducible nitric oxide synthase (NOS2)- and tumor necrosis factor (TNF)-producing dendritic cells (DC), or Tip-DCs. Tumor elimination via NOS2 required the CD40-CD40L pathway. We also uncovered a strong correlation between survival of colorectal cancer patients and NOS2, CD40, and TNF expression in their tumors.
27620275	Gastric Carcinoma	IL17A	Promote immunity (infiltration)	Proinflammatory IL17 is a critical mediator of the recruitment of neutrophils into the invasive margin by CXC chemokines.
27618707	Gastroesophageal Junction Adenocarcinoma; Prostate Adenocarcinoma; Plasma Cell Myeloma; Melanoma; Colon Neuroendocrine Tumor G1; Parotid Gland Pleomorphic Adenoma; Teratoma	GFAP	Promote immunity (T cell function)	Neoplasia was diagnosed within 3 years of neurologic onset in 6 of 16 patients (38%): prostate and gastroesophageal adenocarcinomas, myeloma, melanoma, colonic carcinoid, parotid pleomorphic adenoma, and teratoma. Expression of GFAP has been reported in some of the tumor types identified in paraneoplastic cases. Glial fibrillary acidic protein peptide-specific cytotoxic CD8+ T cells are implicated as effectors in a transgenic mouse model of autoimmune GFAP meningoencephalitis.
27605551	Refractory Non-Hodgkin Lymphoma	CD19	Promote immunity (T cell function)	Immunotherapy with CD19 CAR-T cells in a defined CD4(+)/CD8(+) ratio allowed identification of correlative factors for CAR-T cell expansion, persistence, and toxicity, and facilitated optimization of lymphodepletion that improved disease response and overall and progression-free survival.
27604597	Prostate carcinoma	MUC1	Promote immunity (T cell function); essential for immunotherapy	In conclusion, vaccination with Tn-MUC1-loaded DCs in nmCRPC patients appears to be safe, able to induce significant T-cell responses, and have biological activity as measured by the increase in PSADT following vaccination.
29382670	Melanoma	YAP1	Inhibit immunity (T cell function); resistant to immunotherapy	Activation of YAP, a Hippo pathway effector, is an important resistance mechanism to BRAF inhibitor (BRAFi) in melanoma. Emerging evidence also suggests that YAP is involved in suppression of the antitumor immune response. Here, we show that BRAFi-resistant melanoma cells evade CD8+ T-cell immune responses in a PD-L1-dependent manner by activating YAP, which synchronously supports melanoma cell survival upon BRAF inhibition. PD-L1 expression is elevated in BRAFi-resistant melanoma cells, in which YAP is robustly activated, and YAP knockdown decreases PD-L1 expression. In addition, constitutively active YAP (YAP-5SA) increases PD-L1 expression by binding to an upstream enhancer of the PD-L1 gene and potentiating its transcription.
29379494	Chronic Lymphocytic Leukemia	IL10	Inhibit immunity (T cell function); immunotherapy target	Here, we show that the CXC chemokine ligand 12 (CXCL12)-CXCR4-STAT3 axis regulates IL-10 production by CLL cells and their ability to suppress T-cell effector function through an IL-10 mediated mechanism. We conclude that the capacity of CLL cells to produce IL-10 is mediated by the CXCL12-CXCR4-STAT3 pathway and likely contributes to immunodeficiency in patients. Lenalidomide also suppressed IL-10-induced Y705-STAT3 phosphorylation in healthy T cells, thus reversing CLL-induced T-cell dysfunction.
29379494	Chronic Lymphocytic Leukemia	CXCR4	Inhibit immunity (T cell function); immunotherapy target	Here, we show that the CXC chemokine ligand 12 (CXCL12)-CXCR4-STAT3 axis regulates IL-10 production by CLL cells and their ability to suppress T-cell effector function through an IL-10 mediated mechanism. We conclude that the capacity of CLL cells to produce IL-10 is mediated by the CXCL12-CXCR4-STAT3 pathway and likely contributes to immunodeficiency in patients.
29379494	Chronic Lymphocytic Leukemia	STAT3	Inhibit immunity (T cell function); immunotherapy target	Here, we show that the CXC chemokine ligand 12 (CXCL12)-CXCR4-STAT3 axis regulates IL-10 production by CLL cells and their ability to suppress T-cell effector function through an IL-10 mediated mechanism. We conclude that the capacity of CLL cells to produce IL-10 is mediated by the CXCL12-CXCR4-STAT3 pathway and likely contributes to immunodeficiency in patients.
29379494	Chronic Lymphocytic Leukemia	CXCL12	Inhibit immunity (T cell function); immunotherapy target	Here, we show that the CXC chemokine ligand 12 (CXCL12)-CXCR4-STAT3 axis regulates IL-10 production by CLL cells and their ability to suppress T-cell effector function through an IL-10 mediated mechanism. We conclude that the capacity of CLL cells to produce IL-10 is mediated by the CXCL12-CXCR4-STAT3 pathway and likely contributes to immunodeficiency in patients.
29378267	Non-Small Cell Lung Carcinoma	PDCD1	Inhibit immunity; immunotherapy target	Safety of Combined PD-1 Pathway Inhibition and Intracranial Radiation Therapy in Non-Small Cell Lung Cancer. Treatment with an ICI and cranial RT was not associated with a significant increase in RT-related AEs, suggesting that use of programmed cell death 1/programmed death ligand 1 inhibitors in patients receiving cranial RT may have an acceptable safety profile.
29374065	Ovarian Carcinoma	ENTPD1	Inhibit immunity (T cell function); immunotherapy target	Metformin-Induced Reduction of CD39 and CD73 Blocks Myeloid-Derived Suppressor Cell Activity in Patients with Ovarian Cancer. Furthermore, metformin treatment correlated with longer overall survival in diabetic patients with ovarian cancer, which was accompanied by a metformin-induced reduction in the frequency of circulating CD39+CD73+ MDSC and a concomitant increase in the antitumor activities of circulating CD8+ T cells. Our results highlight a direct effect of metformin on MDSC and suggest that metformin may yield clinical benefit through improvement of antitumor T-cell immunity by dampening CD39/CD73-dependent MDSC immunosuppression in ovarian cancer patients.
29374065	Ovarian Carcinoma	NT5E	Inhibit immunity (T cell function); immunotherapy target	Metformin-Induced Reduction of CD39 and CD73 Blocks Myeloid-Derived Suppressor Cell Activity in Patients with Ovarian Cancer. Furthermore, metformin treatment correlated with longer overall survival in diabetic patients with ovarian cancer, which was accompanied by a metformin-induced reduction in the frequency of circulating CD39+CD73+ MDSC and a concomitant increase in the antitumor activities of circulating CD8+ T cells. Our results highlight a direct effect of metformin on MDSC and suggest that metformin may yield clinical benefit through improvement of antitumor T-cell immunity by dampening CD39/CD73-dependent MDSC immunosuppression in ovarian cancer patients.
29374053	Non-Small Cell Lung Carcinoma	HHLA2	Promote immunity (infiltration)	We demonstrated that HHLA2, a newly identified immune inhibitory molecule, was widely expressed in NSCLC. The triple-positive group had more TIL infiltration than the triple-negative group. B7x-Ig and HHLA2-Ig inhibited TCR-mediated proliferation of CD4 and CD8 T cells more robustly than PD-L1-Ig. All three significantly suppressed cytokine productions by T cells.
29374053	Non-Small Cell Lung Carcinoma	VTCN1	Inhibit immunity (T cell function)	We demonstrated that HHLA2, a newly identified immune inhibitory molecule, was widely expressed in NSCLC. The triple-positive group had more TIL infiltration than the triple-negative group. B7x-Ig and HHLA2-Ig inhibited TCR-mediated proliferation of CD4 and CD8 T cells more robustly than PD-L1-Ig. All three significantly suppressed cytokine productions by T cells.
29371260	Colorectal carcinoma	ASB4	Promote immunity (T cell function); essential for immunotherapy	The Antigen ASB4 on Cancer Stem Cells Serves as a Target for CTL Immunotherapy of Colorectal Cancer. Therefore, ASB4 is a tumor-associated antigen that can elicit CTL responses specific to CSCs and can discriminate between two cellular subsets of colorectal cancer.
29368981	Melanoma	BECN1	Inhibit immunity (NK cell infiltration)	Targeting autophagy blocks melanoma growth by bringing natural killer cells to the tumor battlefield. We showed that genetic targeting of the macroautophagy/autophagy gene Becn1/Beclin1 in B16-F10 tumors inhibits their growth by inducing a massive infiltration of functional natural killer (NK) cells into the tumor bed.
29368981	Melanoma	CCL5	Promote immunity (NK cell function); increase the efficacy of immunotherapy	Such infiltration is primarily due to the ability of BECN1-defective tumor cells to overexpress and release CCL5 cytokine in the tumor microenvironment by a mechanism involving the activation of the MAPK8/JNK-JUN/c-Jun signaling pathway. Clinically, we reported a strong positive correlation between the expression of NK cell marker and CCL5 in human melanoma tumors and more importantly, a significant increased survival is found in melanoma patients expressing a high level of CCL5.
29368647	T Acute Lymphoblastic Leukemia	CD47	Inhibit immunity	MIR-708 promotes phagocytosis to eradicate T-ALL cells by targeting CD47. Functional studies showed that restoration of miR-708 expression in the T-ALL cell line is sufficient to promote phagocytosis by macrophages in the absence or presence of the anti-CD47 antibody to eradicate T-ALL cells, and inhibited tumor engraftment in vivo.
29351920	Ovarian Carcinoma	CD274	Inhibit immunity	Heavy infiltration of the PD-L1-mutated and PD-L1-overexpressing tumor with T cell lymphocytes (ie, CD4+/CD8+ TIL), CD68+ macrophages and CD20+ B cells was detected in the surgical specimen strongly suggesting immune evasion as a key mechanism of tumor growth and survival.
29351920	Ovarian Carcinoma	PDCD1	Immunotherapy target	Anti-PD1 inhibitors may represent a novel treatment option for recurrent/metastatic human tumors refractory to salvage treatment harboring PD-L1 gene structural variations causing aberrant PD-L1 expression.
29341428	Breast Carcinoma	TAP1	Promote immunity (T cell function)	Gene expression analysis of the sorted tumor cells revealed that the Aldefluor+ tumor cells has decreased expression of transporter associated with antigen processing (TAP) genes and co-stimulatory molecule CD80, which would decrease susceptibility to T cells.
29341428	Aldefluor+ Breast Carcinoma	CD80	Promote immunity (T cell function)	Gene expression analysis of the sorted tumor cells revealed that the Aldefluor+ tumor cells has decreased expression of transporter associated with antigen processing (TAP) genes and co-stimulatory molecule CD80, which would decrease susceptibility to T cells.
29339539	Breast carcinoma; Lung carcinoma	TAZ	Inhibit immunity	The Hippo Pathway Component TAZ Promotes Immune Evasion in Human Cancer through PD-L1. The Hippo pathway component WW domain-containing transcription regulator 1 (TAZ) is a transcriptional coactivator and an oncogene in breast and lung cancer. The upstream kinases of the Hippo pathway, mammalian STE20-like kinase 1 and 2 (MST1/2), and large tumor suppressor 1 and 2 (LATS1/2), suppress PD-L1 expression while TAZ and YAP enhance PD-L1 levels in breast and lung cancer cell lines.
29339539	Breast carcinoma; Lung carcinoma	YAP1	Inhibit immunity	The Hippo Pathway Component TAZ Promotes Immune Evasion in Human Cancer through PD-L1. The Hippo pathway component WW domain-containing transcription regulator 1 (TAZ) is a transcriptional coactivator and an oncogene in breast and lung cancer. The upstream kinases of the Hippo pathway, mammalian STE20-like kinase 1 and 2 (MST1/2), and large tumor suppressor 1 and 2 (LATS1/2), suppress PD-L1 expression while TAZ and YAP enhance PD-L1 levels in breast and lung cancer cell lines.
29339377	Melanoma; Prostate carcinoma	CTLA4	Inhibit immunity (infiltration); immunotherapy target	In murine models of melanoma and prostate cancer, the combination of chemotherapy and CTLA-4 blockade induced a shift in the cellular composition of the tumor microenvironment, with infiltrating CD8+ and CD4+ T cells increasing the CD8/Foxp3 T-cell ratio.
29339375	Non-Small Cell Lung Carcinoma	TUSC2	Promote immunity (T/NK cell function); essential for immunotherapy	Because of the role of TUSC2 in regulating immune cells, we assessed TUSC2 efficacy on antitumor immune responses alone and in combination with anti-PD-1 in two Kras-mutant syngeneic mouse lung cancer models. TUSC2 alone significantly reduced tumor growth and prolonged survival compared with anti-PD-1. When combined, this effect was significantly enhanced, and correlated with a pronounced increases in circulating and splenic natural killer (NK) cells and CD8+ T cells, and a decrease in regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and T-cell checkpoint receptors PD-1, CTLA-4, and TIM-3.
29337666	Wiskott-Aldrich Syndrome	ITSN2	Promote immunity (B cell)	Tuning of in vivo cognate B-T cell interactions by Intersectin 2 is required for effective anti-viral B cell immunity. Here we show that mice lacking the adaptor protein ITSN2, a G-nucleotide exchange factor (GEF) for Cdc42 that also interacts with WASp and WIP, exhibited increased mortality during primary infection, incomplete protection after Flu vaccination, reduced germinal centre formation and impaired antibody responses to vaccination. In vivo, ITSN2 deficient B cells show a reduction in the expression of SLAM, CD84 or ICOSL that correlates with a diminished ability to form long term conjugates with T cells, to proliferate in vivo, and to differentiate into germinal centre cells.
29337305	Ovarian carcinoma; Melanoma	CD274	Inhibit immunity (T/NK cell function); immunotherapy target	Host expression of PD-L1 determines efficacy of PD-L1 pathway blockade-mediated tumor regression. Here, we evaluated 3 tumor-bearing mouse models that differ in their sensitivity to PD-L1 blockade and demonstrated a loss of therapeutic efficacy of PD-L1 blockade in immunodeficient mice and in PD-L1- and PD-1-deficient mice. Additionally, expression of PD-L1 on dendritic cells and macrophages in ovarian cancer and melanoma patients correlated with the efficacy of treatment with either anti-PD-1 alone or in combination with anti-CTLA-4.
29336307	Melanoma	GPER1	Promote immunity (T/NK cell function); increase the efficacy of immunotherapy	Activation of G protein-coupled estrogen receptor signaling inhibits melanoma and improves response to immune checkpoint blockade. Selective GPER activation in primary melanocytes and melanoma cells induced long-term changes that maintained a more differentiated cell state as defined by increased expression of well-established melanocyte differentiation antigens, increased pigment production, decreased proliferative capacity, and decreased expression of the oncodriver and stem cell marker c-Myc. GPER signaling also rendered melanoma cells more vulnerable to immunotherapy.
29326691	Colon carcinoma	S100A9	Inhibit immunity; immunotherapy target	S100a9 has been emerged as an important pro-inflammatory mediator in acute and chronic inflammation, and the aberrant expression of S100a9 also contributes to tumorigenic processes such as cell proliferation, angiogenesis, metastasis, and immune evasion. We previously revealed that S100a8 and S100a9 are highly activated and play an important role in the process of colitis-associated carcinogenesis, which suggests an attractive therapeutic target for ulcerative colitis and related colon cancer. The inflammatory response, tumor cell proliferation, and immune cells infiltration in the colon tissues were suppressed by anti-S100a9 antibody.
29324443	Lung carcinoma; Breast Adenocarcinoma	CADM1	Promote immunity (NK cell function); increase the efficacy of immunotherapy	EMT-induced modulation of E-cadherin and cell adhesion molecule 1 (CADM1) mediated increased susceptibility to NK cytotoxicity. Higher CADM1 expression correlates with improved patient survival in 2 lung and 1 breast adenocarcinoma patient cohorts and decreased metastasis.
29324304	Melanoma	TLR3	Promote immunity (T cell function); essential for immunotherapy	Injectable polypeptide hydrogel for dual-delivery of antigen and TLR3 agonist to modulate dendritic cells in vivo and enhance potent cytotoxic T-lymphocyte response against melanoma.
29322496	Thymic carcinoma; Invasive Thymoma	WT1	Promote immunity (T/NK cell function); essential for immunotherapy	WT1 peptide-based immunotherapy for advanced thymic epithelial malignancies. WT1 peptide vaccine immunotherapy may have antitumor potential against thymic malignancies.
29321210	Acute Myeloid Leukemia	TNFRSF4	Promote immunity (T/NK cell function)	The Immune Checkpoint Modulator OX40 and Its Ligand OX40L in NK-Cell Immunosurveillance and Acute Myeloid Leukemia. The TNF receptor family member OX40 promotes activation and proliferation of T cells, which fuels efforts to modulate this immune checkpoint to reinforce antitumor immunity. We report that OX40 is expressed on leukemic blasts in a substantial percentage of patients with acute myeloid leukemia (AML) and that OX40 can, after stimulation with agonistic OX40 antibodies, mediate proliferation and release of cytokines that act as growth and survival factors for the leukemic cells.
29321210	Acute Myeloid Leukemia	TNFSF4	Promote immunity (T/NK cell function)	The Immune Checkpoint Modulator OX40 and Its Ligand OX40L in NK-Cell Immunosurveillance and Acute Myeloid Leukemia. We also demonstrate that pNKC differentially express OX40L, depending on the protocol used for their generation. OX40L signaling promoted NK-cell activation, cytokine production, and cytotoxicity, and disruption of OX40-OX40L interaction impaired pNKC reactivity against primary AML cells.
29320474	Desmoplastic Melanoma	CD274	Inhibit immunity	High response rate to PD-1 blockade in desmoplastic melanomas. Immunohistochemistry analysis from nineteen desmoplastic melanomas and thirteen non-desmoplastic melanomas revealed a higher percentage of PD-L1-positive cells in the tumour parenchyma in desmoplastic melanomas (P?=?0.04); these cells were highly associated with increased CD8 density and PD-L1 expression in the tumour invasive margin.
29316433	Breast carcinoma	CXCR3	Promote immunity	Gene expression analysis identified upregulation of Cxcl9 within intratumoral DCs during combination therapy, and therapeutic efficacy was ablated by CXCR3 blockade, Batf3 deficiency, or Irf8 deficiency.
29316433	Breast carcinoma	BATF3	Increase the efficacy of immunotherapy	Gene expression analysis identified upregulation of Cxcl9 within intratumoral DCs during combination therapy, and therapeutic efficacy was ablated by CXCR3 blockade, Batf3 deficiency, or Irf8 deficiency.
29316433	Breast carcinoma	IRF8	Increase the efficacy of immunotherapy	Gene expression analysis identified upregulation of Cxcl9 within intratumoral DCs during combination therapy, and therapeutic efficacy was ablated by CXCR3 blockade, Batf3 deficiency, or Irf8 deficiency.
29316433	Breast carcinoma	HAVCR2	Inhibit immunity	Here we evaluated the expression of immune regulators by CD103+ DCs in a murine model of breast cancer and identified expression of TIM-3 as a target for therapy.
29309059	Metastatic Melanoma	PDCD1	Immunotherapy target	In particular, inhibition of programmed cell death protein 1 (PD-1) has been found to be effective for the treatment of metastatic melanoma and other cancers.
29305520	Melanoma	SLAMF6	Promote immunity (T/NK cell function); essential for immunotherapy	Soluble SLAMF6 Receptor Induces Strong CD8+ T-cell Effector Function and Improves Anti-Melanoma Activity In Vivo. CD8+ T cells costimulated with seSLAMF6 secreted more IFNγ and displayed augmented cytolytic activity.
29299667	Paraneoplastic Cerebellar Degeneration	CDR2L	Promote immunity (infiltration)	We characterized 26 ovarian carcinomas associated with Yo-PCD for their tumor immune contexture and genetic status of the 2 onconeural Yo-Ags, CDR2 and CDR2L. Yo-PCD tumors differed from the 116 control tumors by more abundant T and B cells infiltration occasionally organized in tertiary lymphoid structures harboring CDR2L protein deposits.
29298869	Glioma	PDCD1	Immunotherapy target	Finally, we show that addition of PD-1 blockade to reovirus enhances systemic therapy in a preclinical glioma model.
29295954	Colon carcinoma	TNFRSF1B	Inhibit immunity (T/NK cell function); immunotherapy target	Those Treg cells that have a high abundance of TNFR2 have the maximal immunosuppressive capacity. We investigated whether targeting TNFR2 could effectively suppress the activity of Treg cells and consequently enhance the efficacy of cancer immunotherapy.
29295954	Breast carcinoma	IL2RA	Inhibit immunity (T/NK cell function); immunotherapy target	Treatment with the combination of TNFR2-blocking antibody and a CD25-targeted antibody also resulted in enhanced inhibition of tumor growth in a syngeneic 4T1 mouse model of breast cancer.
29288236	Pancreatic Carcinoma	CD47	Inhibit immunity	CD47 Blockade as an Adjuvant Immunotherapy for Resectable Pancreatic Cancer. Immunohistochemistry and flow cytometry were used to measure CD47 ("don't eat me signal") expression on tumor cells and characterize macrophages in the tumor microenvironment. Treatment of mice with CD47-blocking antibodies resulted in increased time-to-progression of metastatic tumors and prolonged survival. These findings suggest that following surgical resection of PDAC, adjuvant immunotherapy with anti-CD47 antibody could lead to substantially improved outcomes for patients.
29277894	Non-Small Cell Lung Carcinoma	SPHK2	Inhibit immunity; decrease the efficacy of immunotherapy; immunotherapy target	SphK2 expression predicts poor survival in NSCLC patients, and is associated with Gefitinib-resistance.
29273790	Melanoma	TNF	Inhibit immunity (T cell function); immunotherapy target	TNFα blockade overcomes resistance to anti-PD-1 in experimental melanoma. Our recent work has highlighted that TNFR1-dependent TNF signalling impairs the accumulation of CD8+ tumor-infiltrating T lymphocytes (CD8+ TILs) in mouse melanoma. Herein, our results indicate that TNF or TNFR1 blockade synergizes with anti-PD-1 on anti-cancer immune responses towards solid cancers.
29273790	Melanoma	TNFRSF1A	Inhibit immunity (T cell function); immunotherapy target	Herein, our results indicate that TNF or TNFR1 blockade synergizes with anti-PD-1 on anti-cancer immune responses towards solid cancers.
29267866	Melanoma	TOP1	Inhibit immunity (T cell function); immunotherapy target	We found that Top1 inhibitors increased the sensitivity of patient-derived melanoma cell lines (n?=?7) to T-cell-mediated cytotoxicity (P < .001, Dunnett's test).
29267866	Melanoma	TP53INP1	Promote immunity (T cell function)	This enhancement is mediated by TP53INP1, whose overexpression increased the susceptibility of melanoma cell lines to T-cell cytotoxicity (2549 cell line: P = .009, unpaired t test), whereas its knockdown impeded T-cell killing of Top1 inhibitor-treated melanoma cells (2549 cell line: P < .001, unpaired t test).
29263213	T Acute Lymphoblastic Leukemia	ALCAM	Inhibit immunity (T cell function)	Knockdown of CD166 in primary human T cells by nucleofection abolished the capacity of ILT3.Fc to inhibit CD4+ Th cell proliferation and to induce the generation of CD8+CD28- T suppressor cells.
29258739	Triple-Negative Breast Cancer	MUC1	Promote immunity (T cell function); essential for immunotherapy	Combination Immunotherapy of MUC1 mRNA Nano-vaccine and CTLA-4 Blockade Effectively Inhibits Growth of Triple Negative Breast Cancer. In vivo studies demonstrated that the NP-based mRNA vaccine, targeted to mannose receptors on DCs, could successfully express tumor antigen in the DCs of the lymph node; that the NP vaccine could induce a strong, antigen-specific, in vivo cytotoxic T lymphocyte response against TNBC 4T1 cells; and that combination immunotherapy of the vaccine and anti-CTLA-4 monoclonal antibody could significantly enhance anti-tumor immune response compared to the vaccine or monoclonal antibody alone.
29258739	Triple-Negative Breast Cancer	CTLA4	Inhibit immunity (T cell function)	Combination Immunotherapy of MUC1 mRNA Nano-vaccine and CTLA-4 Blockade Effectively Inhibits Growth of Triple Negative Breast Cancer. In vivo studies demonstrated that the NP-based mRNA vaccine, targeted to mannose receptors on DCs, could successfully express tumor antigen in the DCs of the lymph node; that the NP vaccine could induce a strong, antigen-specific, in vivo cytotoxic T lymphocyte response against TNBC 4T1 cells; and that combination immunotherapy of the vaccine and anti-CTLA-4 monoclonal antibody could significantly enhance anti-tumor immune response compared to the vaccine or monoclonal antibody alone.
29249397	Melanoma	DCT	Promote immunity (T cell function); essential for immunotherapy	LCP mRNA vaccine encoding TRP2 elicited a robust antigen-specific cytotoxic T cell response and a humoral immune response in a C57BL/6 mouse model of B16F10 melanoma.
29243219	Bladder Carcinoma	PDCD1	Inhibit immunity (T cell function); immunotherapy target	PD-1 blockade enhances the antitumor efficacy of GM-CSF surface-modified bladder cancer stem cells vaccine. PD-1 blockade could effectively enhance the functions of tumor-specific T lymphocytes generated by the CSCs vaccine.
24681959	Breast Carcinoma	STAT3	Inhibit immunity; immunotherapy target	Drug-repositioning screening identified piperlongumine as a direct STAT3 inhibitor with potent activity against breast cancer. Signal transducer and activator of transcription (STAT) 3 regulates many cardinal features of cancer including cancer cell growth, apoptosis resistance, DNA damage response, metastasis, immune escape, tumor angiogenesis, the Warburg effect and oncogene addiction and has been validated as a drug target for cancer therapy.
24671426	Melanoma	MAGEA3	Promote immunity (T cell function); essential for immunotherapy	MAGE-A3 with cell-penetrating domain as an efficient therapeutic cancer vaccine. To determine whether generating melanoma antigen family A, 3 (MAGE-A3), a tumor-specific cancer-testis antigen, as a fusion protein with CPD will enhance the cytosolic bioavailability of MAGE-A3. Enhanced cytosolic bioavailability of tumor-specific antigens improves access to human leukocyte antigen (HLA) class I molecules for more efficient cytotoxic T lymphocyte generation.
24667641	Metastatic Melanoma	PDCD1	Inhibit immunity (T cell function)	In all 6 tumors studied, expression of the inhibitory receptors programmed cell death 1 (PD-1; also known as CD279), lymphocyte-activation gene 3 (LAG-3; also known as CD223), and T cell immunoglobulin and mucin domain 3 (TIM-3) on CD8? TILs identified the autologous tumor-reactive repertoire, including mutated neoantigen-specific CD8? lymphocytes, whereas only a fraction of the tumor-reactive population expressed the costimulatory receptor 4-1BB (also known as CD137).
24667641	Metastatic Melanoma	LAG3	Inhibit immunity (T cell function)	In all 6 tumors studied, expression of the inhibitory receptors programmed cell death 1 (PD-1; also known as CD279), lymphocyte-activation gene 3 (LAG-3; also known as CD223), and T cell immunoglobulin and mucin domain 3 (TIM-3) on CD8? TILs identified the autologous tumor-reactive repertoire, including mutated neoantigen-specific CD8? lymphocytes, whereas only a fraction of the tumor-reactive population expressed the costimulatory receptor 4-1BB (also known as CD137).
24667641	Metastatic Melanoma	HAVCR2	Inhibit immunity (T cell function)	In all 6 tumors studied, expression of the inhibitory receptors programmed cell death 1 (PD-1; also known as CD279), lymphocyte-activation gene 3 (LAG-3; also known as CD223), and T cell immunoglobulin and mucin domain 3 (TIM-3) on CD8? TILs identified the autologous tumor-reactive repertoire, including mutated neoantigen-specific CD8? lymphocytes, whereas only a fraction of the tumor-reactive population expressed the costimulatory receptor 4-1BB (also known as CD137).
24667641	Metastatic Melanoma	TNFRSF9	Inhibit immunity (T cell function)	In all 6 tumors studied, expression of the inhibitory receptors programmed cell death 1 (PD-1; also known as CD279), lymphocyte-activation gene 3 (LAG-3; also known as CD223), and T cell immunoglobulin and mucin domain 3 (TIM-3) on CD8? TILs identified the autologous tumor-reactive repertoire, including mutated neoantigen-specific CD8? lymphocytes, whereas only a fraction of the tumor-reactive population expressed the costimulatory receptor 4-1BB (also known as CD137).
24662052	Prostate carcinoma	PTEN	Inhibit immunity (T cell function)	Pten null prostate epithelium promotes localized myeloid-derived suppressor cell expansion and immune suppression during tumor initiation and progression. Using the Pten null murine prostate cancer model, we show an expansion of Gr-1(+) CD11b(+) myeloid-derived suppressor cells (MDSCs) occurring intraprostatically immediately following epithelium-specific Pten deletion without expansion in hematopoietic tissues. Prostatic Gr-1(+) CD11b(+) cells, but not those isolated from the spleen of the same tumor-bearing mice, suppress T cell proliferation and express high levels of Arginase 1 and iNOS. Mechanistically, the loss of PTEN in the epithelium leads to a significant upregulation of genes within the inflammatory response and cytokine-cytokine receptor interaction pathways, including Csf1 and Il1b, two genes known to induce MDSC expansion and immunosuppressive activities.
24658665	Prostate carcinoma	CTLA4	Immunotherapy target	Promising immunotherapeutic agents include poxvirus vaccines and CTLA-4 inhibitor (ipilimumab).
24657487	Malignant Female Reproductive System Neoplasm	VTCN1	Inhibit immunity (T cell function); immunotherapy target	B7-H4 as a potential target for immunotherapy for gynecologic cancers: a closer look. B7-H4 is a transmembrane protein that binds an unknown receptor on activated T cells resulting in inhibition of T-cell effector function via cell cycle arrest, decreased proliferation, and reduced IL-2 production.
24651526	Colon carcinoma	IL6	Immunotherapy target	Embelin reduces colitis-associated tumorigenesis through limiting IL-6/STAT3 signaling. In addition to inhibiting proliferation of tumor epithelial cells, embelin suppressed colonic IL-6 expression and secretion, and subsequently STAT3 activation in vivo.
24651526	Colon carcinoma	STAT3	Immunotherapy target	Embelin reduces colitis-associated tumorigenesis through limiting IL-6/STAT3 signaling. In addition to inhibiting proliferation of tumor epithelial cells, embelin suppressed colonic IL-6 expression and secretion, and subsequently STAT3 activation in vivo.
24647571	Melanoma	TYR	Promote immunity (infiltration)	Furthermore, tyrosinase expression was more frequently lost in metastatic sites outside of the brain and was uniquely correlated with both endogenous CD8(+) and CD4(+) T-cell infiltrates.
24644285	Glioblastoma	EMP2	Inhibit immunity	Epithelial membrane protein-2 (EMP2) activates Src protein and is a novel therapeutic target for glioblastoma. EMP2 had low or undetectable expression in normal brain but was highly expressed in GBM as 95% of patients showed some expression of the protein. As a proof of principle to determine whether EMP2 could serve as a target for therapy, cells were treated using specific anti-EMP2 antibody reagents.
24642245	Cervical carcinoma	TLR9	Promote immunity (T cell function); essential for immunotherapy	Toll-like receptor 9 agonist enhances anti-tumor immunity and inhibits tumor-associated immunosuppressive cells numbers in a mouse cervical cancer model following recombinant lipoprotein therapy. We demonstrate that a TLR9 agonist (unmethylated CpG oligodeoxynucleotide, CpG ODN) enhances CTL responses and eradicates large tumors when combined with rlipo-E7m.
24639349	Melanoma	TNFRSF10B	Promote immunity (T cell function); essential for immunotherapy	Histone deacetylase inhibitor sensitizes apoptosis-resistant melanomas to cytotoxic human T lymphocytes through regulation of TRAIL/DR5 pathway. CTL resistance was due to DR5 downregulation and an inverted ratio of pro- to antiapoptotic molecules, both of which were reversed by the histone deacetylase inhibitor suberoylanilide hydroxanic acid.
24639349	Melanoma	TNFSF10	Promote immunity (T cell function); essential for immunotherapy	Histone deacetylase inhibitor sensitizes apoptosis-resistant melanomas to cytotoxic human T lymphocytes through regulation of TRAIL/DR5 pathway. Furthermore, recombinant human TRAIL and drozitumab (anti-DR5 agonistic mAb) were used to explicitly verify the contribution of the DR5/TRAIL pathway in killing melanomas.
24637363	Chronic Lymphocytic Leukemia	PRDM1	Promote immunity	Variable induction of PRDM1 and differentiation in chronic lymphocytic leukemia is associated with anergy. PRDM1 induction was inversely correlated with the extent of anergy as measured by the ability to mobilize intracellular Ca(2+) following BCR crosslinking. Epigenetic drugs may offer possibilities to reactivate PRDM1 expression as part of novel differentiation therapy approaches.
24623129	Diffuse Large B Cell Lymphoma	CD19	Promote immunity	Differential role of Th1 and Th2 cytokines in autotoxicity driven by CD19-specific second-generation chimeric antigen receptor T cells in a mouse model. In summary, the adoptive transfer of second-generation CD19-specific CAR T cells can result in a cell dose-dependent acute toxicity, whereas the prolonged secretion of high levels of Th2 cytokines from these CAR T cells in vivo drives a granulomatous reaction resulting in chronic toxicity.
24615495	Gastric Carcinoma	KLRK1	Promote immunity (NK cell function); increase the efficacy of immunotherapy	In conclusion, gastric cancer tumors express NKG2D ligands and are highly susceptible to killing by NK cells stimulated by K562-mb15-4.1BBL. These results provide a strong rationale for clinical testing of these NK cells in patients and suggest their use to augment the effects of antibody therapy.
24607504	Pancreatic Neoplasm	KRAS	Inhibit immunity (T cell function); immunotherapy target	The combination of LM-Kras and Treg cell depletion reduced numbers of Foxp3(+)CD4(+) T cells in pancreatic lymph nodes, increased numbers of CD4(+) T cells that secrete interleukin 17 and interferon γ, and caused CD11b(+)Gr1(+) cells in the pancreas to acquire an immunostimulatory phenotype.
24605110	Pancreatic Carcinoma	PTGS2	Inhibit immunity; immunotherapy target	Thus, inhibiting PGE2 with a specific COX-2 inhibitor reverses the immunosuppressive and immature phenotype of KCM-derived MDSCs. This is the first report that clearly suggests a functional role of pancreatic tumor-associated MUC1 in the development of functional MDSCs.
24605110	Pancreatic Carcinoma	MUC1	Inhibit immunity; immunotherapy target	Pancreatic Cancer Cells Isolated from Muc1-Null Tumors Favor the Generation of a Mature Less Suppressive MDSC Population. This is the first report that clearly suggests a functional role of pancreatic tumor-associated MUC1 in the development of functional MDSCs.
24605110	Pancreatic Carcinoma	PTGS2	Inhibit immunity; immunotherapy target	Thus, inhibiting PGE2 with a specific COX-2 inhibitor reverses the immunosuppressive and immature phenotype of KCM-derived MDSCs. This is the first report that clearly suggests a functional role of pancreatic tumor-associated MUC1 in the development of functional MDSCs.
24599129	Oligodendroglioma	SOX2	Inhibit immunity	Sox2 is required to maintain cancer stem cells in a mouse model of high-grade oligodendroglioma. In support of this possibility, an immunotherapeutic approach based on immunization of mice with SOX2 peptides delayed tumor development and prolonged survival.
24598590	Melanoma	CTLA4	Inhibit immunity (T cell function); immunotherapy target	Combination therapy with localized NDV and systemic CTLA-4 blockade led to rejection of preestablished distant tumors and protection from tumor rechallenge in poorly immunogenic tumor models, irrespective of tumor cell line sensitivity to NDV-mediated lysis. Therapeutic effect was associated with marked distant tumor infiltration with activated CD8(+) and CD4(+) effector but not regulatory T cells, and was dependent on CD8(+) cells, natural killer cells, and type I interferon.
24596416	Acute Myeloid Leukemia	IL3RA	Promote immunity (T cell function); essential for immunotherapy	CD123, the transmembrane α chain of the interleukin-3 receptor, is expressed in the majority of AML cells but is also expressed in many normal hematopoietic cells. Here, we show that CD123 is a good target for AML-directed CAR therapy, because its expression increases over time in vivo even in initially CD123(dim) populations, and that human CD123-redirected T cells (CART123) eradicate primary AML in immunodeficient mice.
24590808	Colon carcinoma	CCL19	Inhibit immunity	H17 also stimulated CCL19 expression in tumor cells, which in turn recruited and expanded a population of pluripotent immunoregulatory CD271(+) cells, which included mesenchymal stem cells and myeloid-derived suppressor cells.
24586048	Lung Carcinoma	TGFB1	Inhibit immunity (NK cell function)	Instead, TGF-β depleted DNAX activating protein 12 kDa (DAP12), which is critical for surface NK receptor stabilization and downstream signal transduction. Mechanistic analysis revealed that TGF-β induced microRNA (miR)-183 to repress DAP12 transcription/translation.
24586048	Lung Carcinoma	TYROBP	Promote immunity (NK cell function)	Instead, TGF-β depleted DNAX activating protein 12 kDa (DAP12), which is critical for surface NK receptor stabilization and downstream signal transduction. Mechanistic analysis revealed that TGF-β induced microRNA (miR)-183 to repress DAP12 transcription/translation. Moreover, we documented reduced DAP12 expression in tumor-associated NK cells in lung cancer patients, illustrating this pathway to be consistently perturbed in the human tumor microenvironment.
24583792	Malignant Head and Neck Neoplasm	TP53	Promote immunity (T cell function); essential for immunotherapy	Phase I dendritic cell p53 peptide vaccine for head and neck cancer. p53-specific T-cell frequencies were increased postvaccination in 11 of 16 patients (69%), with IFN-γ secretion detected in four of 16 patients.
24577748	Melanoma	BRAF	Resistant to immunotherapy	Outcomes of patients with metastatic melanoma treated with immunotherapy prior to or after BRAF inhibitors.
24574393	Non-Small Cell Lung Carcinoma	DDX58	Promote immunity	We report that MV-Edm exploits selective autophagy to mitigate the innate immune response mediated by DDX58/RIG-I like receptors (RLRs) in non-small cell lung cancer (NSCLC) cells.
24570975	Glioblastoma	EGFR	Inhibit immunity (T cell function); immunotherapy target	Here, we show that a bscAb targeting the tumor-specific mutation of the epidermal growth factor receptor, EGFRvIII, redirects human CD4(+)CD25(+)FoxP3(+) T(regs) to kill glioblastoma (GBM) cells.
24569779	B-Cell Non-Hodgkin Lymphoma	TGFB1	Inhibit immunity (T cell function)	TGF-β upregulates CD70 expression and induces exhaustion of effector memory T cells in B-cell non-Hodgkin's lymphoma.
24569779	B-Cell Non-Hodgkin Lymphoma	CD70	Inhibit immunity (T cell function)	TGF-β upregulates CD70 expression and induces exhaustion of effector memory T cells in B-cell non-Hodgkin's lymphoma.
24563871	T Lymphoblastic Lymphoma	CD1D	Promote immunity	Invariant natural killer T (iNKT) cells comprise a lineage of CD1d-restricted glycolipid-reactive T lymphocytes with important roles in host immunity to cancer. iNKT cells indirectly participate in antitumor responses by inducing dendritic cell maturation and producing cytokines that promote tumor clearance by CD8+ T and NK cells. They also suggest that the induction of iNKT cell cytotoxic responses in situ might serve as a more effective strategy to prevent and/or treat CD1d+ cancers, such as T lymphoma.
24561793	Chronic Lymphocytic Leukemia	MET	Inhibit immunity	Chronic lymphocytic leukemia nurse-like cells express hepatocyte growth factor receptor (c-MET) and indoleamine 2,3-dioxygenase and display features of immunosuppressive type 2 skewed macrophages. Hepatocyte growth factor may thus have a dual pathophysiological role: directly through enhancement of survival of the leukemic clone and indirectly by favoring T-cell immunosuppression.
24561793	Chronic Lymphocytic Leukemia	IDO1	Inhibit immunity	Chronic lymphocytic leukemia nurse-like cells express hepatocyte growth factor receptor (c-MET) and indoleamine 2,3-dioxygenase and display features of immunosuppressive type 2 skewed macrophages.
24556719	Lung Carcinoma	CD40	Promote immunity	Combined anti-CD40 and anti-IL-23 monoclonal antibody therapy effectively suppresses tumor growth and metastases. Interestingly, in the experimental lung metastases tumor models, we observed that intracellular IL-23 production was specifically restricted to MHC-II(hi)CD11c(+)CD11b(+) cells.
24556719	Lung Carcinoma	IL23A	Inhibit immunity	Combined anti-CD40 and anti-IL-23 monoclonal antibody therapy effectively suppresses tumor growth and metastases. Interestingly, in the experimental lung metastases tumor models, we observed that intracellular IL-23 production was specifically restricted to MHC-II(hi)CD11c(+)CD11b(+) cells.
24550295	Melanoma	ZBTB16	Promote immunity (T cell function)	Polyclonal type II natural killer T cells require PLZF and SAP for their development and contribute to CpG-mediated antitumor response. Importantly, CpG-activated type II NKT cells contribute to the antitumor effect of CpG in the B16 melanoma model.
24550295	Melanoma	SH2D1A	Promote immunity (T cell function)	Polyclonal type II natural killer T cells require PLZF and SAP for their development and contribute to CpG-mediated antitumor response. Importantly, CpG-activated type II NKT cells contribute to the antitumor effect of CpG in the B16 melanoma model.
24550086	Hepatocellular carcinoma	EGFR	Inhibit immunity; immunotherapy target	As tumour regression in our model resembles the targeted inhibition of EGFR in cancer therapy, our observations may provide molecular insights into the targeted inhibition and highlight the importance of immune response in tumour regression.
24548766	Lung Adenocarcinoma	CD274	Inhibit immunity	There may be a possibility for immunotherapy targeting the PD-L1 pathway in patients with lung adenocarcinoma in the future.
24532578	Melanoma	TSC1	Inhibit immunity (T cell function); immunotherapy target	Tuberous sclerosis 1 promotes invariant NKT cell anergy and inhibits invariant NKT cell-mediated antitumor immunity. We report in this study that the tuberous sclerosis 1 (TSC1), a negative regulator of mTOR signaling, plays a crucial role in iNKT cell anergy. Deficiency of TSC1 in iNKT cells results in resistance to α-GalCer-induced anergy, manifested by increased expansion of and cytokine production by iNKT cells in response to secondary Ag stimulation. It is correlated with impaired upregulation of programmed death-1, Egr2, and Grail. TSC1-deficient iNKT cells display enhanced antitumor immunity in a melanoma lung metastasis model. Our data suggest targeting TSC1/2 as a strategy for boosting antitumor immune therapy.
24525743	Hepatocellular carcinoma	IL17A	Inhibit immunity (T cell function); immunotherapy target	IL-17A produced by γδ T cells promotes tumor growth in hepatocellular carcinoma. The tumor-promoting effect of IL-17A was mediated through suppression of antitumor responses, especially CD8(+) T-cell responses. Mechanistic investigations showed that IL-17A induced CXCL5 production by tumor cells to enhance the infiltration of myeloid-derived suppressor cells (MDSC) to tumor sites in a CXCL5/CXCR2-dependent manner. Conversely, IL-17A could also enhance production of IL-1β and IL-23 in MDSC as a positive feedback. These findings offer new insights into how IL-17A influences tumor immunity, with potential implications for the development of tumor immunotherapy.
24525743	Hepatocellular carcinoma	CXCL5	Inhibit immunity (T cell function)	Mechanistic investigations showed that IL-17A induced CXCL5 production by tumor cells to enhance the infiltration of myeloid-derived suppressor cells (MDSC) to tumor sites in a CXCL5/CXCR2-dependent manner.
24525743	Hepatocellular carcinoma	IL1B	Inhibit immunity (T cell function)	Conversely, IL-17A could also enhance production of IL-1β and IL-23 in MDSC as a positive feedback
24525743	Hepatocellular carcinoma	IL23A	Inhibit immunity (T cell function)	Conversely, IL-17A could also enhance production of IL-1β and IL-23 in MDSC as a positive feedback
24523507	T-Cell Non-Hodgkin Lymphoma	CD80	Inhibit immunity	Cutaneous T cell lymphoma expresses immunosuppressive CD80 (B7-1) cell surface protein in a STAT5-dependent manner. Coculture of CTCL cells with normal T lymphocytes consisting of both CD4(+) and CD8(+) populations or the CD4(+) subset alone, transfected with CD152 mRNA, inhibits proliferation of normal T cells in a CD152- and CD80-dependent manner. These data identify a new mechanism of immune evasion in CTCL and suggest that the CD80-CD152 axis may become a therapeutic target in this type of lymphoma.
24523507	T-Cell Non-Hodgkin Lymphoma	CTLA4	Inhibit immunity (T cell function); immunotherapy target	Coculture of CTCL cells with normal T lymphocytes consisting of both CD4(+) and CD8(+) populations or the CD4(+) subset alone, transfected with CD152 mRNA, inhibits proliferation of normal T cells in a CD152- and CD80-dependent manner. These data identify a new mechanism of immune evasion in CTCL and suggest that the CD80-CD152 axis may become a therapeutic target in this type of lymphoma.
24523193	Chronic Myelomonocytic Leukemia; Acute Myelomonocytic Leukemia	GZMB	Promote immunity (T and NK cell function); essential for immunotherapy	The human serine protease granzyme B is a prominent candidate for tumor immunotherapy because it is expressed in cytotoxic T lymphocytes and natural killer cells. We demonstrate that CD64-specific human CFPs kill CMML and AMML cells ex vivo, and that the mutant granzyme B protein R201K is more cytotoxic than the wild-type enzyme in the presence of the granzyme B inhibitor PI9.
24523193	Chronic Myelomonocytic Leukemia; Acute Myelomonocytic Leukemia	FCGR1A	Promote immunity	Here, we report the use of CD64 as a novel target for specific CMML and AMML therapy, and correlate CD64 expression with typical surface markers representing these diseases.
24520093	Plasma Cell Myeloma	MAGEA3	Promote immunity (T/NK cell function); essential for immunotherapy	Combination immunotherapy after ASCT for multiple myeloma using MAGE-A3/Poly-ICLC immunizations followed by adoptive transfer of vaccine-primed and costimulated autologous T cells. A high frequency of vaccine-specific T-cell responses were generated after transplant by combining costimulated autologous T cells with a Poly-ICLC/GM-CSF-primed MAGE-A3 vaccine.
24517146	Thyroid Gland Carcinoma	IDO1	Inhibit immunity (T/NK cell function)	Indoleamine 2,3-dioxygenase 1 (IDO1) is up-regulated in thyroid carcinoma and drives the development of an immunosuppressant tumor microenvironment.
24516200	Ovarian carcinoma	BCL2	Inhibit immunity (T cell function); immunotherapy target	Pan-Bcl-2 inhibitor, GX15-070 (obatoclax), decreases human T regulatory lymphocytes while preserving effector T lymphocytes: a rationale for its use in combination immunotherapy. Furthermore, GX15 increased the apoptosis of regulatory T cells (Tregs), profoundly downregulated FOXP3 and CTLA-4 in a dose-dependent manner, and decreased their suppressive function. Treating PBMCs obtained from ovarian cancer patients with GX15 also resulted in increased CD8(+):Treg and CD4(+):Treg ratios. These results support preclinical studies in which mice vaccinated before treatment with GX15 showed the greatest reduction in metastatic lung tumors as a result of increased apoptotic resistance of mature CD8(+) T cells and decreased Treg function brought about by GX15.
24510590	Ovarian Carcinoma	CD226	Promote immunity (T and NK cell function)	Most tumor-associated NK cells displayed a CD56(bright) , CD16(neg) or CD56(bright) , CD16(dim) phenotype, and very poor cytolytic activities, despite an increased expression of the activation marker CD69. They also showed downregulation of DNAM-1, 2B4, and NTB-A activating receptors, and an altered chemokine receptor repertoire.
24510590	Ovarian Carcinoma	CD244	Promote immunity (T and NK cell function)	Most tumor-associated NK cells displayed a CD56(bright) , CD16(neg) or CD56(bright) , CD16(dim) phenotype, and very poor cytolytic activities, despite an increased expression of the activation marker CD69. They also showed downregulation of DNAM-1, 2B4, and NTB-A activating receptors, and an altered chemokine receptor repertoire.
24510590	Ovarian Carcinoma	SLAMF6	Promote immunity (T and NK cell function)	Most tumor-associated NK cells displayed a CD56(bright) , CD16(neg) or CD56(bright) , CD16(dim) phenotype, and very poor cytolytic activities, despite an increased expression of the activation marker CD69. They also showed downregulation of DNAM-1, 2B4, and NTB-A activating receptors, and an altered chemokine receptor repertoire.
24504816	Hepatitis C virus-associated mixed cryoglobulinemia vasculitis	FCRL5	Inhibit immunity	CD21(-/low) marginal zone B cells highly express Fc receptor-like 5 protein and are killed by anti-Fc receptor-like 5 immunotoxins in hepatitis C virus-associated mixed cryoglobulinemia vasculitis. The anti-FCRL-5 immunotoxins showed specific cytotoxicity against FCRL-5-expressing clonal CD21(-/low) MZ B cells isolated from HCV-infected patients as well as FCRL-5-transfected cell lines.
24504024	Acute Myeloid Leukemia	CD33	Promote immunity (T cell function); essential for immunotherapy	Chimeric antigen receptors against CD33/CD123 antigens efficiently target primary acute myeloid leukemia cells in vivo. AML cells frequently overexpress the myeloid antigens CD33 and CD123, for which specific CARs can be generated.
24504024	Acute Myeloid Leukemia	IL3RA	Promote immunity (T cell function); essential for immunotherapy	Chimeric antigen receptors against CD33/CD123 antigens efficiently target primary acute myeloid leukemia cells in vivo. AML cells frequently overexpress the myeloid antigens CD33 and CD123, for which specific CARs can be generated.
24501220	Fanconi Anemia	FANCA	Promote immunity (T cell function)	Here we report that deletion of Fanca or Fancd2 dysregulates the suppressive activity of regulatory T cells (Tregs), shown functionally as exacerbation of graft-vs-host disease (GVHD) in mice. Analysis of CD25(+)Foxp3(+) Tregs indicated that loss of Fanca or Fancd2 dysregulated Foxp3 target gene expression.
24500981	Lung carcinoma	CCL17	Inhibit immunity	Neutrophils recruit regulatory T-cells into tumors via secretion of CCL17--a new mechanism of impaired antitumor immunity.
24500882	Large B cell lymphoma	CD19	Promote immunity (T cell function); essential for immunotherapy	Targeting high-grade B cell lymphoma with CD19-specific T cells.
24496457	Merkel Cell Carcinoma	PROK2	Promote immunity (infiltration)	Cancers with high tumour PROK2 mRNA content had high counts of tumour infiltrating macrophages (CD68+ and CD163+ cells). The results suggest that prokineticins are associated with MCPyV infection and participate in regulation of the immune response in MCC, and may influence outcome of MCC patients.
24490176	Melanoma	PDCD1	Immunotherapy target	Severe cutaneous and neurologic toxicity in melanoma patients during vemurafenib administration following anti-PD-1 therapy.
24489105	Melanoma	BRAF	Inhibit immunity	Dynamics of chemokine, cytokine, and growth factor serum levels in BRAF-mutant melanoma patients during BRAF inhibitor treatment. These results suggest that BRAF inhibition causes decreased CXCL8 secretion from melanoma cells and induce an immune response against the tumor associated with increased IFN-γ, CCL4, and TNF-α. The decrease in serum CXCL8 levels from PRE to EDT significantly correlated with decreases in markers of melanoma proliferation (Ki-67) and increases in cytotoxic tumor-infiltrating T cells in corresponding tumor biopsies.
24489097	Leukemia	IL2	Promote immunity (T cell function); increase the efficacy of immunotherapy	Human γδ thymocytes are functionally immature and differentiate into cytotoxic type 1 effector T cells upon IL-2/IL-15 signaling. The effects of IL-2/IL-15 depended on MAPK/ERK signaling and induced de novo expression of the transcription factors T-bet and eomesodermin, as well as the cytolytic enzyme perforin, required for the cytotoxic type 1 program. These findings have implications for the manipulation of γδ T cells in cancer immunotherapy.
24489097	Leukemia	IL15	Promote immunity (T cell function); increase the efficacy of immunotherapy	Human γδ thymocytes are functionally immature and differentiate into cytotoxic type 1 effector T cells upon IL-2/IL-15 signaling. The effects of IL-2/IL-15 depended on MAPK/ERK signaling and induced de novo expression of the transcription factors T-bet and eomesodermin, as well as the cytolytic enzyme perforin, required for the cytotoxic type 1 program. These findings have implications for the manipulation of γδ T cells in cancer immunotherapy.
24487434	Diffuse Large B Cell Lymphoma	FAS	Promote immunity (T cell function); increase the efficacy of immunotherapy	Fas ligand-mediated immune surveillance by T cells is essential for the control of spontaneous B cell lymphomas. Impairment of T cell control results in rapid development of DLBCL-like disease, which can be eradicated by polyclonal CD8(+) T cells in a T cell receptor-, CD28- and Fas ligand-dependent manner.
24485523	Melanoma	PDCD1	Immunotherapy target	The potential of combination strategies with these agents has recently been highlighted by clinical observations on CTLA-4+PD-1 combined blockade in melanoma patients.
24485523	Melanoma	CTLA4	Immunotherapy target	The potential of combination strategies with these agents has recently been highlighted by clinical observations on CTLA-4+PD-1 combined blockade in melanoma patients.
18471709	Pancreatic Ductal Adenocarcinoma	IDO1	Inhibit immunity (recruit Treg infiltration); immunotherapy target	Expression of indoleamine 2,3-dioxygenase in metastatic pancreatic ductal adenocarcinoma recruits regulatory T cells to avoid immune detection. In addition, inhibition of IDO in PDA patients can be useful to enhance immunotherapeutic strategies.
18469826	Lymphoma	ALK	Promote immunity	The anaplastic lymphoma kinase is an effective oncoantigen for lymphoma vaccination.
18453571	Melanoma	IL27	Promote immunity (T and NK cell function); essential for immunotherapy	Antiproliferative activity of IL-27 on melanoma. We previously demonstrated that IL-27 has potent antitumor activities, which are mediated through CD8(+) T cells, NK cells, or its own antiangiogenic activity. Although WSX-1 expression was hardly detected in parental mouse melanoma B16F10 cells, IL-27 activated STAT1 and STAT3 and up-regulated MHC class I in B16F10 transfectants expressing wild-type WSX-1. Thus, IL-27 may be an attractive candidate as an antitumor agent applicable to cancer immunotherapy.
18453563	Lung Carcinoma	TNFRSF1B	Inhibit immunity	Cutting edge: expression of TNFR2 defines a maximally suppressive subset of mouse CD4+CD25+FoxP3+ T regulatory cells: applicability to tumor-infiltrating T regulatory cells. In the Lewis lung carcinoma model, more highly suppressive TNFR2(+) Tregs accumulated intratumorally than in the periphery. Thus, TNFR2 identifies a unique subset of mouse Tregs with an activated/memory phenotype and maximal suppressive activity that may account for tumor-infiltrating lymphocyte-mediated immune evasion by tumors.
18442334	Gastric Carcinoma	IL18	Increase the efficacy of immunotherapy	Levels of interleukin-18 are markedly increased in Helicobacter pylori-infected gastric mucosa among patients with specific IL18 genotypes. Biopsy specimens from 128 patients (56 with nonulcer dyspepsia, 28 with gastric ulcers, 28 with duodenal ulcers, and 16 with gastric cancer) were examined; 96 patients had H. pylori infection. IL-18 levels were markedly up-regulated in mucosa infected with H. pylori (P < .001), whereas IL-12 and IFN-gamma levels were independent of H. pylori status. IL18 genotype might be a marker for predicting the effects of eradication therapy.
18438953	Cervical carcinoma	SERPINA1	Inhibit immunity	Elevated expression of SerpinA1 and SerpinA3 in HLA-positive cervical carcinoma. Especially SerpinA1 and SerpinA3 were found to be up-regulated in HLA-positive tumours (3.6- and 8.2-fold, respectively), and this was confirmed by real-time PCR and immunohistochemistry. In a group of 117 tumours, high SerpinA1 and SerpinA3 expression in association with normal/partial HLA expression correlated significantly with poor overall survival (p = 0.035 and p = 0.05, respectively). Thus, HLA-positive tumours are characterized by higher expression of genes associated with an inflammatory profile. In addition, expression of the acute phase proteins SerpinA1 and SerpinA3 in HLA-positive tumours is associated with worse prognosis.
18438953	Cervical carcinoma	SERPINA3	Inhibit immunity	Elevated expression of SerpinA1 and SerpinA3 in HLA-positive cervical carcinoma. Especially SerpinA1 and SerpinA3 were found to be up-regulated in HLA-positive tumours (3.6- and 8.2-fold, respectively), and this was confirmed by real-time PCR and immunohistochemistry. In a group of 117 tumours, high SerpinA1 and SerpinA3 expression in association with normal/partial HLA expression correlated significantly with poor overall survival (p = 0.035 and p = 0.05, respectively). Thus, HLA-positive tumours are characterized by higher expression of genes associated with an inflammatory profile. In addition, expression of the acute phase proteins SerpinA1 and SerpinA3 in HLA-positive tumours is associated with worse prognosis.
18434408	Kaposi Sarcoma	CCR8	Inhibit immunity	Human herpesvirus 8 (HHV-8), which is associated with the endothelial tumor Kaposi's sarcoma, encodes three CC/beta-chemokines. These are expressed early during productive (lytic) infection and are believed to be involved in immune evasion, in addition to viral pathogenesis via induction of angiogenic cytokines. Here we report that two of the HHV-8 chemokines, CCR8 agonists vCCL-1 and vCCL-2, have direct effects on endothelial survival and virus replication.
18427734	Pancreatic Carcinoma	MTOR	Inhibit immunity	Apart from the popular monoclonal antibodies and small molecules tyrosine kinase inhibitors, other novel compounds being tested in preclinical and clinical studies target mTOR, NF-kappaB, proteasome and histone deacetylase. These new drugs along with gene therapy and immunotherapy, which are also under clinical evaluation, may alter the unfavorable natural course of this disease.
18427734	Pancreatic Carcinoma	PSMA1	Immunotherapy target	Apart from the popular monoclonal antibodies and small molecules tyrosine kinase inhibitors, other novel compounds being tested in preclinical and clinical studies target mTOR, NF-kappaB, proteasome and histone deacetylase. These new drugs along with gene therapy and immunotherapy, which are also under clinical evaluation, may alter the unfavorable natural course of this disease.
18427151	Recurrent Grade 1 Follicular Lymphoma	CSF2	Promote immunity; increase the efficacy of immunotherapy	Granulocyte-macrophage colony-stimulating factor potentiates rituximab in patients with relapsed follicular lymphoma: results of a phase II study. GM-CSF plus rituximab results in high response rates, along with a tolerable safety profile in patients with relapsed or progressive FL. The improved efficacy over rituximab monotherapy may be due to increases seen in monocyte, granulocyte, and dendritic cell populations.
18418406	B Acute Lymphoblastic Leukemia	HLA-DPB1	Promote immunity (T cell function)	HLA-DP as specific target for cellular immunotherapy in HLA class II-expressing B-cell leukemia.
18417738	B Acute Lymphoblastic Leukemia	CD1D	Promote immunity (T cell function)	In tumor-bearing mice, we found that type I NKT cells conferred protection in a CD1d-dependent manner, whereas type II NKT cells exhibited inhibitory activity.
18413832	Breast carcinoma	FOXP3	Inhibit immunity	These findings indicate that pCR to neoadjuvant chemotherapy is associated with an immunologic profile combining the absence of immunosuppressive Foxp3 cells and the presence of a high number of CD8 T cells and cytotoxic cells.
18413798	Colon carcinoma; breast carcinoma; Plasma Cell Myeloma; Glioma; Prostate carcinoma	TNFSF10	Promote immunity; essential for immunotherapy	Enhancement of antitumor properties of TRAIL by targeted delivery to the tumor neovasculature. TRAIL plays a role in the innate and adaptive immune response and autoimmune disease and may also be involved in hepatic cell death and inflammation. TRAIL induces apoptosis in a wide range of cell lines and shows substantial antitumor activity in rodent xenograft models, such as colon, breast , multiple myeloma, glioma, and prostate cancers.
18413772	Melanoma; Renal Cell Carcinoma	IL21	Promote immunity (T cell function); increase the efficacy of immunotherapy	Interleukin 21 enhances antibody-mediated tumor rejection. Interleukin-21 (IL-21) is a cytokine with structural and sequence homology to IL-2 and IL-15 that has antitumor activity alone in mouse experimental tumor models and a tolerable safety profile in phase I trials in patients with metastatic melanoma and renal cell carcinoma. Herein, we show that sequentially combining TrimAb with recombinant IL-21 can significantly improve the antitumor activity of this combination against very advanced disease. These data further support the use of IL-21 in adjuvant settings where strong T cell-mediated immune responses to tumors can be generated.
18413767	Melanoma	IL15	Promote immunity (T cell function); essential for immunotherapy	Interleukin-15/interleukin-15R alpha complexes promote destruction of established tumors by reviving tumor-resident CD8+ T cells. Our data provide novel insights into the use of IL-15/IL-15R alpha complexes to relieve tumor-resident T cells from functional suppression by the tumor microenvironment and have significant implications for cancer immunotherapy and treatment of chronic infections.
18413767	Melanoma	IL15RA	Promote immunity (T cell function); essential for immunotherapy	Interleukin-15/interleukin-15R alpha complexes promote destruction of established tumors by reviving tumor-resident CD8+ T cells. Our data provide novel insights into the use of IL-15/IL-15R alpha complexes to relieve tumor-resident T cells from functional suppression by the tumor microenvironment and have significant implications for cancer immunotherapy and treatment of chronic infections.
18412246	Fibrosarcoma	IL1A	Promote immunity	Opposing effects of fibrosarcoma cell-derived IL-1 alpha and IL-1 beta on immune response induction. Induction of a strong immune response by IL-1 alpha demands therapeutic exploitation, which may become more efficient if systemic induction of immunosuppression by IL-1 beta can also be circumvented.
18412246	Fibrosarcoma	IL1B	Promote immunity	Opposing effects of fibrosarcoma cell-derived IL-1 alpha and IL-1 beta on immune response induction. On the other hand, IL-1 beta-competent, IL-1 alpha(-/-) tumors strongly assist CD11b(+)Gr-1(+) myeloid-derived suppressor cell and regulatory T cell expansion, which both suppress with high efficacy activated T helper cell proliferation and CTL lysis. Induction of a strong immune response by IL-1 alpha demands therapeutic exploitation, which may become more efficient if systemic induction of immunosuppression by IL-1 beta can also be circumvented.
18398507	Breast carcinoma	ERBB2	Inhibit immunity (T cell function); immunotherapy target	Antibody association with HER-2/neu-targeted vaccine enhances CD8 T cell responses in mice through Fc-mediated activation of DCs. Trastuzumab, an approved neu-targeted mAb that targets HER-2/neu–expressing (neu-expressing) breast cancers and exerts pleiotropic antitumor effects such as inhibiting neu signaling, suppressing angiogenesis, and inducing tumor apoptosis, with the latter mechanism predominate in patients .
18392040	Melanoma	STAT3	Inhibit immunity (T and NK cell function); immunotherapy target	Synergistic antitumor effects of CpG oligodeoxynucleotide and STAT3 inhibitory agent JSI-124 in a mouse melanoma tumor model. Correlating with these findings, the combination therapy resulted in significantly higher intra-tumoral levels of several proinflammatory, TH1-related cytokines (including IL-12, IFN-gamma, TNF-alpha and IL-2), increases in intra-tumoral CD8+ and CD4+ T cells expressing activation/memory markers and NK cells and increases in activated DCs in the tumors and regional lymph nodes (LNs). Concomitantly, the combination therapy led to a significantly decreased level of immunosuppression, as evidenced by lower intra-tumoral level of VEGF and TGF-beta, and decreased number of CD4+CD25+Foxp3+ regulatory T cells in the regional LNs.
18386791	Lung Carcinoma	FASLG	Promote immunity (T cell function); essential for immunotherapy	Combination of Fasl and GM-CSF confers synergistic antitumor immunity in an in vivo model of the murine Lewis lung carcinoma. In addition, IL-12 production, cytotoxic T-cell activity and IgG against LLC-1 are manifested in mice injected with LLC/FasL/GM-CSF. Taken together, the results indicate that dual gene-based delivery with FasL and GM-CSF may serve as a more effective tumor vaccine to suppress lung cancer cell growth in vivo.
18386791	Lung Carcinoma	CSF2	Promote immunity (T cell function); essential for immunotherapy	Combination of Fasl and GM-CSF confers synergistic antitumor immunity in an in vivo model of the murine Lewis lung carcinoma. In addition, IL-12 production, cytotoxic T-cell activity and IgG against LLC-1 are manifested in mice injected with LLC/FasL/GM-CSF. Taken together, the results indicate that dual gene-based delivery with FasL and GM-CSF may serve as a more effective tumor vaccine to suppress lung cancer cell growth in vivo.
18381453	Renal Cell Carcinoma	VEGFA	Inhibit immunity (T cell function); immunotherapy target	In the future, T cells directed against VEGF as a tumor-associated antigen may represent a possible way of combining peptide-based anti-VEGF immunotherapy with already existent anti-VEGF cancer therapies.
18381452	Breast Carcinoma	IFNG	Promote immunity (T cell function)	We have previously shown T-cell-mediated rejection of the neu-overexpressing mammary carcinoma cells (MMC) in wild-type FVB mice. Gene profiling confirmed that immune rejection is primarily mediated through activation of IFN-stimulated genes and T-cell effector mechanisms. In the present study, we determined that T cells derived from wild-type FVB mice can specifically recognize MMC by secreting IFN-gamma and can induce apoptosis of MMC in vitro.
18381452	Breast Carcinoma	IL10	Inhibit immunity	Interestingly, the tumor tolerance model instead displayed immune suppression pathways through activation of regulatory mechanisms that included in particular the overexpression of interleukin-10 (IL-10), IL-10 receptor, and suppressor of cytokine signaling (SOCS)-1 and SOCS-3.
18381452	Breast Carcinoma	IL10RA	Inhibit immunity	Interestingly, the tumor tolerance model instead displayed immune suppression pathways through activation of regulatory mechanisms that included in particular the overexpression of interleukin-10 (IL-10), IL-10 receptor, and suppressor of cytokine signaling (SOCS)-1 and SOCS-3.
18381452	Breast Carcinoma	SOCS1	Inhibit immunity	Interestingly, the tumor tolerance model instead displayed immune suppression pathways through activation of regulatory mechanisms that included in particular the overexpression of interleukin-10 (IL-10), IL-10 receptor, and suppressor of cytokine signaling (SOCS)-1 and SOCS-3.
18381452	Breast Carcinoma	SOCS3	Inhibit immunity	Interestingly, the tumor tolerance model instead displayed immune suppression pathways through activation of regulatory mechanisms that included in particular the overexpression of interleukin-10 (IL-10), IL-10 receptor, and suppressor of cytokine signaling (SOCS)-1 and SOCS-3.
18366058	Cervical Carcinoma	IFNG	Promote immunity (T cell function)	HPV16 E6 29-38-specific T cells kill cervical carcinoma cells despite partial evasion of T-cell effector function. The absence of killing correlated with limited T-cell degranulation against CaCxCL, but this was not due to antigen processing defects per se; CaCxCL could induce specific T-cell release of IFN-gamma and TNF-alpha, and CaCxCL could be killed in longer cytotoxicity assays (>20 hr).
18364008	Melanoma; Renal Cell Carcinoma; Ovarian Carcinoma; Non-Small Cell Lung Carcinoma	TNFRSF9	Promote immunity	The promise of 4-1BB (CD137)-mediated immunomodulation and the immunotherapy of cancer. A number of different solid tumor types are being tested in these studies, including melanoma, renal cell carcinoma, ovarian carcinoma, and non‐small cell lung cancer. One receptor:ligand pair (4-1BB/CD137 and 4-1BBL/CD137L) is emerging as a target with important potential in its ability to enhance the generation of effective tumor-specific immune responses in situ.
18364008	Melanoma; Renal Cell Carcinoma; Ovarian Carcinoma; Non-Small Cell Lung Carcinoma	TNFSF9	Promote immunity	The promise of 4-1BB (CD137)-mediated immunomodulation and the immunotherapy of cancer. A number of different solid tumor types are being tested in these studies, including melanoma, renal cell carcinoma, ovarian carcinoma, and non‐small cell lung cancer. One receptor:ligand pair (4-1BB/CD137 and 4-1BBL/CD137L) is emerging as a target with important potential in its ability to enhance the generation of effective tumor-specific immune responses in situ.
18363997	Melanoma; Colon Carcinoma; Breast Carcinoma; Lung carcinoma	KDR	Promote immunity (T cell function); essential for immunotherapy	Four novel oral DNA vaccines provide protection against melanoma, colon, breast, and lung carcinoma in mouse models. Vaccines are delivered by attenuated Salmonella typhimurium to secondary lymphoid organs and respectively target vascular endothelial growth factor receptor-2, transcription factor Fos-related antigen-1, anti-apoptosis protein survivin and Legumain, an asparaginyl endopeptidase specifically overexpressed on tumor-associated macrophages (TAMs) in the tumor microenvironment (TME). Key mechanisms induced by these DNA vaccines include efficient suppression of angiogenesis in the tumor vasculature and marked activation of cytotoxic T cells, natural killer cells, and antigen-presenting dendritic cells.
18363997	Melanoma; Colon Carcinoma; Breast Carcinoma; Lung carcinoma	BIRC5	Promote immunity (T cell function); essential for immunotherapy	Four novel oral DNA vaccines provide protection against melanoma, colon, breast, and lung carcinoma in mouse models. Vaccines are delivered by attenuated Salmonella typhimurium to secondary lymphoid organs and respectively target vascular endothelial growth factor receptor-2, transcription factor Fos-related antigen-1, anti-apoptosis protein survivin and Legumain, an asparaginyl endopeptidase specifically overexpressed on tumor-associated macrophages (TAMs) in the tumor microenvironment (TME). Key mechanisms induced by these DNA vaccines include efficient suppression of angiogenesis in the tumor vasculature and marked activation of cytotoxic T cells, natural killer cells, and antigen-presenting dendritic cells.
18363997	Melanoma; Colon Carcinoma; Breast Carcinoma; Lung carcinoma	LGMN	Promote immunity (T cell function); essential for immunotherapy	Four novel oral DNA vaccines provide protection against melanoma, colon, breast, and lung carcinoma in mouse models. Vaccines are delivered by attenuated Salmonella typhimurium to secondary lymphoid organs and respectively target vascular endothelial growth factor receptor-2, transcription factor Fos-related antigen-1, anti-apoptosis protein survivin and Legumain, an asparaginyl endopeptidase specifically overexpressed on tumor-associated macrophages (TAMs) in the tumor microenvironment (TME). Key mechanisms induced by these DNA vaccines include efficient suppression of angiogenesis in the tumor vasculature and marked activation of cytotoxic T cells, natural killer cells, and antigen-presenting dendritic cells.
18362931	Colorectal Carcinoma	CSF2	Promote immunity (T cell function); essential for immunotherapy	Phase I clinical trial of autologous ascites-derived exosomes combined with GM-CSF for colorectal cancer. We found that both therapies were safe and well tolerated, and that Aex plus GM-CSF but not Aex alone can induce beneficial tumor-specific antitumor cytotoxic T lymphocyte (CTL) response. Therefore, our study suggests that the immunotherapy of CRC with Aex in combination with GM-CSF is feasible and safe, and thus can serve as an alternative choice in the immunotherapy of advanced CRC.
18362171	Colon carcinoma; Breast carcinoma	TNFRSF4	Promote immunity (T cell function)	OX40 triggering blocks suppression by regulatory T cells and facilitates tumor rejection. Upon intratumor OX40 triggering, increased numbers of infiltrating dendritic cells (DCs) migrate to draining lymph nodes and generate a new wave of tumor-specific cytotoxic T lymphocytes, as detected by tetramer and CD44 staining of node CD8(+) T lymphocytes.
18354188	Malignant Skin Neoplasm	CXCR4	Inhibit immunity; immunotherapy target	Mast cells express CXCR4(+) and UV exposure up-regulated the expression of its ligand CXCL12 by lymph node B cells. Treating UV-irradiated mice with a CXCR4 antagonist blocked mast cell migration and abrogated UV-induced immune suppression.
18354188	Malignant Skin Neoplasm	CXCL12	Inhibit immunity; immunotherapy target	Mast cells express CXCR4(+) and UV exposure up-regulated the expression of its ligand CXCL12 by lymph node B cells. Treating UV-irradiated mice with a CXCR4 antagonist blocked mast cell migration and abrogated UV-induced immune suppression.
18354183	Melanoma	MICA	Promote immunity (NK cell function); essential for immunotherapy	Intracellular retention of the NKG2D ligand MHC class I chain-related gene A in human melanomas confers immune privilege and prevents NK cell-mediated cytotoxicity. Furthermore, this tumor immune escape strategy can be overcome by gene therapy approaches aimed at overexpressing MICA on tumor cells.
18354176	Acute Myeloid Leukemia	IL23A	Promote immunity (T cell function)	This might be related to the observed inability of LC to release T cell stimulatory cytokines such as IL-12p70, IL-23, and IL-15.
18354176	Acute Myeloid Leukemia	IL15	Promote immunity (T cell function)	This might be related to the observed inability of LC to release T cell stimulatory cytokines such as IL-12p70, IL-23, and IL-15.
18354176	Acute Myeloid Leukemia	IL12A	Promote immunity (T cell function)	This might be related to the observed inability of LC to release T cell stimulatory cytokines such as IL-12p70, IL-23, and IL-15.
18354038	Melanoma	IFNG	Promote immunity (T cell function)	Tumor-specific Th17-polarized cells eradicate large established melanoma. Contrary to the current view that Th1 cells are most important in tumor rejection, we found that Th17-polarized cells better mediated destruction of advanced B16 melanoma. Their therapeutic effect was critically dependent on interferon-gamma (IFN-gamma) production, whereas depletion of interleukin (IL)-17A and IL-23 had little impact.
18349395	Non-Small Cell Lung Carcinoma	EGF	Promote immunity; essential for immunotherapy	Phase II randomized controlled trial of an epidermal growth factor vaccine in advanced non-small-cell lung cancer. Vaccination with EGF was safe and provoked an increase in anti-EGF antibody titers and a decrease in serum EGF.
18349319	Pancreatic Carcinoma	TNFRSF6B	Inhibit immunity (TAM differentiation); immunotherapy target	Decoy receptor 3 (DcR3) is a member of the TNF receptor superfamily and is up-regulated in tumors originating from a diversity of lineages. DcR3 is capable of promoting angiogenesis, inducing dendritic cell apoptosis, and modulating macrophage differentiation. The ERK- and JNK-induced deacetylation of histones associated with the CIITA promoters was responsible for DcR3-mediated down-regulation of MHC-II expression. Furthermore, the expression level of DcR3 in cancer cells correlated inversely with HLA-DR levels on TAMs and with the overall survival time of pancreatic cancer patients. This elucidates the molecular mechanism of impaired MHC-II-mediated antigen presentation by TAMs, and raises the possibility that subversion of TAM-induced immunosuppression via inhibition of DcR3 expression might represent a target for the design of new therapeutics.
18347157	Breast Carcinoma	ERBB2	Inhibit immunity	Administration of TUBO CRCL triggered anti-HER2/neu antibody production and delayed the progression of established tumors. This antitumor activity can be transferred through the serum isolated from TUBO CRCL-immunized animals and involved both B cells and CD4(+) T lymphocytes.
18337760	Kidney Carcinoma	RAF1	Inhibit immunity	Sorafenib, a novel drug for metastatic renal cancer, has broad-spectrum activity against multiple tyrosine kinases, including Raf-1, vascular endothelial growth factor receptor and platelet-derived growth factor receptor.
18337760	Kidney Carcinoma	FLT1	Promote immunity	Sorafenib, a novel drug for metastatic renal cancer, has broad-spectrum activity against multiple tyrosine kinases, including Raf-1, vascular endothelial growth factor receptor and platelet-derived growth factor receptor. These findings suggest that sorafenib may cause the loss of T-cell immune response by inducing apoptosis and targeting LCK. This could potentially lead to immunosuppression in patients with cancer.
18337760	Kidney Carcinoma	PDGFRA	Immunotherapy target	Sorafenib, a novel drug for metastatic renal cancer, has broad-spectrum activity against multiple tyrosine kinases, including Raf-1, vascular endothelial growth factor receptor and platelet-derived growth factor receptor.
18337305	Cervical carcinoma	CD28	Promote immunity (T cell function)	New approach reveals CD28 and IFNG gene interaction in the susceptibility to cervical cancer. Voigt et al. reported that, in CD28-deficient mice, IFN-γ-producing CD8+ T cells were not only reduced in number, but were also less potent in lysing their respective target cells. It is also known that regulation of the NFκB transcription family in T cells involves signaling through CD28.
18326818	Chronic Myelogenous Leukemia, BCR-ABL1 Positive	ABL1	Inhibit immunity (T cell function)	Development and dynamics of robust T-cell responses to CML under imatinib treatment. Imatinib is the first of a new breed of molecular targeted cancer therapies; it inhibits the abl tyrosine kinase3 and has become the first-line therapy for CML. Our data show that antileukemia T-cell responses develop in the majority of CML patients (9 of 14) in remission and that CD4(+) T cells producing tumor necrosis factor-alpha (median 17.6%) represent the major response over interferon-gamma.
18326813	Acute Myeloid Leukemia	PTPRC	Inhibit immunity (T cell function); immunotherapy target	Simultaneously targeting CD45 significantly increases cytotoxicity of the anti-CD33 immunoconjugate, gemtuzumab ozogamicin, against acute myeloid leukemia (AML) cells and improves survival of mice bearing human AML xenografts. Targeting CD33 or CD45 is currently exploited for immunotherapy of acute myeloid leukemia (AML). We found that the anti-CD45 antibody, BC8, dose-dependently increased cytotoxicity induced by GO, and, to a lesser degree, free calicheamicin-gamma(1).
18326813	Acute Myeloid Leukemia	CD33	Inhibit immunity (T cell function); immunotherapy target	Simultaneously targeting CD45 significantly increases cytotoxicity of the anti-CD33 immunoconjugate, gemtuzumab ozogamicin, against acute myeloid leukemia (AML) cells and improves survival of mice bearing human AML xenografts. Targeting CD33 or CD45 is currently exploited for immunotherapy of acute myeloid leukemia (AML).
18323802	Chronic Lymphocytic Leukemia	HMMR	Promote immunity (T cell function); essential for immunotherapy	A significant increase of specific cytotoxic CD8+ T lymphocytes against the leukemia-associated antigens RHAMM or fibromodulin was detected in four patients after DC vaccination.
18323802	Chronic Lymphocytic Leukemia	FMOD	Promote immunity (T cell function); essential for immunotherapy	A significant increase of specific cytotoxic CD8+ T lymphocytes against the leukemia-associated antigens RHAMM or fibromodulin was detected in four patients after DC vaccination.
18323539	Laryngeal Carcinoma	CD1D	Promote immunity (T cell function)	Although epithelial MHC class I and II expression was unchanged by reflux, expression of the nonclassical MHC molecule CD1d increased (P < 0.05, luminal layers). In vitro, laryngeal epithelial cells constitutively expressed CD1d. CD1d and MHC I expression were inversely related in all subjects, in a pattern which appears to be unique to the upper airway. Colocalization of natural killer T (NKT) cells with CD1d increased in patients (P < 0.01).
18322182	Uveal Melanoma	IFNG	Inhibit immunity (T cell function); decrease the efficacy of immunotherapy	Modulation of the tumor cell phenotype by IFN-gamma results in resistance of uveal melanoma cells to granule-mediated lysis by cytotoxic lymphocytes. Treatment with IFN-gamma boosted the MHC class I presentation machinery in uveal melanoma cells but suppressed their MHC class I-restricted CTL lysis.
18319334	Breast Carcinoma	ERBB2	Inhibit immunity	Level of HER-2/neu protein expression in breast cancer may affect the development of endogenous HER-2/neu-specific immunity. Data presented here indicate that endogenous HER-2/neu-specific humoral and T-cell immunity is greater in patients with +3 protein overexpression in their tumors than in patients with lower levels of HER-2/neu expression. Overexpression of a self-tumor-associated protein is a potential mechanism by which immunogenicity is enhanced and may aid in the identification of biologically relevant proteins to target for immune-based molecular cancer therapies.
18318466	Breast Carcinoma	IDO1	Inhibit immunity (T cell function)	Indoleamine 2,3-dioxygenase is the anticancer target for a novel series of potent naphthoquinone-based inhibitors. Based on available information in the NCI database about menadione in different mouse models of cancer, we evaluated whether menadione, administered at levels near the maximum tolerated dose (MTD), would cooperate with paclitaxel in the MMTV-Neu transgenic mouse model of breast cancer, an assay where the antitumor efficacy of various IDO inhibitors has previously been demonstrated.
18316618	Melanoma; Lymphoma; Lung Carcinoma	HPSE	Promote immunity (T cell function); essential for immunotherapy	H-2Kb-restricted CTL epitopes from mouse heparanase elicit an antitumor immune response in vivo.
18307255	B cell non-Hodgkin lymphoma; Chronic Lymphocytic Leukemia; Breast Carcinoma	FCGR3A	Promote immunity (T and NK cell function); increase the efficacy of immunotherapy	Our results show that CD16(+)V gamma 9 V delta 2 T cells recognize monoclonal antibody coated tumor cells via CD16 and exert ADCC similar to that observed with NK cells, even when target cells are relatively resistant to monoclonal antibodies or V gamma 9 V delta 2 T cells alone.
18303116	Prostate carcinoma	CTLA4	Inhibit immunity (T cell function); immunotherapy target	SPAS-1 (stimulator of prostatic adenocarcinoma-specific T cells)/SH3GLB2: A prostate tumor antigen identified by CTLA-4 blockade. Our findings demonstrate that our in vivo CTLA-4 blockade-based T cell expression cloning can identify immunogenic cancer antigens with potential relevance for human immunotherapy.
18303116	Prostate carcinoma	SPATA19	Promote immunity (T cell function); essential for immunotherapy	SPAS-1 (stimulator of prostatic adenocarcinoma-specific T cells)/SH3GLB2: A prostate tumor antigen identified by CTLA-4 blockade.
18292536	Melanoma	IFNG	Promote immunity (infiltration)	Following implantation and treatment, expression of surface class I on tumor cells in vivo was increased in B16/OVA, but not in B16/OVA/DNM tumors, suggesting IFN-gamma acts directly on tumor cells to induce class I up-regulation. Thus, IFN-gamma is instrumental in creating a tumor microenvironment conducive for T cell infiltration and tumor cell target recognition.
18288133	Chronic Lymphocytic Leukemia	HLA-G	Inhibit immunity (NK cell function); immunotherapy target	HLA-G1 surface expression was observed in CLL and was very low or undetectable in MM. Notably, blocking of HLA-G1 with specific antibody on CLL samples increased their susceptibility to NK-mediated killing, demonstrating that HLA-G participates in protecting CLL cells from NK-mediated killing and may thus contribute to their immune escape in vivo.
18287585	T Lymphoblastic Lymphoma	IL2RA	Inhibit immunity	Our results should aid understanding the action of the IL2R-IL15R system in T cell function and also might contribute to the more rationale design of IL2R- or IL15R-targeted immunotherapy agents for treating human leukemia.
18287585	T Lymphoblastic Lymphoma	IL15RA	Immunotherapy target	Our results should aid understanding the action of the IL2R-IL15R system in T cell function and also might contribute to the more rationale design of IL2R- or IL15R-targeted immunotherapy agents for treating human leukemia.
18287062	Melanoma	CTLA4	Inhibit immunity (T cell function); immunotherapy target	Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients. Here we show that periodic infusions of anti-CTLA-4 antibodies after vaccination with irradiated, autologous tumor cells engineered to secrete GM-CSF (GVAX) generate clinically meaningful antitumor immunity without grade 3 or 4 toxicity in a majority of metastatic melanoma patients. Together, these findings help clarify the immunologic and clinical effects of CTLA-4 antibody blockade in previously vaccinated patients and raise the possibility that selective targeting of antitumor Tregs may constitute a complementary strategy for combination therapy.
18287027	Chronic Lymphocytic Leukemia	ROR1	Promote immunity (T cell function)	Antisera induced by infusions of autologous Ad-CD154-leukemia B cells identify ROR1 as an oncofetal antigen and receptor for Wnt5a Five patients made high-titer antibodies against adenovirus and three made IgG reactive with a leukemia-associated surface antigen, which we identified as ROR1.
18281514	Pancreatic Carcinoma	MSLN	Inhibit immunity (T cell function); immunotherapy target	We have shown that mesothelin expression was higher in human pancreatic cancer cells than in human pancreatic duct epithelial cells, and mesothelin mRNA was substantially overexpressed in 18 of 21 (86%) clinical pancreatic adenocarcinoma specimens when compared with the surrounding normal tissues. The increases in mesothelin-specific antibodies and CTL activity and the decrease in regulatory T cells correlated with reduced tumor progression and prolonged survival.
18281483	Primary Cutaneous T-Cell Non-Hodgkin Lymphoma	JAK1	Inhibit immunity (T and NK cell function); immunotherapy target	They also suggest two novel therapeutic approaches to CTCL and, possibly, other CD4+ T-cell lymphomas: inhibition of the Jak1/Jak3 kinase complex and, given the known strong immunostimulatory properties of IL-21 on CD8+ T, natural killer, and B cells, application of this cytokine to boost an immune response against malignant CD4+ T cells.
18281483	Primary Cutaneous T-Cell Non-Hodgkin Lymphoma	JAK3	Inhibit immunity (T and NK cell function); immunotherapy target	They also suggest two novel therapeutic approaches to CTCL and, possibly, other CD4+ T-cell lymphomas: inhibition of the Jak1/Jak3 kinase complex and, given the known strong immunostimulatory properties of IL-21 on CD8+ T, natural killer, and B cells, application of this cytokine to boost an immune response against malignant CD4+ T cells.
18281483	Primary Cutaneous T-Cell Non-Hodgkin Lymphoma	IL21	Promote immunity	They also suggest two novel therapeutic approaches to CTCL and, possibly, other CD4+ T-cell lymphomas: inhibition of the Jak1/Jak3 kinase complex and, given the known strong immunostimulatory properties of IL-21 on CD8+ T, natural killer, and B cells, application of this cytokine to boost an immune response against malignant CD4+ T cells.
18281482	Colorectal Carcinoma; Gastric Carcinoma; Esophageal Carcinoma	STK31	Promote immunity (T cell function); essential for immunotherapy	Reverse transcription-PCR analysis showed that STK31 gene expression levels in cancer samples were significantly higher (P < 0.0001) than those in normal samples. The STK31 gene was frequently expressed not only in colorectal cancer but also in gastric and esophageal cancer. Moreover, STK31 peptide was able to elicit specific CTLs and induced CTLs lysed either peptide-loading or endogenously STK31-expressing target cells. These results showed that the new methodology in this study facilitated identification of CT antigens and that STK31 may be a candidate for cancer immunotherapy against gastrointestinal cancer.
18281283	T-Cell Non-Hodgkin Lymphoma; Chronic Lymphocytic Leukemia; Plasma Cell Myeloma; Recurrent Primary Mediastinal (Thymic) Large B-Cell Cell Lymphoma	NFKB2	Inhibit immunity	The NF-κB2 gene is recurrently mutated in a variety of human lymphoid malignancies, including T-cell lymphoma, chronic lymphocytic leukemia, multiple myeloma, and B cell lymphoma. However, they are predisposed to inflammatory autoimmune disease characterized by multiorgan infiltration of activated lymphocytes, high levels of autoantibodies in the serum, and immune complex glomerulonephritis. p52, but not p80HT, represses Bim expression, leading to defects in apoptotic processes critical for elimination of autoreactive lymphocytes and control of immune response. These findings reveal distinct signaling pathways for actions of NF-kappaB2 mutants and p52 and suggest a causal role for sustained NF-kappaB2 activation in the pathogenesis of autoimmunity.
18276844	Melanoma; Kidney Carcinoma	IL2	Promote immunity (T cell function); essential for immunotherapy	Although IL-2 was identified in 1976 and approved for clinical use in 1992, our appreciation of the full range of its actions is still evolving. IL-2 promotes T-cell proliferation, induces tumor-killing lymphocytes, and causes regression of melanoma and kidney cancer in patients.
18276844	Melanoma; Kidney Carcinoma	IL21	Inhibit immunity (T cell function)	Furthermore, IL-21 repressed expression of IL-2Ra and inhibited IL-2-mediated acquisition of a cytolytic CD8(+) T-cell phenotype.
18276105	Ovarian Carcinoma	IL4	Promote immunity (infiltration)	Expression of the Type-1 cytokine interferon-gamma (IFN gamma), and the Type-2 cytokine interleukin-4 (IL-4) by T-helper (CD4(+)) and T-cytotoxic (CD8(+)) cells was measured under autologous tumor-stimulated, polyclonally-stimulated, or unstimulated conditions. Among cancer patients, marked elevations in unstimulated and tumor-stimulated Type-2 responses were seen, particularly in ascites and tumor-infiltrating lymphocytes (P values<0.01).
18275895	Hodgkin Lymphoma; Non-Hodgkin Lymphoma; Chronic Lymphocytic Leukemia; Myelodysplastic Syndrome; Myelofibrosis	IL15	Promote immunity (NK cell function)	Up-regulation of NK cell activating receptors following allogeneic hematopoietic stem cell transplantation under a lymphodepleting reduced intensity regimen is associated with elevated IL-15 levels. Furthermore, in NK cells cultured with IL-15, we observed an up-regulation of the activating receptors NKG2D, NKp30, and NKp46, associated with an increase in anti-tumor lytic activity.
18272909	Plasma Cell Myeloma	CSF2	Promote immunity (T cell function); essential for immunotherapy	Idiotype vaccination in patients with myeloma reduced circulating myeloma cells (CMC). Eleven patients were immunized with the autologous Id in combinations with granulocyte-macrophage colony-stimulating factor and interleukin 12, and followed for CMC by quantitative real-time allele-specific PCR. Id vaccination reduced CMC, which correlated with vaccine-induced Id-specific T cells.
18272909	Plasma Cell Myeloma	IL12A	Promote immunity (T cell function); essential for immunotherapy	Idiotype vaccination in patients with myeloma reduced circulating myeloma cells (CMC). Eleven patients were immunized with the autologous Id in combinations with granulocyte-macrophage colony-stimulating factor and interleukin 12, and followed for CMC by quantitative real-time allele-specific PCR. Id vaccination reduced CMC, which correlated with vaccine-induced Id-specific T cells.
18272481	Prostate carcinoma	FOLH1	Promote immunity	NPs were formulated by the self-assembly of an amphiphilic triblock copolymer composed of end-to-end linkage of poly(lactic-co-glycolic-acid) (PLGA), polyethyleneglycol (PEG), and the A10 aptamer (Apt), which binds to the prostate-specific membrane antigen (PSMA) on the surface of prostate cancer (PCa) cells, enabling, respectively, controlled drug release, "stealth" properties for immune evasion, and cell-specific targeting.
18268541	Neuroblastoma	HLA-A	Promote immunity (T and NK cell function)	This manifests as increased expression of surface major histocompatibility class I complexes and ICAM-1 molecules and translates into increased sensitivity of NB cells to lysis by cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells.
18268541	Neuroblastoma	ICAM1	Promote immunity (T and NK cell function)	This manifests as increased expression of surface major histocompatibility class I complexes and ICAM-1 molecules and translates into increased sensitivity of NB cells to lysis by cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells.
16524455	Breast Carcinoma	CD40LG	Promote immunity (T cell function)	We expand on that argument by pointing to additional findings that CD40L not only rescues genuine DCs but also functionally improves populations of immature antigen-presenting cells that fill the DC compartment in patients with breast cancer.
16520392	Lymphoma	MS4A1	Promote immunity	CD20 monoclonal antibody (mAb) immunotherapy is effective for lymphoma and autoimmune disease.
16517714	Neuroblastoma	IL12A	Promote immunity (T and NK cell function); essential for immunotherapy	With the transduction of IL-12 and IL-18 genes into the fusion cells (fusion/IL-12/IL-18), the level of IFN-gamma increased more than five times that of other fusion groups. In addition, NK cell activity and CTL activity increased significantly compared with that of mixture/LacZ, fusion/LacZ, DC/LacZ, or C1300/LacZ.
16517714	Neuroblastoma	IL18	Promote immunity (T and NK cell function); essential for immunotherapy	With the transduction of IL-12 and IL-18 genes into the fusion cells (fusion/IL-12/IL-18), the level of IFN-gamma increased more than five times that of other fusion groups. In addition, NK cell activity and CTL activity increased significantly compared with that of mixture/LacZ, fusion/LacZ, DC/LacZ, or C1300/LacZ.
16517711	Breast Carcinoma	IGF1R	Inhibit immunity (T cell function); immunotherapy target	Immunization with murine breast cancer cells treated with antisense oligodeoxynucleotides to type I insulin-like growth factor receptor induced an antitumoral effect mediated by a CD8+ response involving Fas/Fas ligand cytotoxic pathway.
16517708	Head and Neck Squamous Cell Carcinoma	TAP1	Promote immunity (T cell function)	First, lack of recognition of SCCHN cells by CTL is associated with marked down-regulation of the IFN-gamma-inducible APM components low-m.w. protein 2, TAP1, TAP2, and tapasin.
16517708	Head and Neck Squamous Cell Carcinoma	TAP2	Promote immunity (T cell function)	First, lack of recognition of SCCHN cells by CTL is associated with marked down-regulation of the IFN-gamma-inducible APM components low-m.w. protein 2, TAP1, TAP2, and tapasin.
16517708	Head and Neck Squamous Cell Carcinoma	TAPBP	Promote immunity (T cell function)	First, lack of recognition of SCCHN cells by CTL is associated with marked down-regulation of the IFN-gamma-inducible APM components low-m.w. protein 2, TAP1, TAP2, and tapasin.
16517708	Head and Neck Squamous Cell Carcinoma	IFNG	Promote immunity (T cell function)	First, lack of recognition of SCCHN cells by CTL is associated with marked down-regulation of the IFN-gamma-inducible APM components low-m.w. protein 2, TAP1, TAP2, and tapasin. Furthermore, the regulatory nature of the APM defects in SCCHN cells suggests that intralesional administration of IFN-gamma may have a beneficial effect on the clinical course of the disease and on T cell-based immunotherapy of SCCHN by restoring SCCHN cell recognition by CTL.
16516282	Vulvar Intraepithelial Neoplasia	CD1A	Promote immunity (T cell function)	Reduction in CD1a expression may reflect the inability of the host to mount an adequate immune response due to reduced antigen presentation in high grade VIN.
16510582	Glioma	IL23A	Promote immunity (T and NK cell function)	Interleukin-23-expressing bone marrow-derived neural stem-like cells exhibit antitumor activity against intracranial glioma. Depletion of subpopulation lymphocytes showed that CD8(+) T cells were critical for the antitumor immunity of IL-23-expressing BM-NSCs and that CD4(+) T cells and natural killer (NK) cells participated in the activity. Furthermore, the IL-23-expressing BM-NSC-treated survivors were resistant to the same tumor rechallenge associated with enhanced IFN-gamma, but not IL-17, expression in the brain tissue.
16497972	Plasma Cell Myeloma	TYMP	Inhibit immunity	Identification of the angiogenic endothelial-cell growth factor-1/thymidine phosphorylase as a potential target for immunotherapy of cancer. We isolated tumor-reactive cytotoxic CD8(+) T-cell (CTL) clones from a patient successfully treated with donor lymphocyte infusion for relapsed multiple myeloma after allogeneic HLA-matched SCT. Because solid tumors expressing ECGF-1 could also be lysed by the CTL, ECGF-1 is an interesting target for immunotherapy of both hematologic and solid tumors.
16493048	Melanoma	CXCL12	Inhibit immunity (T cell function)	Murine B16 melanomas expressing high levels of the chemokine stromal-derived factor-1/CXCL12 induce tumor-specific T cell chemorepulsion and escape from immune control. We proposed that repulsion of tumor Ag-specific T cells from a tumor expressing high levels of CXCL12 allows the tumor to evade immune control.
16489098	Breast Carcinoma	PTGS2	Inhibit immunity	The cyclooxygenase-2 (PTGS2) 8473T>C polymorphism is associated with breast cancer risk. Cyclooxygenase-2 (COX-2) is involved in carcinogenesis, immune response suppression, apoptosis inhibition, angiogenesis, and tumor cell invasion and metastasis.
16489048	Melanoma; hepatocellular carcinoma	GPC3	Promote immunity (T cell function); essential for immunotherapy	Embryonic stem cell-derived dendritic cells expressing glypican-3, a recently identified oncofetal antigen, induce protective immunity against highly metastatic mouse melanoma, B16-F10. The depletion experiments and immunohistochemical analyses suggest that both CD8+ and CD4+ T cells contributed to the observed antitumor effect. Human dendritic cells expressing glypican-3 would be a promising means for therapy of melanoma and hepatocellular carcinoma.
16489031	Glioblastoma	PTPRB	Inhibit immunity	Targeting of the receptor protein tyrosine phosphatase beta with a monoclonal antibody delays tumor growth in a glioblastoma model.
16488193	Bronchogenic Carcinoma	TNF	Promote immunity; increase the efficacy of immunotherapy	Blockade of TNF-alpha decreases both inflammation and efficacy of intrapulmonary Ad.IFNbeta immunotherapy in an orthotopic model of bronchogenic lung cancer.
28783722	Melanoma	B2M	Promote immunity (T cell function); essential for immunotherapy	For example, loss-of-function mutations in β -2-microglobulin (B2M) and Janus kinases (JAK1 and JAK2) have been reported in patients unresponsive to immunotherapies.; We observed that the reduction in the overall survival of these patients was significantly associated with loss of expression of B2M and TAP1 in tumours biopsied before ipilimumab treatment.; On the basis of our initial optimization of the 2CT-CRISPR assay, we expected that genes directly associated with MHC class I antigen processing and presentation would be enriched in our screens, and found that HLA-A, B2M, TAP1, TAP2, and TAPBP were among the most highly-enriched genes in our screen. Significant resistance was detected in the cells transduced with B2M sgRNAs (72 ± 5%) and with TAP2 sgRNAs (13 ± 2%) against the cytolytic activity of ESO T cells. Loss of expression of these 19 genes within tumours could diminish or extinguish the presentation of tumour antigens (including HLA-A, HLA-F, B2M, TAP1 and TAP2); T cell co- stimulation (ICAM1, CLECL1, LILRA1 and LILRA3); or cytokine production and signalling (JAK2 and STAT1) in the tumour microenvironment that drive infiltration and activation of T cells, and thus serve as a principal mechanism in immune evasion.
28783722	Melanoma	JAK1	Promote immunity (T cell function); essential for immunotherapy	For example, loss-of-function mutations in β -2-microglobulin (B2M) and Janus kinases (JAK1 and JAK2) have been reported in patients unresponsive to immunotherapies. We show that APLNR interacts with JAK1, modulating interferon-γ responses in tumours, and that its functional loss reduces the efficacy of adoptive cell transfer and checkpoint blockade immunotherapies in mouse models.
28783722	Melanoma	JAK2	Promote immunity (T cell function); essential for immunotherapy	For example, loss-of-function mutations in β -2-microglobulin (B2M) and Janus kinases (JAK1 and JAK2) have been reported in patients unresponsive to immunotherapies.; Loss of expression of these 19 genes within tumours could diminish or extinguish the presentation of tumour antigens (including HLA-A, HLA-F, B2M, TAP1 and TAP2); T cell co- stimulation (ICAM1, CLECL1, LILRA1 and LILRA3); or cytokine production and signalling (JAK2 and STAT1) in the tumour microenvironment that drive infiltration and activation of T cells, and thus serve as a principal mechanism in immune evasion.
28783722	Melanoma	TAP1	Promote immunity (T cell function); essential for immunotherapy	We observed that the reduction in the overall survival of these patients was significantly associated with loss of expression of B2M and TAP1 in tumours biopsied before ipilimumab treatment. Loss of expression of these 19 genes within tumours could diminish or extinguish the presentation of tumour antigens (including HLA-A, HLA-F, B2M, TAP1 and TAP2); T cell co- stimulation (ICAM1, CLECL1, LILRA1 and LILRA3); or cytokine production and signalling (JAK2 and STAT1) in the tumour microenvironment that drive infiltration and activation of T cells, and thus serve as a principal mechanism in immune evasion.
28783722	Melanoma	HLA-A	Promote immunity (T cell function); essential for immunotherapy	On the basis of our initial optimization of the 2CT-CRISPR assay, we expected that genes directly associated with MHC class I antigen processing and presentation would be enriched in our screens, and found that HLA-A, B2M, TAP1, TAP2, and TAPBP were among the most highly-enriched genes in our screen
28783722	Melanoma	TAP2	Promote immunity (T cell function); essential for immunotherapy	On the basis of our initial optimization of the 2CT-CRISPR assay, we expected that genes directly associated with MHC class I antigen processing and presentation would be enriched in our screens, and found that HLA-A, B2M, TAP1, TAP2, and TAPBP were among the most highly-enriched genes in our screen.Significant resistance was detected in the cells transduced with B2M sgRNAs (72 ± 5%) and with TAP2 sgRNAs (13 ± 2%) against the cytolytic activity of ESO T cells. Loss of expression of these 19 genes within tumours could diminish or extinguish the presentation of tumour antigens (including HLA-A, HLA-F, B2M, TAP1 and TAP2); T cell co- stimulation (ICAM1, CLECL1, LILRA1 and LILRA3); or cytokine production and signalling (JAK2 and STAT1) in the tumour microenvironment that drive infiltration and activation of T cells, and thus serve as a principal mechanism in immune evasion.
28783722	Melanoma	TAPBP	Promote immunity (T cell function); essential for immunotherapy	On the basis of our initial optimization of the 2CT-CRISPR assay, we expected that genes directly associated with MHC class I antigen processing and presentation would be enriched in our screens, and found that HLA-A, B2M, TAP1, TAP2, and TAPBP were among the most highly-enriched genes in our screen
28783722	Melanoma	SOX10	Promote immunity (T cell function); essential for immunotherapy	In addition, many genes without an established connection to the EFT were ranked amongst the top 20 enriched genes in this genome-scale analysis, such as SOX10, CD58, MLANA, PSMB5, RPL23 and APLNR. Fifteen genes showed significant resistance to T-cell-mediated cytolysis with at least 1 sgRNA in these cells.
28783722	Melanoma	CD58	Promote immunity (T cell function); essential for immunotherapy	In addition, many genes without an established connection to the EFT were ranked amongst the top 20 enriched genes in this genome-scale analysis, such as SOX10, CD58, MLANA, PSMB5, RPL23 and APLNR. Fifteen genes showed significant resistance to T-cell-mediated cytolysis with at least 1 sgRNA in these cells.
28783722	Melanoma	MLANA	Promote immunity (T cell function); essential for immunotherapy	In addition, many genes without an established connection to the EFT were ranked amongst the top 20 enriched genes in this genome-scale analysis, such as SOX10, CD58, MLANA, PSMB5, RPL23 and APLNR. Fifteen genes showed significant resistance to T-cell-mediated cytolysis with at least 1 sgRNA in these cells.
28783722	Melanoma	PSMB5	Promote immunity (T cell function); essential for immunotherapy	In addition, many genes without an established connection to the EFT were ranked amongst the top 20 enriched genes in this genome-scale analysis, such as SOX10, CD58, MLANA, PSMB5, RPL23 and APLNR. Fifteen genes showed significant resistance to T-cell-mediated cytolysis with at least 1 sgRNA in these cells.
28783722	Melanoma	RPL23	Promote immunity (T cell function); essential for immunotherapy	In addition, many genes without an established connection to the EFT were ranked amongst the top 20 enriched genes in this genome-scale analysis, such as SOX10, CD58, MLANA, PSMB5, RPL23 and APLNR. Fifteen genes showed significant resistance to T-cell-mediated cytolysis with at least 1 sgRNA in these cells.; MART-1+ Mel624 cells with sgRNAs targeting each of the 9 candidate genes showed increased resistance against these T cells (Extended Data Fig. 6b, P < 0.05). The genes that we validated across different melanoma cell lines and different antigen–TCR combinations include cellular cytoskeleton genes, COL17A1 (collagen type XVII alpha 1) and TWF1 (twinfilin-1), a microRNA (hsa-mir-101-2) and a 60S ribosomal subunit (RPL23, Supplementary Discussion).
28783722	Melanoma	APLNR	Promote immunity; essential for immunotherapy	We show that APLNR interacts with JAK1, modulating interferon-γ responses in tumours, and that its functional loss reduces the efficacy of adoptive cell transfer and checkpoint blockade immunotherapies in mouse models.
28783722	Melanoma	STAT1	Promote immunity (T cell function); essential for immunotherapy	Loss of expression of these 19 genes within tumours could diminish or extinguish the presentation of tumour antigens (including HLA-A, HLA-F, B2M, TAP1 and TAP2); T cell co- stimulation (ICAM1, CLECL1, LILRA1 and LILRA3); or cytokine production and signalling (JAK2 and STAT1) in the tumour microenvironment that drive infiltration and activation of T cells, and thus serve as a principal mechanism in immune evasion.
28783722	Melanoma	HLA-A	Promote immunity (T cell function); essential for immunotherapy	Loss of expression of these 19 genes within tumours could diminish or extinguish the presentation of tumour antigens (including HLA-A, HLA-F, B2M, TAP1 and TAP2); T cell co- stimulation (ICAM1, CLECL1, LILRA1 and LILRA3); or cytokine production and signalling (JAK2 and STAT1) in the tumour microenvironment that drive infiltration and activation of T cells, and thus serve as a principal mechanism in immune evasion.
28783722	Melanoma	HLA-F	Promote immunity (T cell function); essential for immunotherapy	Loss of expression of these 19 genes within tumours could diminish or extinguish the presentation of tumour antigens (including HLA-A, HLA-F, B2M, TAP1 and TAP2); T cell co- stimulation (ICAM1, CLECL1, LILRA1 and LILRA3); or cytokine production and signalling (JAK2 and STAT1) in the tumour microenvironment that drive infiltration and activation of T cells, and thus serve as a principal mechanism in immune evasion.
28783722	Melanoma	ICAM1	Promote immunity (T cell function); essential for immunotherapy	Loss of expression of these 19 genes within tumours could diminish or extinguish the presentation of tumour antigens (including HLA-A, HLA-F, B2M, TAP1 and TAP2); T cell co- stimulation (ICAM1, CLECL1, LILRA1 and LILRA3); or cytokine production and signalling (JAK2 and STAT1) in the tumour microenvironment that drive infiltration and activation of T cells, and thus serve as a principal mechanism in immune evasion.
28783722	Melanoma	CLECL1	Promote immunity (T cell function); essential for immunotherapy	Loss of expression of these 19 genes within tumours could diminish or extinguish the presentation of tumour antigens (including HLA-A, HLA-F, B2M, TAP1 and TAP2); T cell co- stimulation (ICAM1, CLECL1, LILRA1 and LILRA3); or cytokine production and signalling (JAK2 and STAT1) in the tumour microenvironment that drive infiltration and activation of T cells, and thus serve as a principal mechanism in immune evasion.
28783722	Melanoma	LILRA1	Promote immunity (T cell function); essential for immunotherapy	Loss of expression of these 19 genes within tumours could diminish or extinguish the presentation of tumour antigens (including HLA-A, HLA-F, B2M, TAP1 and TAP2); T cell co- stimulation (ICAM1, CLECL1, LILRA1 and LILRA3); or cytokine production and signalling (JAK2 and STAT1) in the tumour microenvironment that drive infiltration and activation of T cells, and thus serve as a principal mechanism in immune evasion.
28783722	Melanoma	LILRA3	Promote immunity (T cell function); essential for immunotherapy	Loss of expression of these 19 genes within tumours could diminish or extinguish the presentation of tumour antigens (including HLA-A, HLA-F, B2M, TAP1 and TAP2); T cell co- stimulation (ICAM1, CLECL1, LILRA1 and LILRA3); or cytokine production and signalling (JAK2 and STAT1) in the tumour microenvironment that drive infiltration and activation of T cells, and thus serve as a principal mechanism in immune evasion.
28783722	Melanoma	SRP54	Promote immunity (T cell function)	Fifteen genes showed significant resistance to T-cell-mediated cytolysis with at least 1 sgRNA in these cells.
28783722	Melanoma	PTCD2	Promote immunity (T cell function)	We targeted each gene in NY-ESO-1+ melanoma cells, Mel624 and A375, with four sgRNAs and individually measured resistance against ESO-T cells. Fifteen genes showed significant resistance to T cell-mediated cytolysis with at least 1 sgRNA in these cells.
28783722	Melanoma	TAPBP	Promote immunity (T cell function)	Fifteen genes showed significant resistance to T-cell-mediated cytolysis with at least 1 sgRNA in these cells.
28783722	Melanoma	TWF1	Promote immunity (T cell function)	Fifteen genes showed significant resistance to T-cell-mediated cytolysis with at least 1 sgRNA in these cells.; MART-1+ Mel624 cells with sgRNAs targeting each of the 9 candidate genes showed increased resistance against these T cells (Extended Data Fig. 6b, P < 0.05). The genes that we validated across different melanoma cell lines and different antigen–TCR combinations include cellular cytoskeleton genes, COL17A1 (collagen type XVII alpha 1) and TWF1 (twinfilin-1), a microRNA (hsa-mir-101-2) and a 60S ribosomal subunit (RPL23, Supplementary Discussion).
28783722	Melanoma	COL17A1	Promote immunity (T cell function)	Fifteen genes showed significant resistance to T-cell-mediated cytolysis with at least 1 sgRNA in these cells.; MART-1+ Mel624 cells with sgRNAs targeting each of the 9 candidate genes showed increased resistance against these T cells (Extended Data Fig. 6b, P < 0.05). The genes that we validated across different melanoma cell lines and different antigen–TCR combinations include cellular cytoskeleton genes, COL17A1 (collagen type XVII alpha 1) and TWF1 (twinfilin-1), a microRNA (hsa-mir-101-2) and a 60S ribosomal subunit (RPL23, Supplementary Discussion).
28783722	Melanoma	DEFB134	Promote immunity (T cell function)	Fifteen genes showed significant resistance to T-cell-mediated cytolysis with at least 1 sgRNA in these cells.
28723893	Melanoma	CD47	Inhibit immunity; decrease the efficacy of immunotherapy	To confirm that CD47null tumours were more susceptible to GVAX and PD-1 blockade, we generated CD47-null B16 melanoma cells using transient transfection of a Cas9-sgRNA plasmid (Extended Data Fig. 2a) and found that loss of CD47 significantly improved control of tumour growth mediated by GVAX and anti-PD-1 immunotherapy (Extended Data Fig. 2b, P < 0.01). Therefore, in vivo genetic screening recovered genes known to confer immune evasion properties on cancer cells.
28723893	Melanoma	STAT1	Promote immunity; increase the efficacy of immunotherapy	We confirmed this finding in an in vivo competitive assay that compared the relative growth of mixtures of isogenic Stat1-null or control B16 cells in animals treated with immunotherapy (Fig. 1f). In wild-type mice treated with GVAX and anti-PD-1 immunotherapy, the relative proportion of Stat1-null cells increased significantly (Fig. 1g, h; P < 0.01, Student’s t-test), suggesting that Stat1-null cells have a marked growth advantage over wild-type tumour cells when under immune attack.
28723893	Melanoma	JAK1	Promote immunity; increase the efficacy of immunotherapy	We confirmed this finding in an in vivo competitive assay that compared the relative growth of mixtures of isogenic Stat1-null or control B16 cells in animals treated with immunotherapy (Fig. 1f). In wild-type mice treated with GVAX and anti-PD-1 immunotherapy, the relative proportion of Stat1-null cells increased significantly (Fig. 1g, h; P < 0.01, Student’s t-test), suggesting that Stat1-null cells have a marked growth advantage over wild-type tumour cells when under immune attack. Similar results were obtained for Jak1-null and Ifngr1-null cells (Fig. 1h).
28723893	Melanoma	IFNAR1	Promote immunity; increase the efficacy of immunotherapy	We confirmed this finding in an in vivo competitive assay that compared the relative growth of mixtures of isogenic Stat1-null or control B16 cells in animals treated with immunotherapy (Fig. 1f). In wild-type mice treated with GVAX and anti-PD-1 immunotherapy, the relative proportion of Stat1-null cells increased significantly (Fig. 1g, h; P < 0.01, Student’s t-test), suggesting that Stat1-null cells have a marked growth advantage over wild-type tumour cells when under immune attack. Similar results were obtained for Jak1-null and Ifngr1-null cells (Fig. 1h).
28723893	Bladder carcinoma, head and neck squamous cell carcinoma, lung carcinoma, melanoma	STUB1	Inhibit immunity (T cell function); decrease the efficacy of immunotherapy	These genes were Ptpn2, a phosphatase involved in multiple signalling processes; H2-T23, a non-classical MHC-I gene; Ripk1, a kinase that regulates cell death and inflammation; and Stub1, an E3 ubiquitin ligase involved in the regulation of the unfolded protein response. In vivo competition assays showed that tumour cells deleted of each of the four genes were strongly selected against in wild-type animals treated with immunotherapy, but grew at equivalent rates to control tumour cells in vitro and in Tcra?/? mice (Fig. 2b, c; P < 0.01, Student’s t-test). This suggests that loss of function of these genes renders tumour cells more sensitive to immunotherapy, but does not alter their cell growth or survival in the absence of T cells.
28365507	Prostate carcinoma; colorectal carcinoma; pancreatic carcinoma; cervical carcinoma; gastric carcinoma; ovarian carcinoma; head and neck neoplasm; lung carcinoma	IDO1	Inhibit immunity (T cell function); resistant to immunotherapy	In clinicopathologic study, a series ofhuman tumors including prostatic, colorectal, pancreatic, cervical, gastric, ovarian, head, lung, etc. over-express human IDO1 in a constitutive way. Overexpression of IDO1 leads to three downstream alterations that reduces sensitivity to immunotherapy. Firstly, overexpresson of IDO1 accelerated Tryptophan metabolism, leading to activation of GCN2 stress kinase pathway, increasing IL-6 and CCL2, as well as activation of mTOR pathway. These cause cell cycle arrest and autophagy of cytotoxic T cells, also downregulate TCR ζ chain of T cell to indirectly cause T cell anergy and thus affect immune cells, such as CD8+ T cells, NK cells and NK-T cells, through cytotoxic and cytostatic effects. Secondly, overexpression of IDO1 increases Kynurenine metabolite production, first leading to activation of AhR endogenous ligands to inhibit TH17 cell differentiation, then also inhibit effector T cell survival. Elevated toxic Kynurenine also selectively induces TH1 and thymocyte apoptosis as well as favouring T reg cell differentiation. Through CTLA-4 interaction of T reg cell with DCs, it helps suppression of effector T responses. Furthermore, IDO-expressing DCs also inhibit T cell activation via bystander suppression. On the other hand, increased Kynurenine production regulate NK cell function by two independent ways. Firstly, altering the expression and function of NKp46 triggering recptor and NKG2D triggering recptor. Secondly, reducing NK cytokine production, such as IFN-γ and TNF-α. Lastly, overexpression of IDO1 with the presence of high expression level of HLA-E could lead to downregulation of NKG2C activating recptor, thus enhance the binding to NKG2C inhibitory receptor. Thus, overexpression of IDO1 in tumors reduces the sensitivity and effectiveness of T cell, correlating to por prognosis and reduced survival of patients.
29372378	Retinoblastoma	SYK	Promote immunity (T cell function)	However, SYK-DC-CTLs could target SYK overexpressed hTERT-RPE1 cells, suggesting that SYK is a specific antigen for RB. SYK serves as a specific marker for Retinoblastoma. Overexpression of SYK in Retinoblastoma cells leads to dendritic cell mediated cytotoxic T lymphocytes cytotoxicity.
29213088	Head and neck squamous cell carcinoma; Squamous cell lung carcinoma; Sotos syndrome	NSD1	Promote immunity (T cell function)	Further, the NSD1 subtype of HNSC displays an ‘immune cold’ phenotype characterized by low infiltration of tumor-associated leukocytes, particularly macrophages and CD8+ T cells, as well as low expression of genes encoding the immunotherapy target PD-1 immune checkpoint receptor and its ligands. Using an in vivo model, we demonstrate that NSD1 inactivation results in reduced T cell infiltration into the tumor microenvironment, implicating NSD1 as a tumor cell-intrinsic driver of an immune cold phenotype. Choufani et al. reported that germline NSD1 mutations are associated with widespread perturbation (primarily loss) of DNA methylation, i.e., methylation of cytosine to form 5-methylcytosine at CpG dinucleotides. NSD1 is not thought to methylate DNA; therefore H3K36me (or other histone marks) catalyzed by NSD1 apparently regulate DNA methylation. Inactivating mutations of NSD1 also deregulate DNA methylation in HNSC, as we and others have described a HNSC subtype characterized by widespread DNA hypomethylation, that is strongly enriched for NSD1 mutations. Inactivation mutation of NSD1 in head and neck squamous cell carcinoma shows low infiltration of macrophages and CD8+ cytotoxic T cell into tumor microenvironment in vivo, and low expression of PD-1 immune checkpoint receptor and ligand encoding genes. Thus, inactivation of NSD1 drives the immune cold phenotype, resistant to immunotherapy. Mutation of NSD1 also co-occur with worldwide hypomethylation of DNA in various cancers.
28905118	Lymphoma	CTLA4	Immunotherapy target	Overall intratumoral or peri-tDLN administration of the novel combination of anti-CTLA4, anti-CD137, and anti-OX40, all agents in the clinic or clinical trials, demonstrates potent systemic anti-tumor effects. This immunotherapeutic combination is promising for future clinical development via both these safe and highly efficacious routes of administration.
28905118	Lymphoma	TNFRSF9	Immunotherapy target	Overall intratumoral or peri-tDLN administration of the novel combination of anti-CTLA4, anti-CD137, and anti-OX40, all agents in the clinic or clinical trials, demonstrates potent systemic anti-tumor effects. This immunotherapeutic combination is promising for future clinical development via both these safe and highly efficacious routes of administration.
28905118	Lymphoma	TNFRSF4	Immunotherapy target	Overall intratumoral or peri-tDLN administration of the novel combination of anti-CTLA4, anti-CD137, and anti-OX40, all agents in the clinic or clinical trials, demonstrates potent systemic anti-tumor effects. This immunotherapeutic combination is promising for future clinical development via both these safe and highly efficacious routes of administration.
28723893	Melanoma; lung carcinoma; colon carcinoma	PTPN2	Inhibit immunity; resistant to immunotherapy	Tumours were sensitized to immunotherapy by deletion of genes involved in several diverse pathways, including NF-κB signalling, antigen presentation and the unfolded protein response. Loss of PTPN2 lead to alteration in NK-kB signaling, antigen presentaion and unfolded protein reponse, thus, sensitive to immunotherapy.
28630682	Uterine carcinosarcoma; synovial sarcoma; multifocal leiomyosarcoma.	PRAME	Inhibit immunity (T cell function); resistant to immunotherapy	We found that uterine carcinosarcoma highly overexpresses the PRAME antigen, and synovial sarcomas and multifocal leiomyosarcomas also show high expressions suggesting that PRAME may be an effective target of immunotherapies of these tumors. However, we also discovered that PRAME expression negatively correlates with genes involved in antigen presentation, and in synovial sarcoma MHC class I antigen presentation deficiencies are also present, potentially limiting the efficacy of immunotherapies of this malignancy. Overexpression of PRAME negatively correlates to expression of genes in antigen presentation, and correlates to MHC class I antigen presentation deficiencies in synovial sarcoma.
27987020	Breast carcinoma	HMGB1	Inhibit immunity (T and NK cell function); immunotherapy target	Previous data indicate that high mobility group box 1(HMGB1) facilitates MDSC differentiation from bone marrow, suppresses NK cells, CD4+ and CD8+ T cells and is involved in cancer development. HMGB1 blockade by a monoclonal antibody against the HMGB1 B box obviously reduced the accumulation of M-MDSC in tumor-bearing mice, delaying tumor growth and development; additionally, Overepression of HMGB1 alter immune responses by suppressing NK cells, CD4+ and CD8+ T cells, and participate in cancer development. Monoclonal antibody targeting HMGB1 delay tumor growth and development, thus could be a possible immunotherapy target for breast carcinoma. MDSC expansion and HMGB1 up-regulation were also found in breast cancer patients. All these data indicate that HMGB1 might be a potential tumor immunotherapy target.
27865385	Tuberculosis	PDCD1	Inhibit immunity (T cell function)	Decreased expression of PD-1 in Tresp and Teff cells in tuberculosis patient showed increased sensitivitiy to anti-TB therapy. Finally, clinical improvement following effective anti-TB therapy is correlated with significantly decreased expression of PD-1 in Tresp and Teff cells, but not in Treg cells.
27721577	Cervical carcinoma	PDCD1	Inhibit immunity	In summary, our findings demonstrate that elevated levels of PD-1/PD-L1, TGF-β, and IL-10 in peripheral blood of cervical cancer patients may negatively regulate immune response against cervical cancer cells and contribute to the progression of cervical cancer.
27721577	Cervical carcinoma	CD274	Inhibit immunity	In summary, our findings demonstrate that elevated levels of PD-1/PD-L1, TGF-β, and IL-10 in peripheral blood of cervical cancer patients may negatively regulate immune response against cervical cancer cells and contribute to the progression of cervical cancer.
26327203	Endometrioids, malignant mixed Mullerian tumor	ASTL	Inhibit immunity	SAS1B is a potential immunotherapy target for uterine tumors. Targeting of SAS1B help to arrest cell and cause cell death. Gene-specific PCR and immunohistochemical studies revealed ASTL messages and SAS1B protein in both endometrioid [74%] and malignant mixed Mullerian tumors (MMMT) [87%] of the uterus. Treatment of SNU539 cells with anti-SAS1B polyclonal antibodies caused growth arrest in the presence of active complement. A saporin-immunotoxin directed to SAS1B induced growth arrest and cell death.
25964311	Glioblastoma	CD274	Inhibit immunity	Earlier evidence suggested that PD-L1 expression may contribute to immunoresistance of human glioblastoma cells via activation of the PI3K/mTOR pathway and that loss of PTEN function appeared to change the level of PD-L1 expression. PD-L1 is a potential immunotherapy target.
22431037	Oral squamous cell carcinoma	MICA	Promote immunity; essential for immunotherapy	MICA gene modified Tb tumor vaccine resulted in remarkable loss of tumor size and tumor weight in vaccinated Hu-PBL/SCID mice. Flow cytometry and lactate dehydrogenase (LDH) release assay showed MICA gene modified Tb tumor vaccine up-regulated the expression of NKG2D on PBMC and spleen cells and enhanced the cytotoxicity to tumor cells. MICA gene modified oral squamous cell carcinoma vaccine can enhance the ability of antitumor immune response,and MICA may be considered as a promising immunotherapy target of oral squamous cell carcinoma.
22418702	Triple-negative breast carcinoma	MSLN	Promote immunity (T cell function); essential for immunotherapy	MSLN is expressed in majority of triple negative breast carcinoma, while very rare in positive breast cancer. Application of CAR T modified to express MSLN-specific chimeric antibody receptor exert higher anti-tumor cytotoxicity than non-transduced T cells, suggesting that MSLN is a novel immunotherapy target. Therefore, we screened 99 primary breast cancer samples by immunohistochemistry analysis using formalin-fixed paraffin-embedded archival tumor tissues and confirmed that mesothelin was overexpressed in the majority of TNBC (67 %) but only rarely in <5 % ER(+) or Her2-neu(+) breast cancer, respectively. A significantly higher anti-tumor cytotoxicity by mesoCAR T cells was observed (31.7 vs. 8.7 %, p < 0.001). Our results suggest that mesothelin has promise as a novel immunotherapy target for TNBC for which effective targeted therapy is lacking to date.
22389962	Oral squamous cell carcinoma	MICA	Promote immunity (T and NK cell function)	Flow cytometry and LDH release assay showed that MICA-overexpressed OSCC cells enhanced the cytotoxicity to target tumor cells and up-regulated the expression of NKG2D on NK92 and CTL (P<0.05).
29443964	Colorectal carcinoma, hepatocellular carcinoma	TGFB1	Inhibit immunity (T cell function); immunotherapy target	Instead, particular features of the tumour microenvironment, such as lack of T-cell infiltration, low type 1 T-helper cell (TH1) activity and reduced immune cytotoxicity or increased TGFβ levels predict adverse outcomes in patients with colorectal cancer. In mice with progressive liver metastatic disease, blockade of TGFβ signalling rendered tumours susceptible to anti-PD-1-PD-L1 therapy. Immunotherapies directed against TGFβ signalling may therefore have broad applications in treating patients with advanced colorectal cancer.
29443960	Urethral urothelial carcinoma	TGFB1	Inhibit immunity (T cell function); immunotherapy target	Lack of response was associated with a signature of transforming growth factor β (TGFβ) signalling in fibroblasts. This occurred particularly in patients with tumours, which showed exclusion of CD8+ T cells from the tumour parenchyma that were instead found in the fibroblast- and collagen-rich peritumoural stroma; a common phenotype among patients with metastatic urothelial cancer. Using a mouse model that recapitulates this immune-excluded phenotype, we found that therapeutic co-administration of TGFβ-blocking and anti-PD-L1 antibodies reduced TGFβ signalling in stromal cells, facilitated T-cell penetration into the centre of tumours, and provoked vigorous anti-tumour immunity and tumour regression.
28714960	Non-small cell lung carcinoma	BIN1	Promote immunity (infiltration and T cell function)	BIN1 is frequently attenuated or even silenced in human tumors including melanoma, breast, prostate, bladder and lung cancers. In the present study, we observed that there exists a negative correlation between the expression of PD-L1 and BIN1 in NSCLC tissues. The expression levels of BIN1 and PD-L1 were significantly related to the tumor, lymph node and metastasis grade (TNM) stage, invasion range and lymph node metastasis. Simultaneously, for NSCLC patients, the expression statuses of BIN1 and PD-L1 might be independent prognostic factors. Furthermore, the expression of tumor-infiltrating lymphocytes was positively associated with BIN1 expression and negatively related to PD-L1 expression in NSCLC tissues. Importantly, we showed that PD-L1 was under the control of BIN1. Bridging integrator-1 (BIN1) is a MYC-interacting adaptor protein that has features of a tumor suppressor. In addition, the overexpression of BIN1 could inhibit the c-MYC and epithelial growth factor receptor (EGFR)-dependent PD-L1 expression and reverse the suppressive immuno-microenvironment in vivo.
29279355	Hepatocellular carcinoma, ovarian adenocarcinoma	GADD45B	Inhibit immunity (infiltration); immunotherapy target	In various models of solid cancers refractory to immunotherapies, including hepatocellular carcinoma and ovarian adenocarcinoma, Gadd45b inhibition in myeloid cells restored activation of proinflammatory tumor-associated macrophages (TAM) and intratumoral immune infiltration, thereby diminishing oncogenesis.
28228279	Uterine leiomyosarcoma	PTEN	Promote immunity; increase the efficacy of immunotherapy	In summary, immunohistochemical, whole-exome, and whole-transcriptome analyses of pre-treatment and treatment-resistant tumors from one patient have identified PTEN loss and changes in neoantigen expression as potential clinical mechanisms of acquired resistance to immune checkpoint therapy, although further experimental work in mesenchymal tumors is needed.
29263152	Triple-negative breast carcinoma	MUC1	Inhibit immunity (T cell function)	The immune checkpoint ligand PD-L1 and the transmembrane mucin MUC1 are upregulated in triple-negative breast cancer (TNBC), where they contribute to its aggressive pathogenesis. Here, we report that genetic or pharmacological targeting of the oncogenic MUC1 subunit MUC1-C is sufficient to suppress PD-L1 expression in TNBC cells. Mechanistic investigations showed that MUC1-C acted to elevate PD-L1 transcription by recruitment of MYC and NF-κB p65 to the PD-L1 promoter. In an immunocompetent model of TNBC in which Eo771/MUC1-C cells were engrafted into MUC1 transgenic mice, we showed that targeting MUC1-C associated with PD-L1 suppression, increases in tumor-infiltrating CD8+ T cells and tumor cell killing. MUC1 expression in TNBCs also correlated inversely with CD8, CD69, and GZMB, and downregulation of these markers associated with decreased survival.
29195074	Non-small cell lung carcinoma	MYC	Inhibit immunity (T and NK cell function); immunotherapy target	MYC is an oncogene. Co-activation of MYC and KRAS promotes CCL9 and IL-23 which enhances recruitment of macrophage, angiogenesis PD-L1-dependent exclusion of T and B cells, exclusion of adaptive T and B cells and NK cells. Thus, promotes inflammation, angiogenesis and immune suppression. Inhibition of MYC reverse immunosuppression and promotes tumor regression via promotion of return of NK cells.
28939663	Hepatocellular carcinoma	CDK20	Inhibit immunity (T cell function); decrease the efficacy of immunotherapy	Concordant overexpression of CCRK and MDSC markers (CD11b/CD33) positively correlated with poorer survival rates. Hepatocellular CCRK stimulated immunosuppressive CD11b+CD33+HLA-DR? MDSC expansion from human peripheral blood mononuclear cells through upregulating IL-6. Mechanistically, CCRK activated nuclear factor-κB (NF-κB) via enhancer of zeste homolog 2 (EZH2) and facilitated NF-κB-EZH2 co-binding to IL-6 promoter. Hepatic CCRK induction in TG mice activated the EZH2/NF-κB/IL-6 cascade, leading to accumulation of polymorphonuclear (PMN) MDSCs with potent T cell suppressive activity. Notably, tumorous Ccrk depletion upregulated PD-L1 expression and increased intratumorous CD8+ T cells, thus enhancing PD-L1 blockade efficacy to eradicate HCC.
29309058	Prostate carcinoma	PTEN	Inhibit immunity (infiltration)	Loss of PTEN with loss of ZBTB7A or loss of PTEN with loss of TRP53 in mice showed enhanced Gr-1+CD11b+ MDSCs cells infiltration, and recruited T cells and M2-like marcophage. Thus, could promote immune evasion. However, loss of PTEN with loss of PML in mice does not increase immune infiltration. The evasion effect is combination dependent. The Ptenpc?/?; Pmlpc?/? tumors still had limited immune infiltrate, whereas the Ptenpc?/?; Zbtb7apc?/? immunological landscape was dominated by Gr-1+CD11b+ cells. The Gr-1+CD11b+ population was also elevated in Ptenpc?/?; Trp53pc?/? mice, and there was a marked recruitment of T cells and macrophages. Interestingly, further analysis revealed that most macrophages had an M2-like phenotype (CD11b+F4/80+CD206+) and that the increase in CD3+ cells reflected the recruitment of CD4+FoxP3+ T regulatory (Treg) cells, thus defining a potentially favorable microenvironment for cancer immunological evasion.
16482562	Renal Cell Carcinoma; Melanoma	CD274	Inhibit immunity (T cell function); immunotherapy target	Blockade of PD-L1 (B7-H1) augments human tumor-specific T cell responses in vitro. We found PD-L1 to be constitutively expressed on human renal cell carcinoma (RCC) cell lines and upregulated on human melanoma cell lines upon exposure to interferon-gamma.Similar to the data achieved in the murine system, the blockade of PD-L1 on human tumors resulted in enhanced cytolytic activity of TAA-specific CTLs and cytokine production of TAA-specific T helper cells when interacting directly with the tumor.
16479544	Hodgkin Lymphoma; Nasopharyngeal Carcinoma; Primary EBV-Positive Nodal T-Cell or NK-Cell Lymphoma; Chronic Active EBV Infection of T-and NK-Cell Type, Systemic Form	PDLIM7	Promote immunity (T and NK cell function); essential for immunotherapy	Epstein-Barr virus (EBV) latent membrane protein-1-specific cytotoxic T lymphocytes targeting EBV-carrying natural killer cell malignancies. Epstein-Barr virus (EBV)-encoded latent membrane protein (LMP) 1 is a potential target for immunotherapy of some proportion of Hodgkin's disease cases, nasopharyngeal carcinomas, EBV-associated natural killer (NK)/T lymphomas, and chronic active EBV infection (CAEBV).
16474838	Uterine Corpus Leiomyosarcoma	JAK1	Promote immunity (T cell function)	The mutation in the ATP-binding region of JAK1, identified in human uterine leiomyosarcomas, results in defective interferon-gamma inducibility of TAP1 and LMP2. Tumor cells may alter the antigen presentation by HLA class I, allowing them to evade antitumor immunity. In many cases, the lack of antigen presentation can be attributed to the downregulation of genes needed for antigen processing, such as the transporters associated with antigen processing (TAP) 1, and the proteasomal component, low molecular weight proteins (LMP) 2.
16474399	Leukemia	IL15	Promote immunity (T cell function); essential for immunotherapy	Interleukin-15 rescues tolerant CD8+ T cells for use in adoptive immunotherapy of established tumors. Such proliferation abrogated tolerance and the rescued cells became effective in treating leukemia.
16467102	Small Cell Lung Carcinoma	TP53	Promote immunity (T cell function); essential for immunotherapy	Combination of p53 cancer vaccine with chemotherapy in patients with extensive stage small cell lung cancer. p53-specific T cell responses to vaccination were observed in 57.1% of patients.
16467101	Adenocarcinoma	MUC1	Promote immunity (T cell function); essential for immunotherapy	Mannan-MUC1-pulsed dendritic cell immunotherapy: a phase I trial in patients with adenocarcinoma. Immunization produced T-cell responses in all patients with evidence of tumor stabilization in 2 of the 10 advanced cancer patients treated.
16452243	Alveolar Rhabdomyosarcoma	PAX1	Promote immunity (T cell function); essential for immunotherapy	Identification and epitope enhancement of a PAX-FKHR fusion protein breakpoint epitope in alveolar rhabdomyosarcoma cells created by a tumorigenic chromosomal translocation inducing CTL capable of lysing human tumors.
16452243	Alveolar Rhabdomyosarcoma	FOXO1	Promote immunity (T cell function); essential for immunotherapy	Identification and epitope enhancement of a PAX-FKHR fusion protein breakpoint epitope in alveolar rhabdomyosarcoma cells created by a tumorigenic chromosomal translocation inducing CTL capable of lysing human tumors.
16452176	Melanoma	FCGR1A	Promote immunity; increase the efficacy of immunotherapy	The high-affinity IgG receptor, FcgammaRI, plays a central role in antibody therapy of experimental melanoma. MPL did potently boost TA99 antibody-induced effects, and combination therapy was, again, found to be dependent on the presence of FcgammaRI.
16434984	Metastatic Renal Cell Carcinoma	IL2	Promote immunity; essential for immunotherapy	Monocytes and neutrophils as 'bad guys' for the outcome of interleukin-2 with and without histamine in metastatic renal cell carcinoma--results from a randomised phase II trial. Thus, the addition of histamine may potentially improve the efficacy of interleukin-2 (IL-2). The study provides evidence that circulating monocytes and neutrophils are powerful negative prognostic factors for IL-2-based immunotherapy and establishes a biological rationale for the potential use of histamine in conjunction with IL-2 in mRCC.
16434370	Anaplastic Large Cell Lymphoma	ALK	Promote immunity	In vivo T-cell immune response against anaplastic lymphoma kinase in patients with anaplastic large cell lymphomas. Anaplastic lymphoma kinase (ALK) oncogenic fusion proteins, expressed in about 60% of anaplastic large cell lymphomas (ALCL), are tumor-specific molecular targets for such a malignancy. The high number of anti-ALK memory CD8 T cells present in patients' PBMC may represent a valid source of activated CTL suitable for cancer cell lysis.
16432832	Pancreatic carcinoma	SYCP1	Promote immunity	Serological immune response to cancer testis antigens in patients with pancreatic cancer. In conclusion, antibody response to cancer testis antigen SCP-1 is found in a proportion of pancreatic carcinoma patients.
16428502	Breast carcinoma	ERBB2	Inhibit immunity	Human T cells armed with Her2/neu bispecific antibodies divide, are cytotoxic, and secrete cytokines with repeated stimulation. In vitro, Her2Bi-armed ATC were examined for a range of functions after repeated stimulation with the Her2/neu-expressing breast cancer cell line SK-BR-3. These studies show that armed ATC are specific, durable, and highly functional T-cell populations in vitro.
16425224	Melanoma	HSPA4	Promote immunity (T/NK cell function); essential for immunotherapy	HSP70 vaccine in combination with gene therapy with plasmid DNA encoding sPD-1 overcomes immune resistance and suppresses the progression of pulmonary metastatic melanoma.
16424205	Breast Adenocarcinoma	IL21	Promote immunity	CD25+ regulatory T cell depletion augments immunotherapy of micrometastases by an IL-21-secreting cellular vaccine. In conclusion, immunotherapy of micrometastases by an IL-21-based cellular vaccine is strongly potentiated by CD25+ cell depletion.
16424173	Metastatic Renal Cell Carcinoma	IL2	Essential for immunotherapy	CXCR3/CXCR3 ligand biological axis impairs RENCA tumor growth by a mechanism of immunoangiostasis. Metastatic renal cell carcinoma (RCC) responds poorly to chemo- or radiation therapy but appears to respond to systemic immunotherapy (i.e., IL-2 and/or IFN-alpha), albeit with only 5-10% durable response. These data suggest that the combined strategy of systemic IL-2 with intratumor CXCR3 ligand is more efficacious than either strategy alone for reducing tumor-associated angiogenesis and augmenting tumor-associated immunity, the concept of immunoangiostasis.
16424173	Metastatic Renal Cell Carcinoma	IFNA1	Promote immunity	CXCR3/CXCR3 ligand biological axis impairs RENCA tumor growth by a mechanism of immunoangiostasis. Metastatic renal cell carcinoma (RCC) responds poorly to chemo- or radiation therapy but appears to respond to systemic immunotherapy (i.e., IL-2 and/or IFN-alpha), albeit with only 5-10% durable response. These data suggest that the combined strategy of systemic IL-2 with intratumor CXCR3 ligand is more efficacious than either strategy alone for reducing tumor-associated angiogenesis and augmenting tumor-associated immunity, the concept of immunoangiostasis.
16424164	Breast carcinoma	IL2	Promote immunity (NK cell function)	Murine mammary carcinoma exosomes promote tumor growth by suppression of NK cell function. We propose that tumor exosomes contribute to the growth of tumors by blocking IL-2-mediated activation of NK cells and their cytotoxic response to tumor cells.
16424054	Melanoma	HYOU1	Promote immunity	Chaperoning function of stress protein grp170, a member of the hsp70 superfamily, is responsible for its immunoadjuvant activity. In this study, we determine the ability of grp170 and its structural domains to (a) bind to and present melanoma-associated antigen gp100 to the immune system and (b) to bind to receptors on APCs. Therefore, these studies suggest that molecular chaperoning is involved in stress protein interactions with APCs, antigen binding, and in eliciting antitumor immunity, thus bridging this ancient function of stress proteins in prokaryotes to their ability to elicit immunity in higher organisms.
16424053	Melanoma	IL7R	Promote immunity (T cell function); essential for immunotherapy	Efficient induction of tumor antigen-specific CD8+ memory T cells by recombinant lentivectors. Importantly, the majority of anti-Melan-A T cells elicited by rec. lv expressed the memory marker CD127 at the peak of the primary response.
16424052	Breast carcinoma	CD80	Promote immunity (T cell function); essential for immunotherapy	Tumor cells transduced with the MHC class II Transactivator and CD80 activate tumor-specific CD4+ T cells whether or not they are silenced for invariant chain. To determine if Ii expression affects presentation of MHC class II-restricted endogenously synthesized tumor antigens in human tumor cells, HLA-DR-MCF10 breast cancer cells were transduced with the CIITA, CD80 costimulatory molecule gene, and with or without small interfering RNAs (siRNA) specific for Ii.
16424052	Breast carcinoma	CIITA	Promote immunity (T cell function); essential for immunotherapy	Tumor cells transduced with the MHC class II Transactivator and CD80 activate tumor-specific CD4+ T cells whether or not they are silenced for invariant chain. To determine if Ii expression affects presentation of MHC class II-restricted endogenously synthesized tumor antigens in human tumor cells, HLA-DR-MCF10 breast cancer cells were transduced with the CIITA, CD80 costimulatory molecule gene, and with or without small interfering RNAs (siRNA) specific for Ii.
16418292	Chronic Lymphocytic Leukemia	CD200	Inhibit immunity	We searched for cell-surface-associated proteins overexpressed on B cell chronic lymphocytic leukemia (CLL) to use as therapeutic antibody targets. Antibodies binding the immunosuppressive molecule CD200 were identified by cell panning of an antibody phage display library derived from rabbits immunized with primary CLL cells.
16404366	Colon carcinoma; Gastric carcinoma; Prostate carcinoma; Lung carcinoma	EPCAM	Inhibit immunity	Frequent high-level expression of the immunotherapeutic target Ep-CAM in colon, stomach, prostate and lung cancers.
16397267	Pancreatic carcinoma	TNF	Promote immunity (T cell function)	C57BL/6 EL-TGF-alpha x Trp53-/- mice, which develop spontaneous ductal pancreatic carcinoma, were generated. Intratumoral cytokine secretion of tumor necrosis factor-alpha, IFN-gamma, IL-6, and MCP-1 was lower in spontaneous tumors as well as the number of adoptively transferred tumor-specific T cells.
16397267	Pancreatic carcinoma	IFNG	Promote immunity (T cell function)	C57BL/6 EL-TGF-alpha x Trp53-/- mice, which develop spontaneous ductal pancreatic carcinoma, were generated. Intratumoral cytokine secretion of tumor necrosis factor-alpha, IFN-gamma, IL-6, and MCP-1 was lower in spontaneous tumors as well as the number of adoptively transferred tumor-specific T cells.
16397267	Pancreatic carcinoma	IL6	Promote immunity (T cell function)	C57BL/6 EL-TGF-alpha x Trp53-/- mice, which develop spontaneous ductal pancreatic carcinoma, were generated. Intratumoral cytokine secretion of tumor necrosis factor-alpha, IFN-gamma, IL-6, and MCP-1 was lower in spontaneous tumors as well as the number of adoptively transferred tumor-specific T cells.
16397041	Lung carcinoma; Pancreatic carcinoma; Prostate carcinoma; Malignant Brain Neoplasm; Melanoma	CD3G	Promote immunity (T cell function); essential for immunotherapy	Anti-CD3 x anti-epidermal growth factor receptor (EGFR) bispecific antibody redirects T-cell cytolytic activity to EGFR-positive cancers in vitro and in an animal model. Specific cytolytic activity of ATC armed with anti-CD3 x anti-EGFR (EGFRBi) against EGFR-expressing cancer cells derived from lung, pancreas, colon, prostate, brain, skin, or EGFR-negative breast cancer cells was evaluated in (51)Cr release assays.
16397041	Lung carcinoma; Pancreatic carcinoma; Prostate carcinoma; Malignant Brain Neoplasm; Melanoma	EGFR	Inhibit immunity	Anti-CD3 x anti-epidermal growth factor receptor (EGFR) bispecific antibody redirects T-cell cytolytic activity to EGFR-positive cancers in vitro and in an animal model. Specific cytolytic activity of ATC armed with anti-CD3 x anti-EGFR (EGFRBi) against EGFR-expressing cancer cells derived from lung, pancreas, colon, prostate, brain, skin, or EGFR-negative breast cancer cells was evaluated in (51)Cr release assays.
16397021	Breast carcinoma	WT1	Promote immunity (T cell function); essential for immunotherapy	We have tested the working hypotheses that WT1 can be immunogenic in patients with breast cancer and can stimulate CTL of sufficient avidity to kill tumor cells. These results show that WT1-specific CTL can be expanded from the tumor-draining lymph nodes of breast cancer patients and that they can display peptide-specific effector function. This suggests that induction of autologous WT1-specific CTL may offer only limited tumor protection and that strategies that allow a high level of peptide/MHC complex presentation and/or improve CTL avidity may be required.
27433843	Melanoma	JAK1	Promote immunity	Whole-exome sequencing detected clonal selection and outgrowth of the acquired resistant tumors and, in two of the four patients, revealed resistance-associated loss-of-function mutations in the genes encoding interferon-receptor-associated Janus kinase 1 (JAK1) or Janus kinase 2 (JAK2), concurrent with deletion of the wild-type allele. JAK1 and JAK2 truncating mutations resulted in a lack of response to interferon gamma, including insensitivity to its antiproliferative effects on cancer cells.
27433843	Melanoma	JAK2	Promote immunity	Whole-exome sequencing detected clonal selection and outgrowth of the acquired resistant tumors and, in two of the four patients, revealed resistance-associated loss-of-function mutations in the genes encoding interferon-receptor-associated Janus kinase 1 (JAK1) or Janus kinase 2 (JAK2), concurrent with deletion of the wild-type allele. JAK1 and JAK2 truncating mutations resulted in a lack of response to interferon gamma, including insensitivity to its antiproliferative effects on cancer cells.
27433843	Melanoma	B2M	Promote immunity	The B2M truncating mutation led to loss of surface expression of major histocompatibility complex class I.
27430370	Lung Carcinoma	PTPN6	Inhibit immunity (T cell function)	Using this model, we demonstrate that the absence of SHP-1 augments the ability of adoptively transferred CD8(+) T cells to control tumor growth. Despite this caveat, our findings support the development of SHP-1 inhibition strategies in human T cells to complement adoptive transfer therapies in the clinic.
27427982	Glioblastoma	IL13RA2	Promote immunity (T cell function)	We observed that TanCARs engaged HER2 and IL13Rα2 simultaneously by inducing HER2-IL13Rα2 heterodimers, which promoted superadditive T cell activation when both antigens were encountered concurrently. We determined that patient TanCAR T cells showed distinct binding to HER2 or IL13Rα2 and had the capability to lyse autologous glioblastoma.Thus, TanCAR T cells show therapeutic potential to improve glioblastoma control by coengaging HER2 and IL13Rα2 in an augmented, bivalent immune synapse that enhances T cell functionality and reduces antigen escape.
27423427	Hepatocellular carcinoma	IFNA1	Promote immunity (T cell function)	Effector CD8+?T cells recognize hepatocellular antigen and perform effector functions (i.e., IFN-γ production and hepatocyte killing) while still in the intravascular space.
27418644	Plasma cell myeloma	LGALS9	Inhibit immunity (T cell function)	In addition, Galectin-9 and a proliferation-induced ligand (APRIL), secreted by OCs, are significantly upregulated during osteoclastogenesis. Galectin-9 specifically induces apoptosis of T cells while sparing monocytes and MM cells.
27418644	Plasma cell myeloma	CD38	Inhibit immunity (T cell function)	The immune checkpoint molecules programmed death ligand 1 (PD-L1), Galectin-9, herpesvirus entry mediator (HVEM), and CD200, as well as T-cell metabolism regulators indoleamine 2, 3-dioxygenase (IDO), and CD38 are significantly upregulated during osteoclastogenesis.
27418644	Plasma cell myeloma	CD274	Inhibit immunity	The immune checkpoint molecules programmed death ligand 1 (PD-L1), Galectin-9, herpesvirus entry mediator (HVEM), and CD200, as well as T-cell metabolism regulators indoleamine 2, 3-dioxygenase (IDO), and CD38 are significantly upregulated during osteoclastogenesis. Importantly, the levels of these molecules, except CD38, are higher in OCs than in MM cells. Anti-PD-L1 monoclonal antibody (mAb) and IDO inhibitor partly overcome OC-inhibited T-cell responses against MM cells, confirming their roles in OC-suppressed MM cell lysis by cytotoxic T cells.
27418644	Plasma cell myeloma	TNFRSF14	Inhibit immunity (T cell function)	The immune checkpoint molecules programmed death ligand 1 (PD-L1), Galectin-9, herpesvirus entry mediator (HVEM), and CD200, as well as T-cell metabolism regulators indoleamine 2, 3-dioxygenase (IDO), and CD38 are significantly upregulated during osteoclastogenesis.
27418644	Plasma cell myeloma	LGALS9	Inhibit immunity	In addition, Galectin-9 and a proliferation-induced ligand (APRIL), secreted by OCs, are significantly upregulated during osteoclastogenesis. Galectin-9 specifically induces apoptosis of T cells while sparing monocytes and MM cells.
27418644	Plasma cell myeloma	TNFRSF14	Inhibit immunity	When targeted by an anti-CD38 mAb, suppressive T-cell function by OCs is alleviated, associated with downregulation of HVEM and IDO.
27418644	Plasma cell myeloma	IDO1	Inhibit immunity	When targeted by an anti-CD38 mAb, suppressive T-cell function by OCs is alleviated, associated with downregulation of HVEM and IDO.
27418644	Plasma cell myeloma	CD38	Inhibit immunity	When targeted by an anti-CD38 mAb, suppressive T-cell function by OCs is alleviated, associated with downregulation of HVEM and IDO.
27407095	Cervical carcinoma	IL7	Promote immunity (T cell function)	Intravaginal treatment of IL7-Fc, but not native IL7, induces upregulation of chemokines (CXCL10, CCL3, CCL4, and CCL5), cytokines (IFNγ, TNFα, IL6, and IL1β), and an adhesion molecule (VCAM-1) in the genital tract, leading to the recruitment of several leukocytes, including CD4, CD8, γδ T cells, and dendritic cells. Importantly, in this murine cervical cancer model, topical administration of IL7-Fc after intramuscular HPV DNA vaccination increases the number of HPV-specific CD8 T cells in the genital mucosa, but not in the spleen, leading to stronger antitumor activity than the HPV DNA vaccine alone.
27407095	Cervical carcinoma	CXCL10	Promote immunity	Intravaginal treatment of IL7-Fc, but not native IL7, induces upregulation of chemokines (CXCL10, CCL3, CCL4, and CCL5), cytokines (IFNγ, TNFα, IL6, and IL1β), and an adhesion molecule (VCAM-1) in the genital tract, leading to the recruitment of several leukocytes, including CD4, CD8, γδ T cells, and dendritic cells.
27407095	Cervical carcinoma	CCL3	Promote immunity	Intravaginal treatment of IL7-Fc, but not native IL7, induces upregulation of chemokines (CXCL10, CCL3, CCL4, and CCL5), cytokines (IFNγ, TNFα, IL6, and IL1β), and an adhesion molecule (VCAM-1) in the genital tract, leading to the recruitment of several leukocytes, including CD4, CD8, γδ T cells, and dendritic cells.
27407095	Cervical carcinoma	CCL4	Promote immunity	Intravaginal treatment of IL7-Fc, but not native IL7, induces upregulation of chemokines (CXCL10, CCL3, CCL4, and CCL5), cytokines (IFNγ, TNFα, IL6, and IL1β), and an adhesion molecule (VCAM-1) in the genital tract, leading to the recruitment of several leukocytes, including CD4, CD8, γδ T cells, and dendritic cells.
27407095	Cervical carcinoma	CCL5	Promote immunity	Intravaginal treatment of IL7-Fc, but not native IL7, induces upregulation of chemokines (CXCL10, CCL3, CCL4, and CCL5), cytokines (IFNγ, TNFα, IL6, and IL1β), and an adhesion molecule (VCAM-1) in the genital tract, leading to the recruitment of several leukocytes, including CD4, CD8, γδ T cells, and dendritic cells.
27407095	Cervical carcinoma	IFNG	Promote immunity	Intravaginal treatment of IL7-Fc, but not native IL7, induces upregulation of chemokines (CXCL10, CCL3, CCL4, and CCL5), cytokines (IFNγ, TNFα, IL6, and IL1β), and an adhesion molecule (VCAM-1) in the genital tract, leading to the recruitment of several leukocytes, including CD4, CD8, γδ T cells, and dendritic cells.
27407095	Cervical carcinoma	TNF	Promote immunity	Intravaginal treatment of IL7-Fc, but not native IL7, induces upregulation of chemokines (CXCL10, CCL3, CCL4, and CCL5), cytokines (IFNγ, TNFα, IL6, and IL1β), and an adhesion molecule (VCAM-1) in the genital tract, leading to the recruitment of several leukocytes, including CD4, CD8, γδ T cells, and dendritic cells.
27407095	Cervical carcinoma	IL6	Promote immunity	Intravaginal treatment of IL7-Fc, but not native IL7, induces upregulation of chemokines (CXCL10, CCL3, CCL4, and CCL5), cytokines (IFNγ, TNFα, IL6, and IL1β), and an adhesion molecule (VCAM-1) in the genital tract, leading to the recruitment of several leukocytes, including CD4, CD8, γδ T cells, and dendritic cells.
27407095	Cervical carcinoma	IL1B	Promote immunity	Intravaginal treatment of IL7-Fc, but not native IL7, induces upregulation of chemokines (CXCL10, CCL3, CCL4, and CCL5), cytokines (IFNγ, TNFα, IL6, and IL1β), and an adhesion molecule (VCAM-1) in the genital tract, leading to the recruitment of several leukocytes, including CD4, CD8, γδ T cells, and dendritic cells.
27406985	Prostate carcinoma	FOLH1	Promote immunity (T cell function)	In vitro cross-linking of T cells with PSMA-expressing tumor cells by MOR209/ES414 triggered potent target-dependent tumor lysis and induction of target-dependent T-cell activation and proliferation.
27406985	Prostate carcinoma	CD3E	Promote immunity (T cell function)	We have developed a novel humanized bispecific antibody, MOR209/ES414, built on the ADAPTIR (modular protein technology) platform, to redirect T-cell cytotoxicity toward prostate cancer cells by specifically targeting T cells through CD3ε to prostate cancer cells expressing PSMA (prostate-specific membrane antigen).
27404452	Colorectal carcinoma	CD274	Inhibit immunity	However, PD-L1+(I) MSI-H CRCs were characterised by high-density tumour-infiltrating immune cells, including T cells and macrophages, and intense peritumoural lymphoid reactions.
27402485	Pancreatic carcinoma	EGFR	Inhibit immunity	Our results show that myeloid cells support immune evasion in pancreatic cancer through EGFR/MAPK-dependent regulation of PD-L1 expression on tumour cells.
27401038	Acute Myeloid Leukemia	IL3RA	Promote immunity	Infusion of CD123-ENG T cells resulted in regression of AML in xenograft models conferring a significant survival advantage of treated mice in comparison to mice that received control T cells.
27380136	Head and neck squamous cell carcinoma	CXCL16	Promote immunity (T cell function)	Radiation induced tumour lysis results in decreased tumour CXCL10 secretion, but increased CXCL16 secretion by antigen-presenting cells into circulation to attract T cells to the tumour microenvironment.
27376576	Pancreatic ductal adenocarcinoma	PTK2	Inhibit immunity (infiltration)	We found that FAK activity was elevated in human PDAC tissues and correlated with high levels of fibrosis and poor CD8(+) cytotoxic T cell infiltration. Single-agent FAK inhibition using the selective FAK inhibitor VS-4718 substantially limited tumor progression, resulting in a doubling of survival in the p48-Cre;LSL-Kras(G12D);Trp53(flox/+) (KPC) mouse model of human PDAC. We also found that FAK inhibition rendered the previously unresponsive KPC mouse model responsive to T cell immunotherapy and PD-1 antagonists. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME and renders tumors responsive to immunotherapy.
27364554	Melanoma; Lung carcinoma	TNFSF13B	Promote immunity (T cell function)	BAFF and APRIL derived from activin A-treated DCs upregulate proliferation and survival of T cells expressing the corresponding receptors, BAFF-R and TACI. In vivo, activin A-stimulated DCs demonstrate a significantly increased ability to induce tumor-specific CTLs and inhibit the growth of melanoma and lung carcinoma, which relies on DC-derived BAFF and APRIL, as knockdown of the BAFF and APRIL gene expression in activin A-treated DCs blocks augmentation of their antitumor potential.
27364554	Melanoma; Lung carcinoma	SMAD2	Promote immunity	Here we show that activin A triggers SMAD2 and ERK1/2 pathways in dendritic cells (DC) expressing type I and II activin receptors, and upregulates production of the TNFα family cytokines BAFF (TALL-1, TNFSF13B) and APRIL (TALL-2, TNFSF13A), which is blocked by SMAD2 and ERK1/2 inhibitors, respectively.
27364554	Melanoma; Lung carcinoma	INHBE	Promote immunity	In vivo, activin A-stimulated DCs demonstrate a significantly increased ability to induce tumor-specific CTLs and inhibit the growth of melanoma and lung carcinoma, which relies on DC-derived BAFF and APRIL, as knockdown of the BAFF and APRIL gene expression in activin A-treated DCs blocks augmentation of their antitumor potential.
27364554	Melanoma; Lung carcinoma	TNFSF13	Promote immunity (T cell function)	Here we show that activin A triggers SMAD2 and ERK1/2 pathways in dendritic cells (DC) expressing type I and II activin receptors, and upregulates production of the TNFα family cytokines BAFF (TALL-1, TNFSF13B) and APRIL (TALL-2, TNFSF13A), which is blocked by SMAD2 and ERK1/2 inhibitors, respectively. BAFF and APRIL derived from activin A-treated DCs upregulate proliferation and survival of T cells expressing the corresponding receptors, BAFF-R and TACI.
27364554	Melanoma; Lung carcinoma	MAPK1	Promote immunity (T cell function)	Here we show that activin A triggers SMAD2 and ERK1/2 pathways in dendritic cells (DC) expressing type I and II activin receptors, and upregulates production of the TNFα family cytokines BAFF (TALL-1, TNFSF13B) and APRIL (TALL-2, TNFSF13A), which is blocked by SMAD2 and ERK1/2 inhibitors, respectively. BAFF and APRIL derived from activin A-treated DCs upregulate proliferation and survival of T cells expressing the corresponding receptors, BAFF-R and TACI.
27364554	Melanoma; Lung carcinoma	SMAD2	Promote immunity (T cell function)	Here we show that activin A triggers SMAD2 and ERK1/2 pathways in dendritic cells (DC) expressing type I and II activin receptors, and upregulates production of the TNFα family cytokines BAFF (TALL-1, TNFSF13B) and APRIL (TALL-2, TNFSF13A), which is blocked by SMAD2 and ERK1/2 inhibitors, respectively. BAFF and APRIL derived from activin A-treated DCs upregulate proliferation and survival of T cells expressing the corresponding receptors, BAFF-R and TACI.
27364122	Melanoma; Colorectal carcinoma	TNFSF4	Promote immunity (T cell function)	Among these costimulators, locally secreted Fc-OX40L provided superior priming of antigen-specific CD8(+) T cells, compared with combinations with OX40 antibodies or vaccine alone. A cell-based vaccine cosecreting gp96-Ig and Fc-OX40L led to even more pronounced tumor control, complete tumor rejection, and increased tumor antigen-specific T-cell proliferation, including in tumor-infiltrating lymphocytes, as compared with combinations of gp96-Ig vaccine and OX40 antibodies, in mice with established melanoma or colorectal carcinoma.
27364122	Melanoma; Colorectal carcinoma	HSP90B1	Promote immunity (T cell function)	A cell-based vaccine cosecreting gp96-Ig and Fc-OX40L led to even more pronounced tumor control, complete tumor rejection, and increased tumor antigen-specific T-cell proliferation, including in tumor-infiltrating lymphocytes, as compared with combinations of gp96-Ig vaccine and OX40 antibodies, in mice with established melanoma or colorectal carcinoma.
27357626	Melanoma	TNF	Promote immunity	Antitumor efficacy was significantly enhanced with adenoviruses coding for murine interleukin-2 (mIL-2) and tumor necrosis factor-α (mTNFα) when compared with T-cell transfer alone or viruses alone. Mechanistic studies suggest that mIL-2 has an important role in activating T-cells at the tumor, while mTNFα induces chemokine expression.
27357626	Melanoma	IL2	Promote immunity (T cell function)	Mechanistic studies suggest that mIL-2 has an important role in activating T-cells at the tumor, while mTNFα induces chemokine expression.
27354469	B-Cell lymphoma	CTLA4	Inhibit immunity	The therapeutic function of anti-CD20 depends on tumor-specific CD8+?T-cell responses initiated by anti-CD20 through macrophages and DCs. CTLA-4 blockade can synergize with anti-CD20 to overcome adaptive immune response-related resistance in advanced B-cell lymphoma.
27325699	Breast carcinoma	CASP6	Inhibit immunity	Overexpression of Caspase-6 could significantly promote the activation of AAMs. Importantly, we further present evidence that caspase-6 could regulate breast cancer cell invasion by modulating MMP-2 and MMP-9 expression in 4T1 tumor-associated macrophages, as ablation of protein levels or activity of caspase-6 suppressed tumor cell invasion in vitro
27325645	Melanoma	CD14	Inhibit immunity (T cell function)	Here we report the identification of a novel BDCA1(+)CD14(+) population of immunosuppressive myeloid cells that are expanded in melanoma patients and are present in dendritic cell-based vaccines, where they suppress CD4(+) T cells in an antigen-specific manner. Mechanistic investigations showed that BDCA1(+)CD14(+) cells expressed high levels of the immune checkpoint molecule PD-L1 to hinder T-cell proliferation.
27325645	Melanoma	CD1C	Inhibit immunity (T cell function)	Here we report the identification of a novel BDCA1(+)CD14(+) population of immunosuppressive myeloid cells that are expanded in melanoma patients and are present in dendritic cell-based vaccines, where they suppress CD4(+) T cells in an antigen-specific manner. Mechanistic investigations showed that BDCA1(+)CD14(+) cells expressed high levels of the immune checkpoint molecule PD-L1 to hinder T-cell proliferation.
27321181	Ovarian carcinoma	ENTPD1	Inhibit immunity	Adenosine is a major determinant of the immunosuppressive tumor milieu. Sequential hydrolysis of extracellular ATP catalyzed by CD39 and CD73 is the main pathway for the generation of adenosine in the tumor interstitium.
27321181	Ovarian carcinoma	NT5E	Inhibit immunity	Adenosine is a major determinant of the immunosuppressive tumor milieu. Sequential hydrolysis of extracellular ATP catalyzed by CD39 and CD73 is the main pathway for the generation of adenosine in the tumor interstitium. Preclinical data show that targeting the adenosine-generating pathway (that is, CD73) or adenosinergic receptors (that is, A2A) relieves immunosuppresion and potently inhibits tumor growth.\
27297552	Melanoma; Lung carcinoma; Breast carcinoma; liver carcinoma	IL10	Promote immunity	In contrast to its inhibitory effects on many cells, IL10 activates CD8(+) tumor-infiltrating lymphocytes (TIL) and enhances their antitumor activity. However, CD8(+) TILs do not routinely express IL10, as autocrine complement C3 inhibits IL10 production through complement receptors C3aR and C5aR. CD8(+) TILs from C3-deficient mice, however, express IL10 and exhibit enhanced effector function.
27297552	Melanoma; Lung carcinoma; Breast carcinoma; liver carcinoma	C3AR1	Inhibit immunity	However, CD8(+) TILs do not routinely express IL10, as autocrine complement C3 inhibits IL10 production through complement receptors C3aR and C5aR.
27297552	Melanoma; Lung carcinoma; Breast carcinoma; liver carcinoma	C3	Inhibit immunity	However, CD8(+) TILs do not routinely express IL10, as autocrine complement C3 inhibits IL10 production through complement receptors C3aR and C5aR. CD8(+) TILs from C3-deficient mice, however, express IL10 and exhibit enhanced effector function. C3-deficient mice are resistant to tumor development in a T-cell- and IL10-dependent manner; human TILs expanded with IL2 plus IL10 increase the killing of primary tumors in vitro compared with IL2-treated TILs.
27297552	Melanoma; Lung carcinoma; Breast carcinoma; liver carcinoma	C5AR1	Inhibit immunity	Our findings suggest that complement receptors C3aR and C5aR expressed on CD8(+) TILs represent a novel class of immune checkpoints that could be targeted for tumor immunotherapy.
27294525	Small cell lung carcinoma	CD47	Inhibit immunity	CD47 is a cell-surface molecule that promotes immune evasion by engaging signal-regulatory protein alpha (SIRPα), which serves as an inhibitory receptor on macrophages.?In a murine model, administration of CD47-blocking antibodies or targeted inactivation of the Cd47 gene markedly inhibited SCLC tumor growth.
27286797	Giloma	VEGFA	Inhibit immunity (T cell function)	Here we explore whether the TGF-β pathway, which promotes angiogenesis, invasiveness, and immunosuppression, acts as an escape pathway from VEGF inhibition. Our study highlights the biological heterogeneity of murine glioma models and illustrates that cotargeting of the VEGF and TGF-β pathways might lead to improved tumor control only in subsets of glioblastoma.
27281199	Adult T-Cell Leukemia; Diffuse large B-Cell Lymphoma; Gastric Adenocarcinoma	CD274	Inhibit immunity	Disruption of the Pd-l1 3'-UTR in mice enables immune evasion of EG7-OVA tumour cells with elevated Pd-l1 expression in vivo, which is effectively inhibited by Pd-1/Pd-l1 blockade, supporting the role of relevant SVs in clonal selection through immune evasion.
27281199	Adult T-Cell Leukemia; Diffuse large B-Cell Lymphoma; Gastric Adenocarcinoma	PDCD1	Inhibit immunity	Disruption of the Pd-l1 3'-UTR in mice enables immune evasion of EG7-OVA tumour cells with elevated Pd-l1 expression in vivo, which is effectively inhibited by Pd-1/Pd-l1 blockade, supporting the role of relevant SVs in clonal selection through immune evasion.
27267849	Breast carcinoma	ITGAE	Promote immunity (T cell function)	CD8 status showed similar but less significant associations, but the combination of dual CD103+CD8+?TIL status was the most strongly prognostic combination for relapse-free and overall survival (HR = 0.10; 95% CI, 0.07-0.62; P = 0.006 and HR = 0.09; 95% CI, 0.07-0.57; P = 0.003, respectively). CD103 TILs are indicative of a good prognosis specifically within the basal-like subtype of breast cancer.
27267778	Melanoma	TLR1	Promote immunity	Combining TLR1-TLR2 ligand with an agonistic antibody to 4-1BB enhanced the antitumor activity in mice with established melanoma tumors. These studies reveal that the costimulatory effects of TLR1-TLR2 signaling in CD8(+) T cells are in part mediated by 4-1BB and are important for mounting an effective antitumor immune response.
27267778	Melanoma	TNFRSF9	Promote immunity	Combining TLR1-TLR2 ligand with an agonistic antibody to 4-1BB enhanced the antitumor activity in mice with established melanoma tumors. These studies reveal that the costimulatory effects of TLR1-TLR2 signaling in CD8(+) T cells are in part mediated by 4-1BB and are important for mounting an effective antitumor immune response. Cancer Immunol Res; 4(8); 708-16.
27267143	Diffuse-type tenosynovial giant cell tumour	CSF1	Inhibit immunity	The finding that D-TGCT cells overexpress colony-stimulating factor 1 (CSF1), resulting in recruitment of CSF1 receptor (CSF1R)-bearing macrophages that are polyclonal and make up the bulk of the tumour, has led to clinical trials with CSF1R inhibitors.
27265504	Pancreatic ductal adenocarcinoma	CXCR2	Inhibit immunity	Importantly, loss or inhibition of CXCR2 improved T?cell entry, and combined inhibition of CXCR2 and PD1 in mice with established disease significantly extended survival. We show that CXCR2 signaling in the myeloid compartment can promote pancreatic tumorigenesis and is required for pancreatic cancer metastasis, making it an excellent therapeutic target.
23204132	Melanoma	BRAF	Inhibit immunity	These findings provide a strong rationale to evaluate the potential clinical application of combining BRAF inhibition with T-cell-based immunotherapy for the treatment of patients with melanoma. Furthermore, analysis of human melanoma patient tumor biopsies before and during BRAF inhibitor treatment showed downregulation of VEGF consistent with the preclinical murine model.
23197495	Hepatocellular carcinoma	TLR3	Promote immunity	TLR3 activation increased cell death in the TLR3(+) SNU182 HCC cell line (30.5% vs 8.5%, P = .03) and promoted NK-cell activation (32.6% vs 19.4%, P < .001) and cytotoxicity (relative fourfold increase, P = .03) in vitro.
23192659	Mesothelioma and lung carcinoma; breast carcinoma; colon carcinoma; gastric carcinoma; bladder carcinoma; uterus carcinoma	KLRK1	Promote immunity	Tumor cell lysis was primarily mediated by NKG2D and NKp30 and partially by NKp46 and DNAM-1, in agreement with the expression of the corresponding ligands on tumor cells.
23192659	Mesothelioma and lung carcinoma; breast carcinoma; colon carcinoma; gastric carcinoma; bladder carcinoma; uterus carcinoma	NCR1	Promote immunity	Tumor cell lysis was primarily mediated by NKG2D and NKp30 and partially by NKp46 and DNAM-1, in agreement with the expression of the corresponding ligands on tumor cells.
23192659	Mesothelioma and lung carcinoma; breast carcinoma; colon carcinoma; gastric carcinoma; bladder carcinoma; uterus carcinoma	CD226	Promote immunity	Tumor cell lysis was primarily mediated by NKG2D and NKp30 and partially by NKp46 and DNAM-1, in agreement with the expression of the corresponding ligands on tumor cells.
23192659	Mesothelioma and lung carcinoma; breast carcinoma; colon carcinoma; gastric carcinoma; bladder carcinoma; uterus carcinoma	NCR3	Promote immunity	Tumor cell lysis was primarily mediated by NKG2D and NKp30 and partially by NKp46 and DNAM-1, in agreement with the expression of the corresponding ligands on tumor cells.
23192659	Mesothelioma and lung carcinoma; breast carcinoma; colon carcinoma; gastric carcinoma; bladder carcinoma; uterus carcinoma	IL2	Promote immunity	Upon culture in IL-2, they acquired a potent cytolytic activity against both allogeneic and autologous tumor cells.
23188506	Leukemia	CTLA4	Inhibit immunity	Blocking CTLA4 and PD-1 in vivo combined to promote survival of transferred T-cells despite powerful deletional signals that mediate Bim (BCL2L11)-dependent apoptosis. However, this dual blockade was not optimal for stimulating effector function by responding T-cells, which required the additional blockade of LAG3 to induce full expansion and allow the acquisition of robust cytolytic activity.
23188506	Leukemia	LAG3	Inhibit immunity	Blocking CTLA4 and PD-1 in vivo combined to promote survival of transferred T-cells despite powerful deletional signals that mediate Bim (BCL2L11)-dependent apoptosis. However, this dual blockade was not optimal for stimulating effector function by responding T-cells, which required the additional blockade of LAG3 to induce full expansion and allow the acquisition of robust cytolytic activity.
23188505	Epithelial tumor	ITGAE	Promote immunity (T cell function)	Flow-based adhesion assay showed that engagement of CD103 or LFA-1, together with TCR, enhances the strength of the T-cell/target cell interaction.
23184679	Colon carcinoma	MYD88	Inhibit immunity	However, MDSCs obtained from tumor-bearing Myd88(-/-) mice failed to suppress antigen-specific proliferation of CD8(+) T cells and CD4(+) T cells, whereas MDSCs from wild-type mice significantly suppressed both types of T cells. Consistent with this, we found that the levels of costimulatory molecules and MHC class II were significantly increased in MDSCs obtained from Myd88(-/-) mice compared with wild-type mice after tumor challenge. Finally, the blockade of Myd88 signaling by treatment with Myd88 inhibitory peptide, during later tumor stages, significantly inhibited the growth of immunogenic tumors.
23183537	Cervical carcinoma	MSLN	Inhibit immunity	The tumor-homing module is comprised of a single-chain variable fragment (scFv) that specifically binds to mesothelin (Meso), which is commonly overexpressed in human cancers, including ovarian tumors. We show that our therapeutic protein specifically loaded antigenic epitope onto the surface of mesothelin-expressing tumor cells, rendering tumors susceptible to antigen-specific cytotoxic CD8(+) T lymphocytes (CTL)-mediated killing in vitro and in vivo. Our findings have important implications for bypassing immune tolerance to enhance cancer immunotherapy.
23175469	Acute Myeloid Leukemia	CD86	Inhibit immunity	B7-2(+) AML cells significantly contributed to T-cell responses. In conclusion, Th-cell responses can be directly supported by B7-2(+) leukemia subpopulations. However, this interaction can facilitate the acquisition of a suppressive character that may contribute to immune evasion in myeloid leukemia.
23169640	Large B-Cell lymphoma	HDAC4	Inhibit immunity	Interestingly, we found that miR-155 directly targets HDAC4, a corepressor partner of BCL6. Furthermore, ectopic expression of HDAC4 in human-activated B-cell-type diffuse large B-cell lymphoma (DLBCL) cells results in reduced miR-155-induced proliferation, clonogenic potential, and increased apoptosis.
23152566	Prostate carcinoma	ACPP	Promote immunity	Using samples from prostate cancer patients immunized with a DNA vaccine encoding prostatic acid phosphatase (PAP) and a trans-vivo delayed-type hypersensitivity (tvDTH) assay, we found that the detection of PAP-specific effector responses after immunization was prevented by the activity of PAP-specific regulatory cells.
23152566	Prostate carcinoma	CTLA4	Inhibit immunity (T cell function)	hese PAP-specific CD8(+)CTLA-4(+) suppressor T cells expressed IL-35, which was decreased after blockade of CTLA-4, and inhibition of either CTLA-4 or IL-35 reversed PAP-specific suppression of tvDTH response. PAP-specific CD8(+)CTLA-4(+) T cells also suppressed T cell proliferation in an IL-35-dependent, contact-independent fashion.
23152559	Melanoma	CCR5	Inhibit immunity	Expression of CCR5 was preferentially detected on regulatory T cells (Tregs). Accordingly, tumor-infiltrating MO-MDSCs directly attracted high numbers of Tregs via CCR5 in vitro. Intratumoral injection of CCL4 or CCL5 increased tumor-infiltrating Tregs, and deficiency of CCR5 led to their profound decrease. Moreover, in CCR5-deficient mice, RMA-S and B16 tumor growth was delayed emphasizing the importance of CCR5 in the control of antitumor immune responses.
23149919	Melanoma	IL15	Promote immunity (T cell function; NK cell function)	Sushi-IL-15-Apo as a recombinant protein was also bioactive in vivo, became conjugated to HDL, and displayed immunotherapeutic effects against metastatic disease.
23149818	Hodgkin lymphoma	IL15	Promote immunity (T cell function)	We found that in the presence of Tregs, IL-15, but not IL-2, promoted the proliferation, effector function, and resistance to apoptosis of effectors T cells and EBV-CTLs. IL-15 did not reverse or block Tregs but instead preferentially supported the proliferation of CTLs and effector T cells as compared with Tregs.
23147993	Acute Myeloid Leukemia	CTSG	Promote immunity	We showed killing of primary AML by CG1-CTL, but not normal bone marrow. Blocking HLA-A*0201 abrogated CG1-CTL-mediated cytotoxicity, further confirming HLA-A*0201-dependent killing. Finally, we showed functional CG1-CTLs in peripheral blood from AML patients following allogeneic stem cell transplantation. CG is aberrantly expressed and processed in AML and is a novel immunotherapeutic target that warrants further development.
23144293	Brain neoplasm	AHR	Inhibit immunity	Further, it was also recently shown that TDO-2-dependent production of KYN by brain tumors might be a novel mechanism for suppressing antitumor immunity and supporting tumor growth through the activation of the Aryl hydrocarbon receptor (AhR). This newly identified TDO-2-KYN-AhR signaling pathway opens up exciting future research opportunities and may represent a novel therapeutic target in cancer therapy.
23144293	Brain neoplasm	TDO2	Inhibit immunity	Further, it was also recently shown that TDO-2-dependent production of KYN by brain tumors might be a novel mechanism for suppressing antitumor immunity and supporting tumor growth through the activation of the Aryl hydrocarbon receptor (AhR).
23131994	Breast carcinoma	SUSD2	Inhibit immunity; immunotherapy target	Various phenotype assays indicate that SUSD2 increases the invasion of breast cancer cells and contributes to a potential immune evasion mechanism through induction of apoptosis of Jurkat T cells. Using a syngeneic mouse model, we observed accelerated tumor formation and decreased survival in mice with tumors expressing Susd2. We found significantly fewer CD4 tumor infiltrating lymphocytes in mice with tumors expressing Susd2. Together, our findings provide evidence that SUSD2 may represent a promising therapeutic target for breast cancer.
23125418	Breast carcinoma	MIF	Inhibit immunity; immunotherapy target	Specifically, MIF increases the prevalence of a highly immune suppressive subpopulation of myeloid-derived suppressor cells (MDSCs) within the tumor. In vitro, MIF promotes differentiation of myeloid cells into the same population of MDSCs. Pharmacologic inhibition of MIF reduces MDSC accumulation in the tumor similar to MIF depletion and blocks the MIF-dependent in vitro differentiation of MDSCs. Our results demonstrate that MIF is a therapeutically targetable mechanism for control of tumor growth and metastasis through regulation of the host immune response and support the potential utility of MIF inhibitors, either alone or in combination with standard tumor-targeting therapeutic or immunotherapy approaches.
23108143	Colon carcinoma; Colorecterol carcinoma	CSF2	Promote immunity; immnuotherapy target	Here, we show that more than one-third of human colorectal tumors exhibit aberrant DNA demethylation of the GM-CSF promoter and overexpress the cytokine. Mouse engraftment experiments with autologous and homologous colon tumors engineered to repress the ectopic secretion of GM-CSF revealed the tumor-secreted GM-CSF to have an immune-associated antitumor effect.
23108142	Prostate carcinoma	HMGB1	Promote immunity (T cell function)	In this study, we report that the production of HMGB1, an established DAMP released by dying cells, was critical for tumor progression in an established mouse model of prostate cancer. HMGB1 was required for the activation and intratumoral accumulation of T cells that expressed cytokine lymphotoxinα(1)β(2) (LT) on their surface. Taken together, our findings suggest that the release of HMGB1 as an endogenous danger signal is important for priming an adaptive immune response that promotes malignant progression, with implications for cancer prevention and therapy.
23105141	Myeloid leukemia; Breast carcinoma; Melanoma	TMEM37	Promote immunity	PR1 is a HLA-A2-restricted peptide that has been targeted successfully in myeloid leukemia with immunotherapy. We further show that PR1 cross-presentation renders human breast cancer and melanoma cells susceptible to killing by PR1-specific CTLs (PR1-CTL) and the anti-PR1/HLA-A2 Ab 8F4. Together, our data identify cross-presentation as a novel mechanism through which cells that lack endogenous expression of an Ag become susceptible to therapies that target cross-presented Ags and suggest PR1 as a broadly expressed tumor Ag.
23100515	Non-small-cell lung carcinoma	EGFR	Inhibit immunity	A clinical study in non-small cell lung cancer patients demonstrated a positive correlation between EGFR expression levels and the therapeutic efficacy of the EGFR mAb cetuximab. Interestingly, Ab-dependent cell-mediated cytotoxicity (ADCC) by NK cells, monocytes, or polymorphonuclear cells as well as complement-dependent cytotoxicity positively correlated with the number of EGFR molecules. In comparison with ADCC by mononuclear cells, polymorphonuclear cell-mediated ADCC and complement-dependent cytotoxicity required higher EGFR expression levels and higher mAb concentrations to trigger significant tumor cell killing.
23098072	Pancreatic carcinoma	TLR2	Promote immunity; immnuotherapy target	To develop targeted agents for cancer imaging and therapy, we designed, synthesized, and characterized 13 novel, fully synthetic high affinity TLR2 agonists.?After conjugation of near-infrared dye to 10, agonist activity (EC(50) = 34 nM) and binding affinity (K(i) = 11 nM) were retained in 13. Fluorescence signal was present in TLR2 expressing pancreatic tumor xenografts 24 h after injection of 13, while an excess of unlabeled ligand blocked 13 from binding to the tumor, resulting in significantly decreased signal (p < 0.001) demonstrating in vivo selectivity.
23095323	Melanoma	JUN	Inhibit immunity	PD-L1 expression is transcriptionally modulated by c-Jun and augmented by STAT3. We report a novel mechanism that suppresses preexisting immune responses in patients with melanoma receiving BRAFi therapy. BRAFi resistance leads to increased expression of PD-L1 in melanoma cells, mediated by c-Jun and STAT3
23095323	Melanoma	CD274	Inhibit immunity (T cell function)	MEKi in melanoma cells shows dual therapeutic effects with simultaneous suppression of PD-L1 expression and induction of apoptosis. By combining MEKi with BRAFi, an additive effect on the inhibition of PD-L1 expression results.
23093782	Colon carcinoma	NANOG	Inhibit immunity	Inhibition of Nanog in a murine model of colon cancer rendered tumor cells susceptible to immune-mediated clearance and led to successful, long-term control of the disease.
23090488	Melanoma	FOXP3	Inhibit immunity	In the B16F10 melanoma model, we show that single vaccination with irradiated, α-GalCer-loaded tumor cells resulted in suppression of established subcutaneous (s.c.) B16F10 tumor growth, which was mediated by NKT cell-dependent IFN-γ production and enhanced in the absence of IL-17?A. Selective depletion of Foxp3(+) Tregs in transgenic DEpletion of REGulatory T cells (DEREG) mice led to significant inhibition of B16F10 tumor growth and enhanced survival of mice receiving vaccination. Short-term elimination of Foxp3(+) Tregs (<7 days) was sufficient to boost vaccine-induced immunity.
23086756	B-Cell cell lymphoma; T-Cell cell lymphoma	TLR7	Promote immunity (T cell function)	In combination, TLR7/RT therapy leads to the expansion of tumor antigen-specific CD8(+) T cells and improved survival. Furthermore, those mice that achieve long-term clearance of tumor after TLR7/RT therapy are protected from subsequent tumor rechallenge by the generation of a tumor-specific memory immune response.
23072905	Leukemia	ROS1	Inhibit immunity (NK cell function)	Malignant granulocytes from patients with BCR-ABL-positive CML expressed the oxygen radical-producing enzyme NOX, produced large amounts of ROS, and triggered extensive cell death in NK cells.
23070117	Glioblastoma	EPHA2	Inhibit immunity	EphA2-specific T cells recognized EphA2-positive glioma cells as judged by interferon-γ (IFN-γ) and IL-2 production and tumor cell killing. In addition, EphA2-specific T cells had potent activity against human glioma-initiating cells preventing neurosphere formation and destroying intact neurospheres in coculture assays. Adoptive transfer of EphA2-specific T cells resulted in the regression of glioma xenografts in severe combined immunodeficiency (SCID) mice and a significant survival advantage in comparison to untreated mice and mice treated with nontransduced T cells. Thus, EphA2-specific T-cell immunotherapy may be a promising approach for the treatment of EphA2-positive GBM.
23066150	Lymphoma	NCR3LG1	Promote immunity (NK cell function)	Induced self expression of the NKp30 ligand B7-H6 facilitates NK cell-mediated elimination of stressed cells. A fusion protein consisting of the ectodomain of B7-H6 and the CD20 single-chain fragment variable 7D8 was generated to mimic an induced self phenotype required for NK cell-mediated target cell elimination.
23065503	B-Cell cell lymphoma	CD1D	Promote immunity (T cell function)	Invariant natural killer T cells recognize glycolipid antigens such as α-galactosylceramide presented by CD1d. Invariant natural killer T-cell lines from patients lysed CD1d-expressing targets. Irradiated α-galactosylceramide-treated leukemic cells elicited allogeneic and autologous invariant natural killer T-cell proliferation, and α-galactosylceramide treatment led to increased proliferation of conventional T cells in response to tumor.
23064366	Melanoma	IL9	Promote immunity	Lack of IL-9 enhanced tumor growth, while tumor-specific Th9 cell treatment promoted stronger antitumor responses in both prophylactic and therapeutic models.
23045606	Melanoma	NRP1	Inhibit immunity (T cell function)	We provide evidence that Neuropilin 1 (Nrp-1), highly expressed by Foxp3(+) T reg cells, regulates the immunological anti-tumor control by guiding T reg cells into the tumor in response to tumor-derived vascular endothelial growth factor (VEGF).
23032748	Melanoma	UCP1	Promote immunity (T cell function)	Furthermore, the use of UCP strongly improves the efficacy of therapeutic vaccination against established B16-HLA-A*0201 melanoma and promotes tumor infiltration by TERT-specific CD8(+) T cells.
23028051	Lung carcinoma	C5	Inhibit immunity	C5a also contributed to the immunosuppressive microenvironment required for tumor growth. In particular, blockade of C5a receptor significantly reduced myeloid-derived suppressor cells and immunomodulators ARG1, CTLA-4, IL-6, IL-10, LAG3, and PDL1 (B7H1). In conclusion, lung cancer cells have the capacity to generate C5a, a molecule that creates a favorable tumor microenvironment for lung cancer progression.
23022528	Lung carcinoma	IL17A	Promote immunity	As modulation of T cell cytokines such as IL-17A has been recently shown to suppress tumor growth in experimental models, anti-cytokine agents emerge as a promising new approach for treatment of lung cancer.
23014531	Leukemia	KMT2A	Inhibit immunity (NK cell function)	Our data support the use of a triple immunotherapy approach, including an antibody directed against tumor-associated antigen, KIR-mismatched NK cell transplantation, and inhibitory KIR blockade, for the treatment of NK cell-resistant MLL-rearranged leukemias.
23008334	Melanoma	TNFRSF4	Promote immunity (T cell function)	CD4(+) T cells are important and potent mediators of anti-tumor immunity and adoptive transfer of specific CD4(+) T cells can promote tumor regression in mice and patients. OX40, a costimulatory molecule expressed primarily on activated CD4(+) T cells, promotes and enhances anti-tumor immunity with limited success on large tumors in mice.
23001042	Breast carcinoma	NTF3	Inhibit immunity	Ectopic expression of NT-3 in EMT-like breast cancer cells reduces their migratory ability and increases the expression of HER2 (human epidermal growth factor receptor 2) and E-cadherin at the cell-cell junction. In summary, NT-3 appears to promote growth of metastatic breast cancer cells in the brain by facilitating the re-epithelialization of metastatic breast cancer cells and downmodulating the cytotoxic response of microglia.
22981349	Kidney carcinoma	IL15	Promote immunity (T cell function)	By contrast, during allograft rejection, the increased intra-graft IL-15 expression favors tubular destruction facilitating the intraepithelial recruitment of CD8 T cells expressing the E-cadherin ligand CD103. In renal cancer, loss of CD132 by epithelial cells defines a tumoral microenvironment where IL-15 triggers E-cadherin down-regulation and EMT.
22981349	Kidney carcinoma	IL2RG	Promote immunity	Recent data highlight new functions of IL-15 in renal homeostasis mediated by IL-15Rγ (CD132). In renal cancer, loss of CD132 by epithelial cells defines a tumoral microenvironment where IL-15 triggers E-cadherin down-regulation and EMT. Finally, in CD132+ renal cancer stem cells IL-15 induces the generation of non-tumorigenic epithelial cells sensitive to cytotoxic drugs.
19451644	Breast carcinoma; Melanoma; Gastrointestinal cancer	IFNA1	Promote immunity	Impaired-IFN signaling was equally evident in stage II, III, and IV breast cancer patients, and downstream functional defects in T cell activation were identified. Taken together, these findings indicate that defects in lymphocyte IFN signaling arise in patients with breast cancer, melanoma, and gastrointestinal cancer, and these defects may represent a common cancer-associated mechanism of immune dysfunction.
19451266	Hepatocellular carcinoma	CD274	Inhibit immunity (T cell function)	Monocytes activated by tumors strongly express PD-L1 proteins with kinetics similar to their activation status, and significant correlations were found between the levels of PD-L1(+) and HLA-DR(high) on tumor-infiltrating monocytes. Autocrine tumor necrosis factor alpha and interleukin 10 released from activated monocytes stimulated monocyte expression of PD-L1. The PD-L1(+) monocytes effectively suppressed tumor-specific T cell immunity and contributed to the growth of human tumors in vivo; the effect could be reversed by blocking PD-L1 on those monocytes.
19440216	Acute Myeloid Leukemia	CD300LF	Inhibit immunity	In vivo anticancer activity of lead mAbs was observed in an established HL-60 xenograft model with a tumor growth delay of up to 40% and in a model using primary human AML cells, where treatment with anti-IREM-1 mAb resulted in a significant reduction of engrafted human cells. These results demonstrate IREM-1 as a potential novel target for immunotherapy of AML.
19433619	Colon carcinoma	MFGE8	Inhibit immunity	Within the tumor microenvironment, the secreted protein milk fat globule epidermal growth factor-8 (MFG-E8) stimulates disease progression through coordinated alpha(v)beta(3) integrin signaling in tumor and host cells. MFG-E8 enhances tumor cell survival, invasion, and angiogenesis, and contributes to local immune suppression. Collectively, these findings suggest that systemic MFG-E8 blockade might intensify the antitumor activities of existing therapeutic regimens through coordinated cell-autonomous and immune-mediated mechanisms.
19431148	Non-small-cell lung carcinoma	CXCL8	Promote immunity (T cell function)	Furthermore, all NSCLC cell lines secreted immunoreactive IL-8, albeit at different levels. IL-8 was as effective as TNFalpha in triggering ARG1 release and the 2 cytokines acted synergistically. Secreted ARG1 was biologically active and catabolized extracellular arginine.
19431148	Non-small-cell lung carcinoma	ARG1	Inhibit immunity (T cell function)	Arginase 1 (ARG1) inhibits T-cell proliferation by degrading extracellular arginine, which results in decreased responsiveness of T cells to CD3/TCR stimulation.
19430493	Ovarian carcinoma	HDAC3	Inhibit immunity (NK cell function)	Furthermore, by small interfering RNA-mediated knockdown and overexpression of HDAC1-3, we showed that HDAC3 is a repressor of ULBPs expression in epithelial cancer cells. Remarkably, TSA treatment caused the complete release of HDAC3 from the ULBP1-3 promoters.
19430493	Ovarian carcinoma	KLRK1	Promote immunity	The expression of the NKG2D ligands on cancer cells leads to their recognition and elimination by host immune responses mediated by natural killer and T cells. UL16-binding proteins (ULBPs) are NKG2D ligands, which are scarcely expressed in epithelial tumours, favouring their evasion from the immune system.
19427884	Neuroblastoma	IL10	Inhibit immunity	Interleukin 10 (IL-10) suppresses antigen presenting cell activation contributing to tumour-mediated immune suppression. In principle, combination of TL-asCpG and antibodies against IL-10 receptor (aIL-10R) could prolong immune system activation, leading to better therapeutic results.
19427690	Giloma	TNFSF10	Promote immunity	This study revealed a significant increase of cytotoxicity in vitro following the combined application of FA-PEG-PEI/pCD/5-FC and FA-PEG-PEI/pTRAIL treatments in C6 glioma cells. Animal studies showed a significant growth inhibition of the C6 glioma xenografts using the combined treatment.
19417017	Melanoma	TYR	Promote immunity	TriMix DCs coelectroporated with tyrosinase are able to stimulate tyrosinase-specific CD8(+) T cells in vitro from the blood of nonvaccinated melanoma patients.
19414774	Lung carcinoma	ITGAM	Inhibit immunity (T cell function)	A natural counterpart of CD11b(high)Ia(low) DCs was identified in tumor tissue, and CD11b(high)Ia(low) DCs sorted from 3LL lung cancer tissue expressed arginase I and inhibited T cell response.
19414558	Melanoma	TNFRSF4	Promote immunity	We report that the combined use of the alkylating agent cyclophosphamide (CTX) and an agonist antibody targeting the co-stimulatory receptor OX40 (OX86) provides potent antitumor immunity capable of regressing established, poorly immunogenic B16 melanoma tumors.
19404979	Hepatocellular carcinoma	CD226	Promote immunity	Finally, we showed by combined mAb-mediated blockade that DNAM-1 and NKG2D could cooperate in the cell lysis of HCC.
19402060	Renal cell carcinoma	IL2	Promote immunity	The most consistent antitumor activity has been reported with interferon-alpha (IFN-alpha) and interleukin-2 (IL-2). In recent years, randomized trials have suggested that high-dose, intravenous bolus IL-2 is superior in terms of response rate and possibly in terms of response quality to regimens that involve either low-dose IL-2 and IFN-alpha, intermediate- or low-dose IL-2 alone, or low-dose IFN-alpha alone.
19401350	Chronic lymphocytic leukemia	NXF2	Promote immunity; immnuotherapy target	Our findings suggest that NXF2 could be further pursued as an immunotherapeutic target in CLL, and that treatment with demethylating agents could be exploited to specifically modulate CTA expression and effective antigen presentation in malignant B cells.
19391137	Hodgkin's lymphoma	IL7	Inhibit immunity	Here, we demonstrate that HL-derived cell lines (L-428, KM-H2, HDLM-2, L-1236 and L-540) and primary H-RS cells from lymph node tissues of HL patients express the IL-7(R) receptor. IL-7 appears to be involved in autocrine circuitries of HL because L-1236, HDLM-2 and KM-H2 cells display the constitutive production of IL-7 and neutralizing anti-IL-7 antibodies induces a statistically significant inhibition of their basal proliferation.
19389880	Acute Myeloid Leukemia	WT1	Promote immunity	This WT1 vaccination study provides immunologic, molecular, and preliminary evidence of potential clinical efficacy in AML patients, warranting further investigations.
19380816	Head and neck squamous cell carcinoma	CYBB	Inhibit immunity (T cell function)	The increased ROS production by MDSC is mediated by up-regulated activity of NADPH oxidase (NOX2). MDSC from tumor-bearing mice had significantly higher expression of NOX2 subunits, primarily p47(phox) and gp91(phox), compared with immature myeloid cells from tumor-free mice. Expression of NOX2 subunits in MDSC was controlled by the STAT3 transcription factor. In the absence of NOX2 activity, MDSC lost the ability to suppress T cell responses and quickly differentiated into mature macrophages and dendritic cells.
19380802	Breast carcinoma	KDR	Promote immunity	Targeting a central cell type involved in angiogenesis, endothelial cells, we immunized against host vascular endothelial growth factor receptor 2 to fight the growth of Her-2/neu(+) breast tumors. Using the bacterial vector, Listeria monocytogenes (Lm), we fused polypeptides from the mouse vascular endothelial growth factor receptor 2 molecule (fetal liver kinase-1) to the microbial adjuvant, listeriolysin-O, and used Lm to deliver the Ags and elicit potent antitumor CTL responses.
19380767	Mesothelioma	TLR7	Promote immunity	Topical application of tumors with the TLR7 agonist imiquimod is an effective adjunct treatment for a range of primary dermatological cancers.?These results demonstrate that antitumor responses induced by locally delivered TLR7 agonists can be harnessed systemically for treating distal tumor.
19380767	Mesothelioma	CD40	Promote immunity (T cell function)	Because local imiquimod treatment did not induce significant CD4 T cell responses, we investigated the efficacy of combining imiquimod with agonistic CD40 Ab (as a surrogate for CD4 T cell help). Combination of locally delivered imiquimod with systemic anti-CD40 immunotherapy not only significantly enhanced the local antitumor response, with 30% complete resolution, but it was also effective at significantly retarding growth of distal tumor.
19380765	Colorectal carcinoma	CD59	Inhibit immunity (T cell function)	In this study, we explored the role of CD59 on human CD4(+) T cells. Our data demonstrate that CD59 is up-regulated on activated CD4(+) T cells and serves to down-modulate their activity in response to polyclonal and Ag-specific stimulation. The findings were striking and indicated that blockade of CD59 significantly enhanced the CD4(+) T cell response to two different tumor Ags. These data highlight the potential for manipulating CD59 expression on T cells for boosting weak immune responses, such as those found in individuals with cancer.
19378341	Ovarian carcinoma	CD86	Promote immunity (T cell function)	Upon IFNgamma exposure, TAM purified from ovarian cancer ascites recover a M1 phenotype (IL-10(low), IL-12(high)), express high levels of CD86 and low levels of ILT3, enhance the proliferation of CD4(+) T lymphocytes and potentiate the cytotoxic properties of a MelanA-specific CD8(+) T cell clone.
19378341	Ovarian carcinoma	IFNG	Promote immunity	Upon IFNgamma exposure, TAM purified from ovarian cancer ascites recover a M1 phenotype (IL-10(low), IL-12(high)), express high levels of CD86 and low levels of ILT3, enhance the proliferation of CD4(+) T lymphocytes and potentiate the cytotoxic properties of a MelanA-specific CD8(+) T cell clone. IFNgamma-treated TAM also secreted reduced levels of mediators promoting suppressive T cell accumulation (CCL18) and trophic for tumors (VEGF and MMP9).
19377047	Hodgkin lymphoma	CCR4	Promote immunity	We now show that forced expression of CCR4 by effector T cells enhances their migration to HL cells. Furthermore, T lymphocytes expressing both CCR4 and a chimeric antigen receptor directed to the HL associated antigen CD30 sustain their cytotoxic function and cytokine secretion in vitro, and produce enhanced tumor control when infused intravenously in mice engrafted with human HL.
19377047	Hodgkin lymphoma	CCL17	Inhibit immunity	The Reed-Stemberg cells of Hodgkin lymphoma (HL) predominantly produce thymus- and activation-regulated chemokine/CC chemokine ligand 17 (TARC/CCL17) and macrophage-derived chemokine (MDC/CCL22), which preferentially attract type 2 T helper (Th2) cells and regulatory T cells (Tregs) that express the TARC/MDC-specific chemokine receptor CCR4, thus generating an immunosuppressed tumor environment.
19377047	Hodgkin lymphoma	CCL22	Inhibit immunity	The Reed-Stemberg cells of Hodgkin lymphoma (HL) predominantly produce thymus- and activation-regulated chemokine/CC chemokine ligand 17 (TARC/CCL17) and macrophage-derived chemokine (MDC/CCL22), which preferentially attract type 2 T helper (Th2) cells and regulatory T cells (Tregs) that express the TARC/MDC-specific chemokine receptor CCR4, thus generating an immunosuppressed tumor environment.
19377047	Hodgkin lymphoma	CCR4	Promote immunity	By contrast, effector CD8(+) T cells lack CCR4, are nonresponsive to these chemokines and are rarely detected at the tumor site. We now show that forced expression of CCR4 by effector T cells enhances their migration to HL cells. Furthermore, T lymphocytes expressing both CCR4 and a chimeric antigen receptor directed to the HL associated antigen CD30 sustain their cytotoxic function and cytokine secretion in vitro, and produce enhanced tumor control when infused intravenously in mice engrafted with human HL.
19376606	Malignant Splenic Neoplasm; Liver Neuroendocrine Tumor	TP53	Promote immunity (T cell function)	Administration of alpha-GalCer resulted in generation of p53 peptide-specific cytotoxic T lymphocytes (CTLs) in mice bearing liver CMS4 tumor, aberrantly expressing p53, but not in mice bearing spleen CMS4 tumor.
19372261	Lymphoma	CD22	Promote immunity	Each bsAb translocates both CD22 and CD20 into lipid rafts, induces apoptosis and growth inhibition without second-antibody crosslinking, and is significantly more potent in killing lymphoma cells in vitro than their parental antibodies.
19366986	Melanoma	IDO1	Inhibit immunity	The immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) is expressed by a subset of murine plasmacytoid DCs (pDCs) in tumor-draining lymph nodes (TDLNs), where it can potently activate Foxp3+ regulatory T cells (Tregs). IDO regulated this conversion by dominantly suppressing production of IL-6 in pDCs, in a GCN2-kinase dependent fashion. In vivo, using a model of established B16 melanoma, the combination of an IDO-inhibitor drug plus antitumor vaccine caused up-regulation of IL-6 in pDCs and in situ conversion of a majority of Tregs to the TH17 phenotype, with marked enhancement of CD8+ T-cell activation and antitumor efficacy.
19366834	Prostate carcinoma	TNFSF13B	Promote immunity	The transition from normal to neoplastic glands in prostate cancer (PCa) is marked by a dramatic decline of IL-7 and BAFF/BLyS production. These results suggest that epithelial IL-7 and BAFF/BLyS production support intraprostatic lymphocyte survival.
19366834	Prostate carcinoma	IL7	Promote immunity	The transition from normal to neoplastic glands in prostate cancer (PCa) is marked by a dramatic decline of IL-7 and BAFF/BLyS production. These results suggest that epithelial IL-7 and BAFF/BLyS production support intraprostatic lymphocyte survival.
19361506	Colon carcinoma	TNFSF10	Promote immunity (NK cell function)	Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) promotes apoptosis in cancer cells, but not normal cells, and is critically involved in tumor rejection through natural killer (NK) cell-mediated immune surveillance.
19361506	Colon carcinoma	GMDS	Promote immunity (NK cell function)	When mock and GMDS-rescued cells were transplanted into athymic mice, tumor growth and metastasis of the GMDS-rescued cells were dramatically suppressed through NK cell-mediated tumor surveillance.
19351841	Gastrointestinal stromal tumor	IFNG	Promote immunity	The NK cell IFN-gamma production after 2 months of treatment could be considered an independent predictor of long term survival in advanced GISTs treated with IM.
19351755	Leukemia	WT1	Promote immunity	We developed a novel Ad vector encoding a truncated version of WT1 (Ad-tWT1) lacking the highly conserved COOH terminus zinc finger domains and tested its ability to stimulate WT1-specific immune responses and antitumor immunity in two murine models of WT1-expressing tumors. In addition, vaccination of C57BL/6 mice with Ad-tWT1 generated WT1-specific cell-mediated and humoral immune responses and conferred protection against challenge with the leukemia cell line, mWT1-C1498. Moreover, in a tumor therapy model, Ad-tWT1 vaccination of TRAMP-C2 tumor-bearing mice significantly suppressed tumor growth.
19349689	Melanoma	CD226	Promote immunity (NK cell function)	Here we show that human melanoma cell lines derived from LN metastases express ligands for natural cytotoxicity receptors (NCRs) and DNAX accessory molecule-1 (DNAM-1), two emerging NK cell receptors key for cancer cell recognition, but not NK group 2 member D (NKG2D).
19337999	Melanoma	BIRC5	Promote immunity	Survivin is overexpressed in several malignancies and in tumor-associated endothelium making it an attractive target for therapeutic cytotoxic T-cell responses. In summary, we demonstrated the immunogenicity of two K(b)-restricted peptide epitopes derived from the murine survivin protein; moreover, survivin-specific vaccination not only resulted in a reduction of tumor cells but also the tumor supplying blood vessels.
19337234	Prostate carcinoma	PSCA	Promote immunity	EP-assisted delivery of the pmPSCA evoked strong specific responses and could, in neoadjuvant or adjuvant settings, provide a safe and effective immune control of prostate cancer, given that there is significant homology between human and mouse PSCA.
19332800	Chronic lymphocytic leukemia	TCL1A	Inhibit immunity	With development of leukemia, Emu-TCL1 transgenic mice developed functional T-cell defects and alteration of gene and protein expression closely resembling changes seen in CLL human patients. Furthermore, infusion of CLL cells into young Emu-TCL1 mice induced defects
19332764	Primary Cutaneous T-Cell Non-Hodgkin Lymphoma	PTPRC	Promote immunity	Radioimmunotherapy (RIT) options for T-cell non-Hodgkin lymphomas (T-NHLs) are limited. We evaluated anti-CD45-RIT in human (h) and murine (m) T-NHL. CD45 was highly expressed on hT-NHL patient samples (median, 2.3 x 10(5) antigen-binding capacity units/cell) and hT-NHL cell lines (3.4 x 10(5) CD45 antigen-binding capacity units/cell). These data indicate that the high CD45 expression of T-NHL allows reliable tumor targeting and disease control supporting anti-CD45 RIT for T-NHL patients.
19326449	Cervical carcinoma	SPAG9	Promote immunity	The aim of the current study was to evaluate the clinical utility of SPAG9 expression and humoral immune response in cervical carcinomas. The current study findings revealed that in early stage cervical cancer, a substantial number of patients exhibited SPAG9 expression and generated SPAG9 antibodies, supporting its potential role in early detection and diagnosis in cervical cancer management.
19318546	Non-Hodgkin's lymphoma	CRY2	Inhibit immunity	The current study examined Cryptochrome 2 (CRY2), a core circadian gene and transcriptional repressor, as a potential circadian biomarker for NHL. In conclusion, both genetic association and functional analyses suggest that the circadian gene CRY2 may play an important role in NHL development.
19318495	Melanoma	CD28	Promote immunity (T cell function; NK cell function)	Furthermore, fibroblasts expressing CD3L and CD86 suppressed the growth of neighboring B16 cancer cells in vivo, and direct intratumoral injection of adenoviral vectors expressing CD3L and CD86 or CD3L and a membrane-tethered anti-CD28 antibody significantly suppressed the growth of subcutaneous tumors.
19318477	Melanoma	CTLA4	Inhibit immunity	Ipilimumab is a monoclonal antibody that blocks the immune-inhibitory interaction between CTL antigen 4 (CTLA-4) and its ligands on T cells. Clinical trials in cancer patients with ipilimumab have shown promising antitumor activity, particularly in patients with advanced melanoma. Our results show that Melan-A may be a major target for both the autoimmune and antitumor reactions in patients treated with anti-CTLA-4, and describe for the first time the antigen specificity of CD8-positive T cells that mediate tumor rejection in a patient undergoing treatment with an anti-CTLA-4 antibody.
19318471	Melanoma	PMEL	Promote immunity (T cell function)	Priming immunization with gp100(209-2M) without coadministration of CD4(+) helper T cell-restricted antigens induced the effective expansion of peptide-specific central and effector memory CD8(+) T cells with high proliferation potential in vaccine-draining lymph nodes of stage I to III melanoma patients.
19318244	Prostate carcinoma	FOXP3	Inhibit immunity	We had previously documented that prostate cancer islets are surrounded by clustered accumulations of CD3+ lymphocytes, which lack perforin and interferon-gamma (IFNgamma) expression, thus are apparently quiescent. Here, we report that these clusters contain numerous CD25+ and FOXP3+ cells. These markers are associated with regulatory T cells, and their presence in lymphocyte clusters near prostate cancer regions indicates an environment with negative impact on immune response against cancer cells.
19306372	Giloma	STAT3	Inhibit immunity	Finally, the effect of Stat3 inhibition on tumor growth was assessed in intracranial GL261 gliomas. GL261-CM increased Stat3 activity in N9 cells in vitro and resulted in overexpression of IL-10 and IL-6, and downregulation of IL1-beta, a pro-inflammatory cytokine. Inhibition of Stat3 by CPA-7 or siRNA reversed glioma-induced cytokine expression profile in N9 cells. Furthermore, inactivation of Stat3 in intracranial GL261 tumors by siRNA resulted in MG/MP activation and tumor growth inhibition. Glioma-induced MG and MP suppression may be mediated thorough Stat3. Inhibition of Stat3 function in tumor MG/MP may result in their activation and can potentially be used as an adjunct immunotherapy approach for gliomas.
19299748	Plasma cell myeloma	TLR3	Promote immunity	In conclusion, our results show that TLR3 ligand induces NF-kappaB pathway activation in MM and support a switching function of type I IFN in the functional outcome of TLR3 triggering in tumor cells.
19299748	Plasma cell myeloma	NFKB1	Promote immunity (B cell function)	In conclusion, our results show that TLR3 ligand induces NF-kappaB pathway activation in MM and support a switching function of type I IFN in the functional outcome of TLR3 triggering in tumor cells.
19299748	Plasma cell myeloma	IFNA1	Promote immunity	We next demonstrated that p38 MAPK pathway controlled both IFN-alpha secretion and IFN-alpha-mediated cell death. Moreover, cell death also involved activation of ERK1/2 pathway.
19299748	Plasma cell myeloma	MAPK3	Promote immunity	We next demonstrated that p38 MAPK pathway controlled both IFN-alpha secretion and IFN-alpha-mediated cell death. Moreover, cell death also involved activation of ERK1/2 pathway.
19299748	Plasma cell myeloma	MAPK1	Promote immunity	We next demonstrated that p38 MAPK pathway controlled both IFN-alpha secretion and IFN-alpha-mediated cell death. Moreover, cell death also involved activation of ERK1/2 pathway.
19293260	T-cell malignancies	CD2	Promote immunity	Reductions in CD4(+) and CD8(+) cell count numbers in response to therapy were seen in all patients, but in those patients developing EBV-LPD a significantly greater reduction in natural killer (NK) cell number and CD2 expression on T cells was seen. These findings highlight the importance of NK-cell depletion and CD2 expression in addition to T-cell depletion in the etiology of EBV-LPD.
19291796	Neuroblastoma	BIRC5	Promote immunity	This response was as effective as a survivin full-length vaccine and was associated with an increased target cell lysis, increased presence of CD8(+) T-cells at the primary tumor site and enhanced production of proinflammatory cytokines by systemic CD8(+) T cells.
19282460	Melanoma	CSF2	Promote immunity	Altogether, our results strongly suggest that although endogenous GM-CSF and IL-5 are not required to induce tumor immunity, signaling through betac receptor is critically needed for efficient cancer vaccination in both genetically modified GM-CSF-secreting tumor cells and a spontaneously immunogenic models.
19282460	Melanoma	IL5	Promote immunity	Altogether, our results strongly suggest that although endogenous GM-CSF and IL-5 are not required to induce tumor immunity, signaling through betac receptor is critically needed for efficient cancer vaccination in both genetically modified GM-CSF-secreting tumor cells and a spontaneously immunogenic models.
19278954	Leukemia	ZAP70	Promote immunity	This combination activated phospho-ZAP70 and phospho-ERK1/2 signaling in TCRVgamma9(+) cells and strongly enhanced their ADCC activity.
19278954	Leukemia	MAPK3	Promote immunity	This combination activated phospho-ZAP70 and phospho-ERK1/2 signaling in TCRVgamma9(+) cells and strongly enhanced their ADCC activity.
19278954	Leukemia	MAPK1	Promote immunity	This combination activated phospho-ZAP70 and phospho-ERK1/2 signaling in TCRVgamma9(+) cells and strongly enhanced their ADCC activity.
19276356	Breast carcinoma	CDKN1A	Promote immunity	p21 loss has been implicated in conferring oncogenic activity to known tumor suppressor gene KLF4 and cancer drug tamoxifen. Regulators of p21, therefore, play critical roles in tumorigenesis.
19276262	Melanoma	CTAG1B	Promote immunity	NY-ESO-1 is a highly immunogenic antigen expressed in a variety of malignancies, making it an excellent target for cancer vaccination. The proportion of patients with circulating NY-ESO-1-specific CD4(+) T cells was also reduced, and although many patients had CD8(+) T cells specific to a broad range of NY-ESO-1 epitopes, the majority of these responses were preexisting.
19265159	Lung carcinoma	FAS	Inhibit immunity	Therefore, our results demonstrate that Fas signal can promote lung cancer growth by recruiting MDSC via cancer cell-derived PGE(2), thus providing new mechanistic explanation for the role of inflammation in cancer progression and immune escape.
19265159	Lung carcinoma	PTGS2	Inhibit immunity	Furthermore, in vivo administration of cyclooxygenase-2 inhibitor can significantly reduce MDSC accumulation in the Fas-overexpressing tumor.
19265113	Kidney carcinoma; colon carcinoma	CD1D	Promote immunity; immnuotherapy target	The ability of anti-CD1d mAbs to coincidently activate CD1d(+) APCs to release IL-12 and inhibit CD1d-restricted type II NKT cells makes CD1d an exciting new target for immunotherapy of cancer based on tumor immunoregulation.
19264916	Glioblastoma	CD274	Inhibit immunity; immunotherapy target	Human glioblastoma is well known for its capacity to interfere with effective antitumor immune responses. B7-H1 is the third member of the B7 family that plays important roles in tumor immune evasion. B7-H1 was significantly upregulated at the growing edge of the tumors.
19258507	Melanoma	STAT3	Inhibit immunity (T cell function)	CpG directly activates Stat3 within minutes through TLR9. Ablating Stat3 in hematopoietic cells results in rapid activation of innate immunity by CpG, with enhanced production of IFN-gamma, tumor necrosis factor-alpha, IL-12, and activation of macrophages, neutrophils, and natural killer cells marked with Stat1 activation. Innate immune responses induced by CpG in mice with a Stat3-ablated hematopoietic system cause potent antitumor effects, leading to eradication of large (>1 cm) B16 melanoma tumors within 72 h. Our results further suggest that targeting Stat3 can drastically improve CpG-based immunotherapeutic approaches.
19251937	Urothelial carcinoma	KDM5D	Promote immunity	Animals treated with subtotal RF ablation showed significant increases in tumor-specific class I and II responses to HY antigens and tumor regression.
19240164	Melanoma	VEGFA	Inhibit immunity	These data support prior observations regarding the effect of VEGF on immune cell function and suggests consideration of VEGF inhibitors in future cancer immunotherapy clinical studies in metastatic melanoma.
19225534	Mantle cell lymphoma	CCND1	Promote immunity; immnuotherapy target	These results indicate that these T cells are potent cytotoxic T cells and recognize cyclin D1 peptides naturally presented by patient lymphoma cells in the context of HLA-A(*)0201 molecules. Taken together, our work identifies cyclin D1 as a potentially important antigen for immunotherapy of MCL.
19223535	Melanoma	FASLG	Promote immunity	Fas ligand (FasL) is a transmembrane protein that induces apoptosis in cells expressing its receptor, Fas. When grafted into mice, FasL-expressing tumor cells break immunologic tolerance to self-antigens and induce antibody-mediated tumor immunity.
19223507	Breast carcinoma	CCNB1	Inhibit immunity	Our data support the notion of cyclin B1 as a prominent target for immunologic recognition in cancer patients harboring p53-mutated cancer cells. Because mutation of p53 is one of the most frequent genetic alterations in human cancers, this suggests that immunotherapy based on targeting of cyclin B1 is broadly applicable in a large proportion of cancer patients.
28598415	Breast Carcinoma; Colorectal Carcinoma	TREX1	Inhibit immunity (infiltration); Resistant to immunotherapy.	We show that the DNA exonuclease Trex1 is induced by radiation doses above 12-18 Gy in different cancer cells, and attenuates their immunogenicity by degrading DNA that accumulates in the cytosol upon radiation. Repeated irradiation at doses that do not induce Trex1 amplifies interferon-β production, resulting in recruitment and activation of Batf3-dependent dendritic cells.
28592285	Head and Neck Squamous Cell Carcinoma	ADORA2A	Inhibit immunity (T cell function)	The adenosine A2A receptor (A2AR) could protect cancerous tissues from immune clearance via inhibiting T cells response. Immunostaining of HNSCC tissue samples revealed that increased expression of A2AR on tumor infiltrating immune cells correlated with advanced pathological grade, larger tumor size and positive lymph node status.
28585539	Colorectal Carcinoma; Melanoma; Bladder Carcinoma	IL21	Promote immunity (T cell function)	IL-21-mediated reversal of NK cell exhaustion facilitates anti-tumour immunity in MHC class I-deficient tumours.
28585539	Colorectal Carcinoma; Melanoma; Bladder Carcinoma	HAVCR2	Inhibit immunity (T cell function)	During this process, we find that the co-expression of Tim-3 and PD-1 marks functionally exhausted NK cells in advanced tumours and that MHC-I downregulation in tumours is closely associated with the induction of NK-cell exhaustion in both tumour-bearing mice and cancer patients.
28585539	Colorectal Carcinoma; Melanoma; Bladder Carcinoma	PDCD1	Inhibit immunity (T cell function)	During this process, we find that the co-expression of Tim-3 and PD-1 marks functionally exhausted NK cells in advanced tumours and that MHC-I downregulation in tumours is closely associated with the induction of NK-cell exhaustion in both tumour-bearing mice and cancer patients.
28581441	Melanoma; Prostate Carcinoma; Breast Carcinoma	HPSE	Promote immunity (infiltration)	However, mice lacking heparanase specifically in NK cells (Hpsefl/fl NKp46-iCre mice) were highly tumor prone when challenged with the carcinogen methylcholanthrene (MCA). Cytokine and immune checkpoint blockade immunotherapy for metastases was compromised when NK cells lacked heparanase. NK cell invasion of primary tumors and recruitment to the site of metastasis were strictly dependent on the presence of heparanase.
28576927	Hodgkin Lymphoma	CD19	Promote immunity	However, Hodgkin lymphoma lacks CD19 and contains a highly immunosuppressive tumor microenvironment (TME).
28576927	Hodgkin Lymphoma	IL3RA	Inhibit immunity (T cell function); essential for immunotherapy	We demonstrated CD123 on both Hodgkin lymphoma cells and TME, including tumor-associated macrophages (TAM).In vitro, Hodgkin lymphoma cells convert macrophages toward immunosuppressive TAMs that inhibit T-cell proliferation. In contrast, anti-CD123 CART recognized and killed TAMs, thus overcoming immunosuppression.
28575677	Melanoma; Head and Neck Squamous Cell Carcinoma	IFNG	Promote immunity	show that interferon gamma production by a subset of regulatory T?cells in the tumor microenvironment triggers Treg instability locally and restores anti-tumor immunity.
28574228	Cholangiocarcinoma	PRKCI	Inhibit immunity	aPKC-ι induced EMT and immunosuppression by regulating Snail in vitro and in vivo, although aPKC-ι did not directly interact with Snail in coimmunoprecipitation experiments.
28574228	Cholangiocarcinoma	SNAI1	Inhibit immunity	Our findings further indicated that CCA cells with EMT-like features appear to generate immunosuppressive natural T regulatory-like cluster of differentiation 4-positive (CD4+)CD25-cells rather than to increase CD4+CD25+natural T regulatory cells, in part by mediating T regulatory-inducible cytokines such as transforming growth factor β1 and interleukin 2.These results demonstrate that aPKC-ι promotes EMT and induces immunosuppression through the aPKC-ι/P-Sp1/Snail signaling pathway and may be a potential therapeutic target for CCA.
28574228	Cholangiocarcinoma	SP1	Inhibit immunity	P-Sp1 also regulated aPKC-ι/Snail-induced EMT-like changes and immunosuppression in CCA cells.
28574228	Cholangiocarcinoma	TGFB1	Inhibit immunity (T cell function)	Our findings further indicated that CCA cells with EMT-like features appear to generate immunosuppressive natural T regulatory-like cluster of differentiation 4-positive (CD4+)CD25-cells rather than to increase CD4+CD25+natural T regulatory cells, in part by mediating T regulatory-inducible cytokines such as transforming growth factor β1 and interleukin 2.These results demonstrate that aPKC-ι promotes EMT and induces immunosuppression through the aPKC-ι/P-Sp1/Snail signaling pathway and may be a potential therapeutic target for CCA.
28552348	Melanoma; Head and Neck Squamous Cell Carcinoma.	NRP1	Inhibit immunity (T cell function)	Using a mouse model of melanoma where Nrp1-deficient (Nrp1-/-) and wild-type (Nrp1+/+) Tregscan be assessed in a competitive environment, we find that a high proportion of intratumoral Nrp1-/-Tregsproduce interferon-γ (IFNγ), which drives the fragility of surrounding wild-type Tregs, boosts anti-tumor immunity, and facilitates tumor clearance.
28550091	Glioma	IL15	Promote immunity	No autonomous IL13Rα2-CAR.IL15 T-cell proliferation was observed; however, IL15 expression increased IL13Rα2-CAR T-cell viability in the absence of exogenous cytokines or antigen.In vivo, IL13Rα2-CAR.IL15 T cells persisted longer and had greater antiglioma activity than IL13Rα2-CAR T cells, resulting in a survival advantage.
28548102	Thymoma; Mastocytoma	IL33	Promote immunity	Superior anti-tumour efficacy of artLCMV immunotherapy depends on interleukin-33 signalling, and a massive CTLeffinflux triggers an inflammatory conversion of the tumour microenvironment.
28539123	Colorectal Carcinoma	JAK1	Essential for immunotherapy	JAK1 loss-of-function mutations were validated with an overall frequency of 20% in Norwegian and British patients, and mutated tumors had up-regulation of transcriptional signatures associated with resistance to anti-PD-1 treatment.
28536100	Mesothelioma	CSF1R	Inhibit immunity	We show that M-CSFR inhibition using the CSF-1R kinase inhibitor PLX3397 (pexidartinib) effectively reduced numbers of tumor-associated macrophages (TAMs) . TAM depletion could potentially reactivate antitumor immunity.
28536100	Mesothelioma	MAPK1	Inhibit immunity	We show that M-CSFR inhibition using the CSF-1R kinase inhibitor PLX3397 (pexidartinib) effectively reduced numbers of tumor-associated macrophages (TAMs) . TAM depletion could potentially reactivate antitumor immunity.
28533357	Prostate Carcinoma	TLR9	Inhibit immunity	TLR9 expression and secretion of LIF by prostate cancer cells stimulates accumulation and activity of polymorphonuclear MDSCs. The PMN-MDSCs from tetracycline-treated RM9-Tlr9ONtumors increased the immunosuppressive activity of the STAT3 transcription factor, thereby more potently inhibiting T cell proliferation.
28533357	Prostate Carcinoma	LIF	Inhibit immunity	TLR9 expression and secretion of LIF by prostate cancer cells stimulates accumulation and activity of polymorphonuclear MDSCs. The PMN-MDSCs from tetracycline-treated RM9-Tlr9ONtumors increased the immunosuppressive activity of the STAT3 transcription factor, thereby more potently inhibiting T cell proliferation.
28533357	Prostate Carcinoma	STAT3	Inhibit immunity (T cell function)	The PMN-MDSCs from tetracycline-treated RM9-Tlr9ONtumors increased the immunosuppressive activity of the STAT3 transcription factor, thereby more potently inhibiting T cell proliferation.
28533357	Prostate Carcinoma	IL6	Inhibit immunity	TLR9 expression and secretion of LIF by prostate cancer cells stimulates accumulation and activity of polymorphonuclear MDSCs. The PMN-MDSCs from tetracycline-treated RM9-Tlr9ONtumors increased the immunosuppressive activity of the STAT3 transcription factor, thereby more potently inhibiting T cell proliferation. We identified LIF, an IL-6-type cytokine and STAT3 activator, as a potential mediator of crosstalk between TLR9-expressing prostate cancer cells and PMN-MDSCs.
28533272	Melanoma; Renal Cell Carcinoma; Squamous Cell Carcinoma; Glioblastoma; Mastocytoma; Hepatocellular Carcinoma	MAPK1	Promote immunity (T cell function)	PD-1:28 engineering reinstated Th1 function in tumor-infiltrating lymphocytes that had been functionally disabled in the human renal cell carcinoma environment without unleashing undesired Th2 cytokines or IL10. Involved mechanisms may be correlated to restoration of ERK and AKT signaling pathways.
28529313	Acute Myeloid Leukemia	NCR1	Promote immunity	We observed that presence of unlicensed NK cells impacted favorably on clinical outcome, in particular among patients harboring functional NK cells reflected by high expression of the natural cytotoxicity receptor (NCR) NKp46.
28526770	Ovarian Carcinoma	TNF	Promote immunity (infiltration)	We demonstrate superior antitumor efficacy for IgE compared with an otherwise identical IgG in a syngeneic immunocompetent animal, and we identify TNFα/MCP-1 signaling as an IgE-mediated mechanism of monocyte and macrophage activation and recruitment to tumors.
28526770	Ovarian Carcinoma	CCL2	Inhibit immunity	We demonstrate superior antitumor efficacy for IgE compared with an otherwise identical IgG in a syngeneic immunocompetent animal, and we identify TNFα/MCP-1 signaling as an IgE-mediated mechanism of monocyte and macrophage activation and recruitment to tumors.
28512172	Prostate Carcinoma	HMOX1	Inhibit immunity	In this study, we assessed how hemin, a pharmacologic inducer of heme oxygenase-1 (HO-1), has an impact on prostate cancer development in an in vivo conditioning model. Conditioning resulted in increased tumor latency and decreased initial growth rate. Histologic analysis of tumors grown in conditioned mice revealed impaired vascularization. Hemin-treated human umbilical vein endothelial cells (HUVEC) exhibited decreased tubulogenesis in vitro only in the presence of TRAMP-C1-conditioned media. In addition, hemin boosted CD8+ T-cell proliferation and degranulation in vitro and antigen-specific cytotoxicity in vivo A significant systemic increase in CD8+ T-cell frequency was observed in preconditioned tumor-bearing mice.
28512172	Prostate Carcinoma	LGALS1	Inhibit immunity	To gain clinical insight, we used prostate cancer patient-derived samples in our studies to assess the expression of HO-1 and other relevant genes.Results:Conditioning resulted in increased tumor latency and decreased initial growth rate. Tumors from hemin-conditioned mice showed reduced expression of galectin-1 (Gal-1), key modulator of tumor angiogenesis and immunity, evidencing persistent remodeling of the microenvironment.
28507029	Cervical Carcinoma	CD63	Promote immunity (T cell function)	CD63-Mediated Antigen Delivery into Extracellular Vesicles via DNA Vaccination Results in Robust CD8+T Cell Responses. CD63 delivery into EVs led to better CD8+T cell responses than calnexin delivery into the endoplasmic reticulum.
28504304	Lung Carcinoma	CD5	Inhibit immunity	We focus on the regulation of the anti-tumor immune response by two paradigmatic SRs: the lymphocyte receptor CD5 and the more broadly distributed scavenger receptor class B type 1 (SR-B1). Cancer immunity can be boosted by blockade of SRs working as immune checkpoint inhibitors (CD5) and/or by proper engagement of SRs working as innate danger receptor (SR-B1).
28504304	Lung Carcinoma	SCARB1	Inhibit immunity (T cell function); essential for immunotherapy	We focus on the regulation of the anti-tumor immune response by two paradigmatic SRs: the lymphocyte receptor CD5 and the more broadly distributed scavenger receptor class B type 1 (SR-B1). Cancer immunity can be boosted by blockade of SRs working as immune checkpoint inhibitors (CD5) and/or by proper engagement of SRs working as innate danger receptor (SR-B1).
28497804	Glioma	STAT3	Inhibit immunity (T cell function); essential for immunotherapy	However, some preclinical trial data suggest that addition of immunomodulatory reagents such as immune checkpoint inhibitors, transforming growth factor-β inhibitors, signal transducer and activator of transcription 3 inhibitors, or modifiers of tryptophan metabolism could augment the therapeutic activity of vaccination and overcome glioma-associated immunosuppression.
28497804	Glioma	TGFB1	Inhibit immunity (T cell function); essential for immunotherapy	However, some preclinical trial data suggest that addition of immunomodulatory reagents such as immune checkpoint inhibitors, transforming growth factor-β inhibitors, signal transducer and activator of transcription 3 inhibitors, or modifiers of tryptophan metabolism could augment the therapeutic activity of vaccination and overcome glioma-associated immunosuppression.
28497796	Melanoma	IL2	Promote immunity (T cell function)	Potent antitumour activity of interleukin-2-Fc fusion proteins requires Fc-mediated depletion of regulatory T-cells. Here we describe a novel determinant of antitumour activity using fusion proteins consisting of IL-2 and the antibody fragment crystallizable (Fc) region.
28494239	Endemic Burkitt Lymphoma	CFLAR	Inhibit immunity	Our systematic approach uncovered key mechanisms by which EBV oncoproteins activate the PI3K/AKT pathway and evade tumor suppressor responses. LMP1-induced cFLIP was found to be critical for LCL defense against TNFα-mediated programmed cell death, whereas EBV-induced BATF/IRF4 were critical for BIM suppression and MYC induction in LCLs.
28494239	Endemic Burkitt Lymphoma	BATF	Inhibit immunity	Our systematic approach uncovered key mechanisms by which EBV oncoproteins activate the PI3K/AKT pathway and evade tumor suppressor responses. LMP1-induced cFLIP was found to be critical for LCL defense against TNFα-mediated programmed cell death, whereas EBV-induced BATF/IRF4 were critical for BIM suppression and MYC induction in LCLs.
28494239	Endemic Burkitt Lymphoma	IRF4	Inhibit immunity	Our systematic approach uncovered key mechanisms by which EBV oncoproteins activate the PI3K/AKT pathway and evade tumor suppressor responses. LMP1-induced cFLIP was found to be critical for LCL defense against TNFα-mediated programmed cell death, whereas EBV-induced BATF/IRF4 were critical for BIM suppression and MYC induction in LCLs.
28486109	Melanoma	ITGAE	Promote immunity (T cell function)	Our data indicate that lack of CD103+DCs within the tumor microenvironment dominantly resists the effector phase of an anti-tumor T?cell response, contributing to immune escape.
28486109	Melanoma	CXCL10	Promote immunity (infiltration)	Mechanistically, this was due to the absence of CXCL9/10, which we found to be produced by CD103+dendritic cells (DCs) in T?cell-inflamed tumors. Our data indicate that lack of CD103+DCs within the tumor microenvironment dominantly resists the effector phase of an anti-tumor T?cell response, contributing to immune escape.
28486109	Melanoma	CXCL9	Promote immunity (infiltration)	Mechanistically, this was due to the absence of CXCL9/10, which we found to be produced by CD103+dendritic cells (DCs) in T?cell-inflamed tumors. Our data indicate that lack of CD103+DCs within the tumor microenvironment dominantly resists the effector phase of an anti-tumor T?cell response, contributing to immune escape.
28484017	Melanoma	CTLA4	Inhibit immunity (T cell function); essential for immunotherapy	In particular, the use of function blocking monoclonal antibodies targeting checkpoint inhibitors such as CTLA-4 and PD-1 have proven to be highly effective for the systemic activation of the human immune system to treat a wide range of cancers. Ipilimumab is a fully human antibody targeting CTLA-4 that received FDA approval for the treatment of metastatic melanoma in 2011. This structure reveals that ipilimumab contacts the front β-sheet of CTLA-4 and intersects with the CTLA-4:Β7 recognition surface, indicating that direct steric overlap between ipilimumab and the B7 ligands is a major mechanistic contributor to ipilimumab function.
28483787	Breast Neoplasm	TNFRSF4	Promote immunity (T cell function)	Immune cell infiltrates of untreated tumor-bearing neu/N mice expressed high numbers of PD1 and OX40 receptors on their CD8+T cells, and PD-L1 was highly expressed on both myeloid and tumor cells. Modulating PD-L1 and OX40 receptor signaling combined with intratumoral ADU S-100 administration enhanced HER-2-specific CD8+T-cell activity, clearing tumors in 40% of neu/N mice.
28483787	Breast Neoplasm	CD274	Inhibit immunity (T cell function); essential for immunotherapy	Immune cell infiltrates of untreated tumor-bearing neu/N mice expressed high numbers of PD1 and OX40 receptors on their CD8+T cells, and PD-L1 was highly expressed on both myeloid and tumor cells. Modulating PD-L1 and OX40 receptor signaling combined with intratumoral ADU S-100 administration enhanced HER-2-specific CD8+T-cell activity, clearing tumors in 40% of neu/N mice.
28483787	Breast Neoplasm	IFNB1	Promote immunity (T cell function)	Stimulator of interferon genes (STING) signaling induces IFNβ production by intratumoral dendritic cells (DC), driving T-cell priming and recruitment into the tumor microenvironment (TME).
28478231	Non-Small Cell Lung Carcinoma	STAT3	Inhibit immunity (T cell function)	Radiotherapy may up-regulate PD-L1 expression through the phosphoinositide 3-kinase/AKT and signal transducer and activator of transcription 3 pathways.
28478231	Non-Small Cell Lung Carcinoma	PIK3CG	Inhibit immunity (T cell function)	Radiotherapy may up-regulate PD-L1 expression through the phosphoinositide 3-kinase/AKT and signal transducer and activator of transcription 3 pathways.
28478231	Non-Small Cell Lung Carcinoma	AKT1	Inhibit immunity (T cell function)	Radiotherapy may up-regulate PD-L1 expression through the phosphoinositide 3-kinase/AKT and signal transducer and activator of transcription 3 pathways.
28473400	Colon Carcinoma	IL2	Promote immunity	combining administration of an engineered mouse serum albumin/IL-2 fusion with an Fc fusion to an integrin-binding peptide (2.5F-Fc), significant survival improvements are achieved in three syngeneic mouse tumor models, including complete responses with protective immunity.
28473315	Triple-Negative Breast Carcinoma	TNFRSF9	Promote immunity (T cell function)	4-1BB-Enhanced Expansion of CD8+TIL from Triple-Negative Breast Cancer Unveils Mutation-Specific CD8+T Cells. This observation led us to hypothesize that CD8+TIL could be utilized in autologous adoptive cell therapy for TNBC, although this concept has proven to be challenging, given the difficulty in expanding CD8+TILs in solid cancers other than in melanoma. To overcome this obstacle, we used an agonistic antibody (urelumab) to a TNFR family member, 4-1BB/CD137, which is expressed by recently activated CD8+T cells.
28470686	Pancreatic Carcinoma; Ampulla of Vater Carcinoma	CD274	Inhibit immunity (T cell function)	Our aim was to examine the expression of the immune inhibiting molecules PD-L1, Galectin-9, HVEM, IDO and HLA-G, as well as CD8+ and FoxP3+ tumor infiltrating lymphocytes (TIL), in pancreatic and ampullary cancers, and to relate their individual, as well as their combined expression, to cancer survival. Expression of immune inhibitory molecules and TIL was examined by immunohistochemistry. We show that immune inhibitory molecules are prevalently expressed. Moreover, high tumor expression of PD-L1 (p?=?0.002), Gal-9 (p?=?0.003), HVEM (p?=?0.001), IDO (p?=?0.049), HLA-G (p?=?0.004) and high CD8/FoxP3 TIL ratio (p?=?0.006) were associated with improved cancer-specific survival.
28470686	Pancreatic Carcinoma; Ampulla of Vater Carcinoma	LGALS9	Inhibit immunity (T cell function)	Our aim was to examine the expression of the immune inhibiting molecules PD-L1, Galectin-9, HVEM, IDO and HLA-G, as well as CD8+ and FoxP3+ tumor infiltrating lymphocytes (TIL), in pancreatic and ampullary cancers, and to relate their individual, as well as their combined expression, to cancer survival. Expression of immune inhibitory molecules and TIL was examined by immunohistochemistry. We show that immune inhibitory molecules are prevalently expressed. Moreover, high tumor expression of PD-L1 (p?=?0.002), Gal-9 (p?=?0.003), HVEM (p?=?0.001), IDO (p?=?0.049), HLA-G (p?=?0.004) and high CD8/FoxP3 TIL ratio (p?=?0.006) were associated with improved cancer-specific survival.
28470686	Pancreatic Carcinoma; Ampulla of Vater Carcinoma	TNFRSF14	Inhibit immunity (T cell function)	Our aim was to examine the expression of the immune inhibiting molecules PD-L1, Galectin-9, HVEM, IDO and HLA-G, as well as CD8+ and FoxP3+ tumor infiltrating lymphocytes (TIL), in pancreatic and ampullary cancers, and to relate their individual, as well as their combined expression, to cancer survival. Expression of immune inhibitory molecules and TIL was examined by immunohistochemistry. We show that immune inhibitory molecules are prevalently expressed. Moreover, high tumor expression of PD-L1 (p?=?0.002), Gal-9 (p?=?0.003), HVEM (p?=?0.001), IDO (p?=?0.049), HLA-G (p?=?0.004) and high CD8/FoxP3 TIL ratio (p?=?0.006) were associated with improved cancer-specific survival.
28470686	Pancreatic Carcinoma; Ampulla of Vater Carcinoma	IDO1	Inhibit immunity (T cell function)	Our aim was to examine the expression of the immune inhibiting molecules PD-L1, Galectin-9, HVEM, IDO and HLA-G, as well as CD8+ and FoxP3+ tumor infiltrating lymphocytes (TIL), in pancreatic and ampullary cancers, and to relate their individual, as well as their combined expression, to cancer survival. Expression of immune inhibitory molecules and TIL was examined by immunohistochemistry. We show that immune inhibitory molecules are prevalently expressed. Moreover, high tumor expression of PD-L1 (p?=?0.002), Gal-9 (p?=?0.003), HVEM (p?=?0.001), IDO (p?=?0.049), HLA-G (p?=?0.004) and high CD8/FoxP3 TIL ratio (p?=?0.006) were associated with improved cancer-specific survival.
28470686	Pancreatic Carcinoma; Ampulla of Vater Carcinoma	HLA-G	Inhibit immunity (T cell function)	Our aim was to examine the expression of the immune inhibiting molecules PD-L1, Galectin-9, HVEM, IDO and HLA-G, as well as CD8+ and FoxP3+ tumor infiltrating lymphocytes (TIL), in pancreatic and ampullary cancers, and to relate their individual, as well as their combined expression, to cancer survival. Expression of immune inhibitory molecules and TIL was examined by immunohistochemistry. We show that immune inhibitory molecules are prevalently expressed. Moreover, high tumor expression of PD-L1 (p?=?0.002), Gal-9 (p?=?0.003), HVEM (p?=?0.001), IDO (p?=?0.049), HLA-G (p?=?0.004) and high CD8/FoxP3 TIL ratio (p?=?0.006) were associated with improved cancer-specific survival.
28470686	Pancreatic Carcinoma; Ampulla of Vater Carcinoma	FOXP3	Inhibit immunity (T cell function)	Our aim was to examine the expression of the immune inhibiting molecules PD-L1, Galectin-9, HVEM, IDO and HLA-G, as well as CD8+ and FoxP3+ tumor infiltrating lymphocytes (TIL), in pancreatic and ampullary cancers, and to relate their individual, as well as their combined expression, to cancer survival. Expression of immune inhibitory molecules and TIL was examined by immunohistochemistry. We show that immune inhibitory molecules are prevalently expressed. Moreover, high tumor expression of PD-L1 (p?=?0.002), Gal-9 (p?=?0.003), HVEM (p?=?0.001), IDO (p?=?0.049), HLA-G (p?=?0.004) and high CD8/FoxP3 TIL ratio (p?=?0.006) were associated with improved cancer-specific survival.
28468914	Melanoma	DDX58	Promote immunity (T cell function)	Scavenging of hypoxia-induced reactive oxygen species by vitamin C restored the inducible expression of RIG-I under hypoxiain vitro, boostedin vitroanti-melanoma NK- and CD8+T-cell attack, and augmented 3pRNA antitumor efficacyin vivoThese results demonstrate that RIG-I remains operational under hypoxia and that RIG-I function is largely insensitive to lower cell surface expression of the IFNα receptor.
28465528	Chronic Lymphocytic Leukemia	WNT5A	Inhibit immunity (T cell function)	Wnt5a induces ROR1 to associate with 14-3-3ζ for enhanced chemotaxis and proliferation of chronic lymphocytic leukemia cells. Wnt5a can activate Rho GTPases in chronic lymphocytic leukemia (CLL) cells by inducing the recruitment of ARHGEF2 to ROR1. The capacity of Wnt5a to induce ROR1 to complex with 14-3-3ζ could be blocked in CLL cells by treatment with cirmtuzumab, a humanized mAb targeting ROR1.
28465528	Chronic Lymphocytic Leukemia	ROR1	Inhibit immunity (T cell function); essential for immunotherapy	Wnt5a induces ROR1 to associate with 14-3-3ζ for enhanced chemotaxis and proliferation of chronic lymphocytic leukemia cells. Wnt5a can activate Rho GTPases in chronic lymphocytic leukemia (CLL) cells by inducing the recruitment of ARHGEF2 to ROR1. The capacity of Wnt5a to induce ROR1 to complex with 14-3-3ζ could be blocked in CLL cells by treatment with cirmtuzumab, a humanized mAb targeting ROR1.
28465453	Lung Carcinoma	CD47	Inhibit immunity	In this issue ofCancer Immunology Research, Zhang and colleagues reduced tumors by inhibiting CD47 in a lung carcinoma model, a treatment that inadvertently induced autophagy through inhibition of the Akt/mTOR pathway.
28465358	Glioma	IDH1	Promote immunity (T cell function)	Also, we showed that IDH1 mutations caused down-regulation of leukocyte chemotaxis, resulting in repression of the tumor-associated immune system.
28465341	Chronic Lymphocytic Leukemia	CD1D	Inhibit immunity (T cell function)	CD1d-restricted invariant natural killer T (iNKT) cells are innate-like T lymphocytes strongly implicated in tumor surveillance. We found that Tcl1-CLL cells express CD1d and that iNKT cells critically delay disease onset but become functionally impaired upon disease progression. In patients, disease progression correlates with high CD1d expression on CLL cells and impaired iNKT cells. Conversely, disease stability correlates with negative or low CD1d expression on CLL cells and normal iNKT cells, suggesting indirect leukemia control.
28453702	Ovarian Seromucinous Carcinoma	TLR8	Promote immunity	A phase 2, randomized, placebo-controlled trial was conducted in women with recurrent epithelial ovarian carcinoma to evaluate the efficacy and safety of motolimod-a Toll-like receptor 8 (TLR8) agonist that stimulates robust innate immune responses-combined with pegylated liposomal doxorubicin (PLD), a chemotherapeutic that induces immunogenic cell death.
28446465	Lung Carcinoma	LDHA	Inhibit immunity (T cell function)	Our results suggest that expressions of LDH-A and lactate by macrophage in the tumor microenvironment are major drivers of T-cell immunosuppression, strongly supporting the concept of targeting stromal LDH-A as an effective strategy to blunt tumoral immune escape.
28443091	Head and Neck Squamous Cell Carcinoma	KLRK1	Promote immunity (NK and T cell function)	The natural killer group 2D (NKG2D) receptors on natural killer (NK) cells and several T cell subsets play an important role for immunosurveillance of HNSCC and are thus targeted by tumor immune evasion strategies in particular by shedding of various NKG2D ligands (NKG2DLs).
28442553	Pancreatic Carcinoma	NLRP3	Inhibit immunity (T cell function); essential for immunotherapy	NLRP3 signaling drives macrophage-induced adaptive immune suppression in pancreatic carcinoma. Pharmacological inhibition or deletion of NLRP3, ASC (apoptosis-associated speck-like protein containing a CARD complex), or caspase-1 protected against PDA and was associated with immunogenic reprogramming of innate and adaptive immunity within the TME.
28442553	Pancreatic Carcinoma	IL10	Inhibit immunity (T cell function)	NLRP3 signaling drives macrophage-induced adaptive immune suppression in pancreatic carcinoma. The suppressive effects of NLRP3 signaling were IL-10 dependent.
28442553	Pancreatic Carcinoma	PYCARD	Inhibit immunity (T cell function)	Pharmacological inhibition or deletion of NLRP3, ASC (apoptosis-associated speck-like protein containing a CARD complex), or caspase-1 protected against PDA and was associated with immunogenic reprogramming of innate and adaptive immunity within the TME.
28442553	Pancreatic Carcinoma	CASP1	Inhibit immunity (T cell function)	Pharmacological inhibition or deletion of NLRP3, ASC (apoptosis-associated speck-like protein containing a CARD complex), or caspase-1 protected against PDA and was associated with immunogenic reprogramming of innate and adaptive immunity within the TME.
23619361	Acute Myeloid Leukemia	CD40	Promote immunity (T cell function)	CD40 ligation reverses T cell tolerance in acute myeloid leukemia. Administration of agonistic anti-CD40 Ab to activate host APCs enhanced accumulation of functional T cells and prolonged survival.
23613317	Glioma	IL10	Inhibit immunity (T cell function)	Stimulation of monocytes with IL-10 alone could significantly increase B7-H1 expression, sufficient to induce T-cell apoptosis when cocultured with stimulated monocytes. Gliomas can upregulate B7-H1 expression in circulating monocytes and tumor-infiltrative macrophages through modulation of autocrine/paracrine IL-10 signaling, resulting in an immunosuppressive phenotype.
23613317	Glioma	CD274	Inhibit immunity (T cell function)	Stimulation of monocytes with IL-10 alone could significantly increase B7-H1 expression, sufficient to induce T-cell apoptosis when cocultured with stimulated monocytes. Gliomas can upregulate B7-H1 expression in circulating monocytes and tumor-infiltrative macrophages through modulation of autocrine/paracrine IL-10 signaling, resulting in an immunosuppressive phenotype.
23612011	Lung Carcinoma	MST1R	Inhibit immunity (T cell function)	Our data show that loss of Ron function promotes an effective antitumor CD8(+) T-cell response, which specifically inhibits outgrowth of seeded metastatic colonies.
23610143	Colorectal Carcinoma	ERAP1	Inhibit immunity (T cell function)	BALB/c mice with reduced ERAAP expression challenged with CT26 induced protective immunity that was mediated by CD8(+) T cells. Furthermore, boosting the tumor immunogenicity through inhibition of ERAAP function with the small molecule inhibitor leucinethiol in vitro, or in established tumors in vivo, abrogated tumor growth and prolonged survival.
23601686	Melanoma	SOCS1	Inhibit immunity (T cell function)	Consistently, enforced expression of SOCS-1 in CD8(+) T?cells phenocopied the miRNA-155 deficiency, whereas SOCS-1 silencing augmented tumor destruction. These findings identify miRNA-155 and its target SOCS-1 as key regulators of effector CD8(+) T?cells that can be modulated to potentiate immunotherapies for infectious diseases and cancer.
23580578	Lung Carcinoma	CTLA4	Inhibit immunity (T cell function); essential for immunotherapy	Immunomodulatory antibodies directed against cytotoxic T cell-associated antigen 4 (CTLA-4/CD152) and programmed cell death ligand 1 (PDL1/CD274) showed clinical efficacy in patients with lung cancer.
23580578	Lung Carcinoma	CD274	Inhibit immunity (T cell function)	Immunomodulatory antibodies directed against cytotoxic T cell-associated antigen 4 (CTLA-4/CD152) and programmed cell death ligand 1 (PDL1/CD274) showed clinical efficacy in patients with lung cancer.
23580577	Lymphoma	NCR3	Promote immunity	Marked elevations in expression of activation receptors, natural cytotoxicity receptors (NKp30, NKp44), and adhesion molecules (CD11a, ICAM-1) were associated with high tumor-lytic capacity, in both in vitro and in vivo models.
23580577	Lymphoma	NCR2	Promote immunity	Marked elevations in expression of activation receptors, natural cytotoxicity receptors (NKp30, NKp44), and adhesion molecules (CD11a, ICAM-1) were associated with high tumor-lytic capacity, in both in vitro and in vivo models.
23580577	Lymphoma	ITGAL	Promote immunity	Marked elevations in expression of activation receptors, natural cytotoxicity receptors (NKp30, NKp44), and adhesion molecules (CD11a, ICAM-1) were associated with high tumor-lytic capacity, in both in vitro and in vivo models.
23580577	Lymphoma	ICAM1	Promote immunity	Marked elevations in expression of activation receptors, natural cytotoxicity receptors (NKp30, NKp44), and adhesion molecules (CD11a, ICAM-1) were associated with high tumor-lytic capacity, in both in vitro and in vivo models.
23562161	Colon Carcinoma	P2RX7	Promote immunity (infiltration)	Manipulations preventing tumor infiltration by CD11c(+)CD11b(+)Ly6C(hi) cells,?such as the local overexpression of ectonucleotidases, the blockade of purinergic receptors, or the neutralization of CD11b, abolished the immune?system-dependent antitumor activity of anthracyclines.
23562161	Colon Carcinoma	ITGAM	Inhibit immunity	Manipulations preventing tumor infiltration by CD11c(+)CD11b(+)Ly6C(hi) cells,?such as the local overexpression of ectonucleotidases, the blockade of purinergic receptors, or the neutralization of CD11b, abolished the immune?system-dependent antitumor activity of anthracyclines.
23536636	Melanoma	PDCD1	Inhibit immunity (T cell function)	Concomitantly, tumor-specific CD4(+) T effector cells showed traits of chronic exhaustion, as evidenced by their high expression of the PD-1, TIM-3, 2B4, TIGIT, and LAG-3 inhibitory molecules. Although blockade of the PD-1/PD-L1 pathway with anti-PD-L1 Abs or depletion of tumor-specific regulatory T cells (Tregs) alone failed to reverse tumor recurrence, the combination of PD-L1 blockade with tumor-specific Treg depletion effectively mediated disease regression.
23536636	Melanoma	HAVCR2	Inhibit immunity	Concomitantly, tumor-specific CD4(+) T effector cells showed traits of chronic exhaustion, as evidenced by their high expression of the PD-1, TIM-3, 2B4, TIGIT, and LAG-3 inhibitory molecules. Although blockade of the PD-1/PD-L1 pathway with anti-PD-L1 Abs or depletion of tumor-specific regulatory T cells (Tregs) alone failed to reverse tumor recurrence, the combination of PD-L1 blockade with tumor-specific Treg depletion effectively mediated disease regression.
23536636	Melanoma	CD244	Inhibit immunity (T cell function); essential for immunotherapy	Concomitantly, tumor-specific CD4(+) T effector cells showed traits of chronic exhaustion, as evidenced by their high expression of the PD-1, TIM-3, 2B4, TIGIT, and LAG-3 inhibitory molecules. Although blockade of the PD-1/PD-L1 pathway with anti-PD-L1 Abs or depletion of tumor-specific regulatory T cells (Tregs) alone failed to reverse tumor recurrence, the combination of PD-L1 blockade with tumor-specific Treg depletion effectively mediated disease regression.
23536636	Melanoma	TIGIT	Inhibit immunity (T cell function); essential for immunotherapy	Concomitantly, tumor-specific CD4(+) T effector cells showed traits of chronic exhaustion, as evidenced by their high expression of the PD-1, TIM-3, 2B4, TIGIT, and LAG-3 inhibitory molecules. Although blockade of the PD-1/PD-L1 pathway with anti-PD-L1 Abs or depletion of tumor-specific regulatory T cells (Tregs) alone failed to reverse tumor recurrence, the combination of PD-L1 blockade with tumor-specific Treg depletion effectively mediated disease regression.
23536636	Melanoma	LAG3	Inhibit immunity (T cell function); essential for immunotherapy	Concomitantly, tumor-specific CD4(+) T effector cells showed traits of chronic exhaustion, as evidenced by their high expression of the PD-1, TIM-3, 2B4, TIGIT, and LAG-3 inhibitory molecules. Although blockade of the PD-1/PD-L1 pathway with anti-PD-L1 Abs or depletion of tumor-specific regulatory T cells (Tregs) alone failed to reverse tumor recurrence, the combination of PD-L1 blockade with tumor-specific Treg depletion effectively mediated disease regression.
23530148	Myeloid Leukemia; Burkitt Lymphoma; Colon Carcinoma	CRTAM	Promote immunity (T cell function)	CRTAM receptor engagement by Necl-2 on tumor cells triggers cell death of activated Vγ9Vδ2 T cells.
23530146	Lymphoma	ADIPOQ	Inhibit immunity (NK cell function)	Previously, we found that adiponectin (APN) suppresses IL-2-induced NK cell activation by downregulating the expression of the IFN-γ-inducible TNF-related apoptosis-inducing ligand and Fas ligand. In this study, we assessed the role of APN in immune cell function, including NK cells, CTLs, and myeloid-derived suppressor cells, in EL4 and B16F10 tumor-bearing APN knockout (KO) mice. In APNKO mice, splenic NK cells showed enhanced cytotoxicity with and without IL-2 stimulation.
23530146	Lymphoma	IFNG	Promote immunity (T cell function)	Previously, we found that adiponectin (APN) suppresses IL-2-induced NK cell activation by downregulating the expression of the IFN-γ-inducible TNF-related apoptosis-inducing ligand and Fas ligand. In this study, we assessed the role of APN in immune cell function, including NK cells, CTLs, and myeloid-derived suppressor cells, in EL4 and B16F10 tumor-bearing APN knockout (KO) mice. In APNKO mice, splenic NK cells showed enhanced cytotoxicity with and without IL-2 stimulation.
23530146	Lymphoma	TNFSF10	Promote immunity (T cell function)	Previously, we found that adiponectin (APN) suppresses IL-2-induced NK cell activation by downregulating the expression of the IFN-γ-inducible TNF-related apoptosis-inducing ligand and Fas ligand. In this study, we assessed the role of APN in immune cell function, including NK cells, CTLs, and myeloid-derived suppressor cells, in EL4 and B16F10 tumor-bearing APN knockout (KO) mice. In APNKO mice, splenic NK cells showed enhanced cytotoxicity with and without IL-2 stimulation.
23530146	Lymphoma	FASLG	Promote immunity (T cell function)	Previously, we found that adiponectin (APN) suppresses IL-2-induced NK cell activation by downregulating the expression of the IFN-γ-inducible TNF-related apoptosis-inducing ligand and Fas ligand. In this study, we assessed the role of APN in immune cell function, including NK cells, CTLs, and myeloid-derived suppressor cells, in EL4 and B16F10 tumor-bearing APN knockout (KO) mice. In APNKO mice, splenic NK cells showed enhanced cytotoxicity with and without IL-2 stimulation.
23526433	Breast Carcinoma; Pancreatic Carcinoma; Prostate Carcinoma	MICA	Promote immunity (T cell function)	The interaction of the MHC class I-related chain molecules A and B (MICA and MICB) with the corresponding natural killer group 2, member D (NKG2D) receptor triggers cytotoxic effector activity of natural killer cells and certain T-cell subsets and provides a costimulatory signal for cytokine production. Flow cytometry and enzyme-linked immunosorbent assay (ELISA) revealed that all tested tumor cells constitutively expressed MICA and MICB on the cell surface and also released NKG2D ligands into the supernatant. Studies using RNA interference not only revealed a prominent role of ADAM10 and ADAM17 in NKG2D ligand shedding but also a tumor cell-specific role of ADAM10 and/or ADAM17 in shedding of MICA or MICB. These data indicate that the release of NKG2D ligands from individual tumor entities is by far more complex than suggested in previously reported MICA/B transfection systems.
23526433	Breast Carcinoma; Pancreatic Carcinoma; Prostate Carcinoma	MICB	Promote immunity (T cell function)	The interaction of the MHC class I-related chain molecules A and B (MICA and MICB) with the corresponding natural killer group 2, member D (NKG2D) receptor triggers cytotoxic effector activity of natural killer cells and certain T-cell subsets and provides a costimulatory signal for cytokine production. Flow cytometry and enzyme-linked immunosorbent assay (ELISA) revealed that all tested tumor cells constitutively expressed MICA and MICB on the cell surface and also released NKG2D ligands into the supernatant. Studies using RNA interference not only revealed a prominent role of ADAM10 and ADAM17 in NKG2D ligand shedding but also a tumor cell-specific role of ADAM10 and/or ADAM17 in shedding of MICA or MICB. These data indicate that the release of NKG2D ligands from individual tumor entities is by far more complex than suggested in previously reported MICA/B transfection systems.
23526433	Breast Carcinoma; Pancreatic Carcinoma; Prostate Carcinoma	KLRK1	Promote immunity (NK cell function)	The interaction of the MHC class I-related chain molecules A and B (MICA and MICB) with the corresponding natural killer group 2, member D (NKG2D) receptor triggers cytotoxic effector activity of natural killer cells and certain T-cell subsets and provides a costimulatory signal for cytokine production. Flow cytometry and enzyme-linked immunosorbent assay (ELISA) revealed that all tested tumor cells constitutively expressed MICA and MICB on the cell surface and also released NKG2D ligands into the supernatant. Studies using RNA interference not only revealed a prominent role of ADAM10 and ADAM17 in NKG2D ligand shedding but also a tumor cell-specific role of ADAM10 and/or ADAM17 in shedding of MICA or MICB. These data indicate that the release of NKG2D ligands from individual tumor entities is by far more complex than suggested in previously reported MICA/B transfection systems.
23526433	Breast Carcinoma; Pancreatic Carcinoma; Prostate Carcinoma	ADAM10	Inhibit immunity (NK cell function)	The interaction of the MHC class I-related chain molecules A and B (MICA and MICB) with the corresponding natural killer group 2, member D (NKG2D) receptor triggers cytotoxic effector activity of natural killer cells and certain T-cell subsets and provides a costimulatory signal for cytokine production. Flow cytometry and enzyme-linked immunosorbent assay (ELISA) revealed that all tested tumor cells constitutively expressed MICA and MICB on the cell surface and also released NKG2D ligands into the supernatant. Studies using RNA interference not only revealed a prominent role of ADAM10 and ADAM17 in NKG2D ligand shedding but also a tumor cell-specific role of ADAM10 and/or ADAM17 in shedding of MICA or MICB. These data indicate that the release of NKG2D ligands from individual tumor entities is by far more complex than suggested in previously reported MICA/B transfection systems.
23526433	Breast Carcinoma; Pancreatic Carcinoma; Prostate Carcinoma	ADAM17	Inhibit immunity (T cell function)	The interaction of the MHC class I-related chain molecules A and B (MICA and MICB) with the corresponding natural killer group 2, member D (NKG2D) receptor triggers cytotoxic effector activity of natural killer cells and certain T-cell subsets and provides a costimulatory signal for cytokine production. Flow cytometry and enzyme-linked immunosorbent assay (ELISA) revealed that all tested tumor cells constitutively expressed MICA and MICB on the cell surface and also released NKG2D ligands into the supernatant. Studies using RNA interference not only revealed a prominent role of ADAM10 and ADAM17 in NKG2D ligand shedding but also a tumor cell-specific role of ADAM10 and/or ADAM17 in shedding of MICA or MICB. These data indicate that the release of NKG2D ligands from individual tumor entities is by far more complex than suggested in previously reported MICA/B transfection systems.
23520337	Leukemia; Lymphoma	TLR3	Promote immunity	Stimulation of TLR3, which among host hematopoietic APC subsets is predominantly expressed on CD8(+) DCs, enhanced GVT without exacerbating GVHD.
23514705	Pancreatic Carcinoma	IL6	Inhibit immunity (T cell function)	Luminex analysis indicated that PSC but not human fetal primary pancreatic fibroblast cells (HPF; negative controls) produced MDSC-promoting cytokines [interleukin (IL-6), VEGF, macrophage colony-stimulating factor (M-CSF) ] and chemokines (SDF-1, MCP-1).
23514705	Pancreatic Carcinoma	VEGFA	Inhibit immunity (T cell function)	Luminex analysis indicated that PSC but not human fetal primary pancreatic fibroblast cells (HPF; negative controls) produced MDSC-promoting cytokines [interleukin (IL-6), VEGF, macrophage colony-stimulating factor (M-CSF) ] and chemokines (SDF-1, MCP-1).
23514705	Pancreatic Carcinoma	CSF1	Inhibit immunity (T cell function)	Luminex analysis indicated that PSC but not human fetal primary pancreatic fibroblast cells (HPF; negative controls) produced MDSC-promoting cytokines [interleukin (IL-6), VEGF, macrophage colony-stimulating factor (M-CSF) ] and chemokines (SDF-1, MCP-1).
23514705	Pancreatic Carcinoma	CXCL12	Inhibit immunity (T cell function)	Luminex analysis indicated that PSC but not human fetal primary pancreatic fibroblast cells (HPF; negative controls) produced MDSC-promoting cytokines [interleukin (IL-6), VEGF, macrophage colony-stimulating factor (M-CSF) ] and chemokines (SDF-1, MCP-1).
23514705	Pancreatic Carcinoma	CCL2	Inhibit immunity (T cell function)	Luminex analysis indicated that PSC but not human fetal primary pancreatic fibroblast cells (HPF; negative controls) produced MDSC-promoting cytokines [interleukin (IL-6), VEGF, macrophage colony-stimulating factor (M-CSF) ] and chemokines (SDF-1, MCP-1).
23514705	Pancreatic Carcinoma	STAT3	Inhibit immunity (T cell function)	Pancreatic cancer-associated stellate cells promote differentiation of myeloid-derived suppressor cells in a STAT3-dependent manner.
23509364	Breast Carcinoma; Hepatocellular Carcinoma; Colorectal Carcinoma	KLRK1	Promote immunity	NK group 2, member D (NKG2D) is an NK cell-activating receptor crucially involved in cancer immunosurveillance.
23509364	Breast Carcinoma; Hepatocellular Carcinoma	GSK3B	Inhibit immunity	NK group 2, member D (NKG2D) is an NK cell-activating receptor crucially involved in cancer immunosurveillance. In this study, we show that induction of EMT by TGF-β stimulation of human keratinocytes, by glycogen synthase kinase-3β inhibition in several epithelial tumor cell lines, and by Snail1 overexpression in colorectal cancer cells strongly upregulated the expression of NKG2D ligands (NKG2DLs), MHC class I chain-related molecules A and B (MICA/B) and ULBP1-3.
23509364	Colorectal Carcinoma	SNAI1	Promote immunity	NK group 2, member D (NKG2D) is an NK cell-activating receptor crucially involved in cancer immunosurveillance. In this study, we show that induction of EMT by TGF-β stimulation of human keratinocytes, by glycogen synthase kinase-3β inhibition in several epithelial tumor cell lines, and by Snail1 overexpression in colorectal cancer cells strongly upregulated the expression of NKG2D ligands (NKG2DLs), MHC class I chain-related molecules A and B (MICA/B) and ULBP1-3.
23509364	Breast Carcinoma; Hepatocellular Carcinoma; Colorectal Carcinoma	MICA	Promote immunity	NK group 2, member D (NKG2D) is an NK cell-activating receptor crucially involved in cancer immunosurveillance. In this study, we show that induction of EMT by TGF-β stimulation of human keratinocytes, by glycogen synthase kinase-3β inhibition in several epithelial tumor cell lines, and by Snail1 overexpression in colorectal cancer cells strongly upregulated the expression of NKG2D ligands (NKG2DLs), MHC class I chain-related molecules A and B (MICA/B) and ULBP1-3.
23509364	Breast Carcinoma; Hepatocellular Carcinoma; Colorectal Carcinoma	MICB	Promote immunity	NK group 2, member D (NKG2D) is an NK cell-activating receptor crucially involved in cancer immunosurveillance. In this study, we show that induction of EMT by TGF-β stimulation of human keratinocytes, by glycogen synthase kinase-3β inhibition in several epithelial tumor cell lines, and by Snail1 overexpression in colorectal cancer cells strongly upregulated the expression of NKG2D ligands (NKG2DLs), MHC class I chain-related molecules A and B (MICA/B) and ULBP1-3.
23509364	Breast Carcinoma; Hepatocellular Carcinoma; Colorectal Carcinoma	ULBP1	Promote immunity	NK group 2, member D (NKG2D) is an NK cell-activating receptor crucially involved in cancer immunosurveillance. In this study, we show that induction of EMT by TGF-β stimulation of human keratinocytes, by glycogen synthase kinase-3β inhibition in several epithelial tumor cell lines, and by Snail1 overexpression in colorectal cancer cells strongly upregulated the expression of NKG2D ligands (NKG2DLs), MHC class I chain-related molecules A and B (MICA/B) and ULBP1-3.
23509364	Breast Carcinoma; Hepatocellular Carcinoma; Colorectal Carcinoma	SP1	Promote immunity	Overexpression of Snail1 and inhibition of glycogen synthase kinase-3β in colorectal tumor cells markedly induced the activity of Sp1 transcription factor, which plays a key role in the upregulation of NKG2DL expression during EMT.
23509357	Breast Carcinoma	MMP9	Promote immunity (infiltration)	In addition to increased generation of endostatin, AdMMP-9 promoted an antitumor immune response by inducing massive neutrophil infiltration.
23509156	Chronic Lymphocytic Leukemia	BAG6	Inhibit immunity (NK cell infiltration)	Soluble CLL plasma factors suppressed NK cell cytotoxicity and down-regulated the surface receptors CD16 and CD56 on NK cells of healthy donors. The inhibition of NK cell cytotoxicity was attributed to the soluble ligand BAG6/BAT3 that engages the activating receptor NKp30 expressed on NK cells.
23493799	Melanoma	MICA	Promote immunity	Interestingly, this MICA overexpression makes melanoma cells more sensitive to in vitro lysis by NK cells. Interestingly, this MICA overexpression makes melanoma cells more sensitive to in vitro lysis by NK cells.
23493799	Melanoma	PPARG	Promote immunity	Peroxisome Proliferator-Activated Receptor gamma is involved in this statin-induced MICA overexpression, which is independent of Ras and Rho GTPase signaling pathways.
23486482	Breast Carcinoma	STAT1	Inhibit immunity (T cell function)	Ectopic overexpression of constitutively active STAT1 in TM40D cells promoted mobilization of myeloid-derived suppressor cells (MDSCs) and inhibition of antitumor T cells, resulting in aggressive tumor growth in tumor-transplanted, immunocompetent mice.
23481325	Neuroblastoma	IFNG	Promote immunity	Vγ9Vδ2 T lymphocytes were attracted to NB-tumor masses of mice receiving ZOL where they actively modified tumor microenvironment by producing interferon-γ (IFN-γ), that in turn induced CXCL10 expression in NB cells. This study shows that human Vγ9Vδ2 T cells and ZOL in combination inhibit NB growth in vivo and may provide the rationale for a phase I clinical trial in patients with high-risk NB.
23481325	Neuroblastoma	CXCL10	Promote immunity	Vγ9Vδ2 T lymphocytes were attracted to NB-tumor masses of mice receiving ZOL where they actively modified tumor microenvironment by producing interferon-γ (IFN-γ), that in turn induced CXCL10 expression in NB cells. This study shows that human Vγ9Vδ2 T cells and ZOL in combination inhibit NB growth in vivo and may provide the rationale for a phase I clinical trial in patients with high-risk NB.
23479624	Prostate Carcinoma	LGALS3	Inhibit immunity	Here, we show that a β-galactoside-binding lectin [galectin-3 (gal3)] that recognizes the Thomsen-Friedenreich disaccharide (TFD, Galβ1,3GalNAc) present on the surface of most cancer cells is involved in promoting angiogenesis, tumor-endothelial cell adhesion, and metastasis of prostate cancer cells, as well as evading immune surveillance through killing of activated T cells.
23474221	Breast Carcinoma; Lung Carcinoma; Ovarian Carcinoma	CD46	Inhibit immunity	The therapeutic potential of anticancer antibodies is limited by the resistance of tumor cells to complement-mediated attack, primarily through the over-expression of membrane complement regulatory proteins (mCRPs: CD46, CD55 and CD59). Delivery of chemically stabilized anti-mCRP siRNAs using cationic lipoplexes, AtuPLEXes, to HER2-over-expressing BT474, SK-BR-3 (breast), SKOV3 (ovarian) and Calu-3 (lung) cancer cells reduced mCRPs expression by 85-95%.
23474221	Breast Carcinoma; Lung Carcinoma; Ovarian Carcinoma	CD55	Inhibit immunity (T cell function); essential for immunotherapy	The therapeutic potential of anticancer antibodies is limited by the resistance of tumor cells to complement-mediated attack, primarily through the over-expression of membrane complement regulatory proteins (mCRPs: CD46, CD55 and CD59). Delivery of chemically stabilized anti-mCRP siRNAs using cationic lipoplexes, AtuPLEXes, to HER2-over-expressing BT474, SK-BR-3 (breast), SKOV3 (ovarian) and Calu-3 (lung) cancer cells reduced mCRPs expression by 85-95%.
23474221	Breast Carcinoma; Lung Carcinoma; Ovarian Carcinoma	CD59	Inhibit immunity (T cell function); essential for immunotherapy	The therapeutic potential of anticancer antibodies is limited by the resistance of tumor cells to complement-mediated attack, primarily through the over-expression of membrane complement regulatory proteins (mCRPs: CD46, CD55 and CD59). Delivery of chemically stabilized anti-mCRP siRNAs using cationic lipoplexes, AtuPLEXes, to HER2-over-expressing BT474, SK-BR-3 (breast), SKOV3 (ovarian) and Calu-3 (lung) cancer cells reduced mCRPs expression by 85-95%.
23460744	Plasma Cell Myeloma	S100A9	Inhibit immunity (T cell function)	S100A9 knockout (KO) mice, which are deficient in their ability to accumulate MDSC in tumor-bearing hosts, demonstrated reduced MDSC accumulation in BM after injection of MM cells compared with wild-type mice.
23460536	Prostate Carcinoma	TNFRSF9	Promote immunity	Food and Drug Administration approval of ipilumimab, an antibody that blocks the inhibitory action of CTLA-4, and clinical trials targeting 4-1BB and PD-1 or PD-L1, have underscored the therapeutic potential of using immunomodulatory antibodies to stimulate protective immunity in human patients. In a proof-of-concept study in mice, we have shown that an agonistic 4-1BB-binding aptamer conjugated to a prostate-specific membrane antigen (PSMA)-binding aptamer led to the inhibition of PSMA-expressing tumors, was more effective than, and synergized with, vaccination, and exhibited a superior therapeutic index compared with nontargeted costimulation with 4-1BB antibodies or 4-1BB aptamers.
23459515	Hodgkin Lymphoma	NCR3	Promote immunity	Hodgkin lymphoma (HL) is characterized by CD30(+) tumor cells and a massive infiltration of immune effector cells in affected lymph nodes. Impaired NK cell function correlated with elevated serum levels of soluble ligands for NK cell receptors NKp30 (BAG6/BAT3) and NKG2D (MICA), factors known to constrict NK cell function. In vitro, NK cell cytotoxicity could be restored by an NKG2D/NKp30-independent bispecific antibody construct (CD30xCD16A).
23459515	Hodgkin Lymphoma	KLRK1	Promote immunity	Hodgkin lymphoma (HL) is characterized by CD30(+) tumor cells and a massive infiltration of immune effector cells in affected lymph nodes. Impaired NK cell function correlated with elevated serum levels of soluble ligands for NK cell receptors NKp30 (BAG6/BAT3) and NKG2D (MICA), factors known to constrict NK cell function. In vitro, NK cell cytotoxicity could be restored by an NKG2D/NKp30-independent bispecific antibody construct (CD30xCD16A).
23455497	Breast Carcinoma	CD274	Inhibit immunity (T cell function)	Importantly, tumor-associated neutrophils strongly bound B7x protein and inhibited the proliferation of both CD4 and CD8 T cells. These results suggest that host B7x may enable metastasizing cancer cells to escape local antitumor immune responses through interactions with the innate and adaptive immune systems.
23454771	Melanoma	CCL2	Inhibit immunity (infiltration)	We found that PLX4720 treatment downregulated tumor Ccl2 gene expression and decreased tumor CCL2 expression in both Braf(V600E) mouse melanoma transplants and in de novo melanomas in a manner that was coincident with reduced tumor growth. While PLX4720 did not directly increase tumor immunogenicity, analysis of SM1 tumor-infiltrating leukocytes in PLX4720-treated mice demonstrated a robust increase in CD8(+) T/FoxP3(+)CD4(+) T cell ratio and NK cells.
23447383	Chronic Lymphocytic Leukemia	VEGFA	Inhibit immunity (T cell function)	In our study, we characterized mRNA levels of VEGF receptors including NRP1 in a large cohort of CLL patients (n = 114), additionally we performed a detailed characterization of NRP1 expression on B cells, plasmacytoid dendritic cells (PDCs) and regulatory T cells (Tregs). The expression of NRP1 was significantly higher on leukemic lymphocytes compared to control B lymphocytes on mRNA and protein levels (22.72% vs. 0.2%, p = 0.0003, respectively), Tregs (42.6% vs. 16.05%, p = 0.0003) and PDCs (100% vs. 98% p < 0.0001). In functional studies, we found higher NRP1 expression on CLL cells after stimulation with VEGF. The correlation between expression of VEGF receptors: FLT1, NRP1 and FOXP3 expression (r(2) = 0.53, p < 0.0001 and r(2) = 0.49, p < 0.0001, respectively) was observed.
23447383	Chronic Lymphocytic Leukemia	FLT1	Inhibit immunity (T cell function)	In our study, we characterized mRNA levels of VEGF receptors including NRP1 in a large cohort of CLL patients (n = 114), additionally we performed a detailed characterization of NRP1 expression on B cells, plasmacytoid dendritic cells (PDCs) and regulatory T cells (Tregs). The expression of NRP1 was significantly higher on leukemic lymphocytes compared to control B lymphocytes on mRNA and protein levels (22.72% vs. 0.2%, p = 0.0003, respectively), Tregs (42.6% vs. 16.05%, p = 0.0003) and PDCs (100% vs. 98% p < 0.0001). In functional studies, we found higher NRP1 expression on CLL cells after stimulation with VEGF. The correlation between expression of VEGF receptors: FLT1, NRP1 and FOXP3 expression (r(2) = 0.53, p < 0.0001 and r(2) = 0.49, p < 0.0001, respectively) was observed.
23447383	Chronic Lymphocytic Leukemia	NRP1	Inhibit immunity (T cell function)	In our study, we characterized mRNA levels of VEGF receptors including NRP1 in a large cohort of CLL patients (n = 114), additionally we performed a detailed characterization of NRP1 expression on B cells, plasmacytoid dendritic cells (PDCs) and regulatory T cells (Tregs). The expression of NRP1 was significantly higher on leukemic lymphocytes compared to control B lymphocytes on mRNA and protein levels (22.72% vs. 0.2%, p = 0.0003, respectively), Tregs (42.6% vs. 16.05%, p = 0.0003) and PDCs (100% vs. 98% p < 0.0001). In functional studies, we found higher NRP1 expression on CLL cells after stimulation with VEGF. The correlation between expression of VEGF receptors: FLT1, NRP1 and FOXP3 expression (r(2) = 0.53, p < 0.0001 and r(2) = 0.49, p < 0.0001, respectively) was observed.
23447383	Chronic Lymphocytic Leukemia	FOXP3	Inhibit immunity (T cell function)	In our study, we characterized mRNA levels of VEGF receptors including NRP1 in a large cohort of CLL patients (n = 114), additionally we performed a detailed characterization of NRP1 expression on B cells, plasmacytoid dendritic cells (PDCs) and regulatory T cells (Tregs). The expression of NRP1 was significantly higher on leukemic lymphocytes compared to control B lymphocytes on mRNA and protein levels (22.72% vs. 0.2%, p = 0.0003, respectively), Tregs (42.6% vs. 16.05%, p = 0.0003) and PDCs (100% vs. 98% p < 0.0001). In functional studies, we found higher NRP1 expression on CLL cells after stimulation with VEGF. The correlation between expression of VEGF receptors: FLT1, NRP1 and FOXP3 expression (r(2) = 0.53, p < 0.0001 and r(2) = 0.49, p < 0.0001, respectively) was observed.
23444403	Hodgkin Lymphoma	LGALS1	Inhibit immunity (T cell function)	Hodgkin lymphoma (HL) Reed-Sternberg cells overexpress and secrete Gal1, which selectively kills T helper (Th)1 and Th17 cells and cytotoxic T cells and promotes the immunosuppressive Th2/regulatory T-cell-predominant HL microenvironment.
23440424	Neuroblastoma	NCAM1	Promote immunity	The final products contained more than 90% CD56(+) cells and could kill neuroblastoma cells effectively that were originally highly resistant to nonprocessed NK cells. Mechanistically, cytolysis of neuroblastoma was mediated through natural cytotoxicity receptor (NCR), DNAX accessory molecule-1 (DNAM-1; CD226), perforin, and granzyme B.
23440424	Neuroblastoma	CD226	Promote immunity	The final products contained more than 90% CD56(+) cells and could kill neuroblastoma cells effectively that were originally highly resistant to nonprocessed NK cells. Mechanistically, cytolysis of neuroblastoma was mediated through natural cytotoxicity receptor (NCR), DNAX accessory molecule-1 (DNAM-1; CD226), perforin, and granzyme B.
23440424	Neuroblastoma	PRF1	Promote immunity	The final products contained more than 90% CD56(+) cells and could kill neuroblastoma cells effectively that were originally highly resistant to nonprocessed NK cells. Mechanistically, cytolysis of neuroblastoma was mediated through natural cytotoxicity receptor (NCR), DNAX accessory molecule-1 (DNAM-1; CD226), perforin, and granzyme B.
23440424	Neuroblastoma	GZMB	Promote immunity	The final products contained more than 90% CD56(+) cells and could kill neuroblastoma cells effectively that were originally highly resistant to nonprocessed NK cells. Mechanistically, cytolysis of neuroblastoma was mediated through natural cytotoxicity receptor (NCR), DNAX accessory molecule-1 (DNAM-1; CD226), perforin, and granzyme B.
23440412	Breast Carcinoma	IDO1	Inhibit immunity (T cell function)	The proportion of MDSCs with the phenotype of CD45(+)CD13(+)CD33(+)CD14(-)CD15(-) significantly increased in primary cancer tissues and patients' peripheral blood. IDO expression was significantly upregulated in MDSCs isolated from fresh breast cancer tissues (fresh MDSCs [fMDSCs]), which correlated with increased infiltration of Foxp3(+) regulatory T cells in tumors and lymph node metastasis in patients.
23440412	Breast Carcinoma	IL2	Promote immunity (T cell function)	The proportion of MDSCs with the phenotype of CD45(+)CD13(+)CD33(+)CD14(-)CD15(-) significantly increased in primary cancer tissues and patients' peripheral blood. IDO expression was significantly upregulated in MDSCs isolated from fresh breast cancer tissues (fresh MDSCs [fMDSCs]), which correlated with increased infiltration of Foxp3(+) regulatory T cells in tumors and lymph node metastasis in patients. fMDSCs inhibited IL-2 and anti-CD3/CD28 mAb-induced T cell amplification and Th1 polarization but stimulated apoptosis in T cells in an IDO-dependent manner.
23440412	Breast Carcinoma	STAT3	Inhibit immunity (T cell function)	The proportion of MDSCs with the phenotype of CD45(+)CD13(+)CD33(+)CD14(-)CD15(-) significantly increased in primary cancer tissues and patients' peripheral blood. IDO expression was significantly upregulated in MDSCs isolated from fresh breast cancer tissues (fresh MDSCs [fMDSCs]), which correlated with increased infiltration of Foxp3(+) regulatory T cells in tumors and lymph node metastasis in patients. IDO expression was upregulated in induced MDSCs, which required phosphorylation of STAT3, but not STAT1.
23436794	Melanoma	IL2	Promote immunity	Immunostimulatory agonists such as anti-CD137 and interleukin (IL)-2 have elicited potent antitumor immune responses in preclinical studies, but their clinical use is limited by inflammatory toxicities that result upon systemic administration. We anchored anti-CD137 and an engineered IL-2Fc fusion protein to the surfaces of PEGylated liposomes, whose physical size permitted dissemination in the tumor parenchyma and tumor-draining lymph nodes but blocked entry into the systemic circulation following intratumoral injection. In the B16F10 melanoma model, intratumoral liposome-coupled anti-CD137 + IL-2Fc therapy cured a majority of established primary tumors while avoiding the lethal inflammatory toxicities caused by equivalent intratumoral doses of soluble immunotherapy.
23436794	Melanoma	TNFRSF9	Promote immunity	Immunostimulatory agonists such as anti-CD137 and interleukin (IL)-2 have elicited potent antitumor immune responses in preclinical studies, but their clinical use is limited by inflammatory toxicities that result upon systemic administration. We anchored anti-CD137 and an engineered IL-2Fc fusion protein to the surfaces of PEGylated liposomes, whose physical size permitted dissemination in the tumor parenchyma and tumor-draining lymph nodes but blocked entry into the systemic circulation following intratumoral injection. In the B16F10 melanoma model, intratumoral liposome-coupled anti-CD137 + IL-2Fc therapy cured a majority of established primary tumors while avoiding the lethal inflammatory toxicities caused by equivalent intratumoral doses of soluble immunotherapy.
23420584	Malignant Splenic Neoplasm	ARG1	Inhibit immunity (T cell function)	Here, we show that lactic acid, or more specifically the acidification it causes, increases arginase I (ARG1) expression in macrophages to inhibit T-cell proliferation and activation. We show that dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinases, targets macrophages to suppress activation of the IL-23/IL-17 pathway and the expression of ARG1 by lactic acid. DCA treatment decreased ARG1 expression in tumor-infiltrating immune cells and increased the number of IFN-γ-producing CD8+ T cells and NK cells in tumor-bearing mouse spleen.
23420584	Malignant Splenic Neoplasm	IL17A	Inhibit immunity (T cell function)	Here, we show that lactic acid, or more specifically the acidification it causes, increases arginase I (ARG1) expression in macrophages to inhibit T-cell proliferation and activation. We show that dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinases, targets macrophages to suppress activation of the IL-23/IL-17 pathway and the expression of ARG1 by lactic acid. DCA treatment decreased ARG1 expression in tumor-infiltrating immune cells and increased the number of IFN-γ-producing CD8+ T cells and NK cells in tumor-bearing mouse spleen.
23420539	T-Cell Non-Hodgkin Lymphoma	CD37	Promote immunity (T cell function)	We provide evidence that an increased susceptibility to tumors observed in CD37(-/-) mice coincides with a striking failure to induce antigen-specific IFN-γ-secreting T cells. We also show that CD37 ablation impairs several aspects of DC function including: in vivo migration from skin to draining lymph nodes; chemo-tactic migration; integrin-mediated adhesion under flow; the ability to spread and form actin protrusions and in vivo priming of adoptively transferred na?ve T cells.
23418320	Prostate Carcinoma	CSF1	Inhibit immunity (infiltration)	Enhanced macrophage migration induced by conditioned media from irradiated tumor cells was completely blocked by a selective inhibitor of CSF1R. These findings were confirmed in patients with prostate cancer, where serum levels of CSF1 increased after radiotherapy.
23418320	Prostate Carcinoma	CSF1R	Inhibit immunity (infiltration)	Enhanced macrophage migration induced by conditioned media from irradiated tumor cells was completely blocked by a selective inhibitor of CSF1R. These findings were confirmed in patients with prostate cancer, where serum levels of CSF1 increased after radiotherapy.
23401488	Chronic Myelogenous Leukemia	IFNA1	Inhibit immunity (T cell function)	Effector CTLs were only able to eliminate LSCs in a situation with minimal leukemia load where CTL-secreted IFN-γ levels were low.
23400852	Neuroblastoma	NTRK1	Promote immunity (T cell function)	Corresponding to this upregulation, T cell activity and cytoxicity was enhanced in the presence of SY5Y-TrkA cells or by medium conditioned by them, suggesting the existence of additional soluble factors stimulating the T cell response. Activation of natural killer (NK) cells was only increased in the presence of SY5Y-TrkA conditioned medium (CM) and not in co-culture assays, suggesting a dominant inhibitory effect of upregulated MHC class I as the primary NK cell escape mechanism of TrkA-expressing neuroblastomas.
23400852	Neuroblastoma	HLA-A	Promote immunity (T cell function)	Corresponding to this upregulation, T cell activity and cytoxicity was enhanced in the presence of SY5Y-TrkA cells or by medium conditioned by them, suggesting the existence of additional soluble factors stimulating the T cell response. Activation of natural killer (NK) cells was only increased in the presence of SY5Y-TrkA conditioned medium (CM) and not in co-culture assays, suggesting a dominant inhibitory effect of upregulated MHC class I as the primary NK cell escape mechanism of TrkA-expressing neuroblastomas.
23390297	Melanoma	MIF	Inhibit immunity (T cell function)	Finally, we report for the first time, to our knowledge, that our previously discovered MIF small molecule antagonist, 4-iodo-6-phenylpyrimidine, recapitulates MIF deficiency in vitro and in vivo, and attenuates tumor-polarized macrophage alternative activation, immunosuppression, neoangiogenesis, and melanoma tumor outgrowth.
23390011	Colon Carcinoma	PTGER4	Inhibit immunity (infiltration)	PGE2 signals through four different receptors (EP1-EP4) and targeting individual receptor(s) may avoid these side effects, while retaining significant anticancer benefits. This antitumor effect was associated with reduced Fas ligand expression and attenuated tumor-induced immune suppression. In particular, tumor infiltration by CD4(+) CD25(+) Foxp3(+) regulatory T cells was decreased, whereas the cytotoxic activity of isolated splenocytes against CT26 cells was increased.
23390011	Colon Carcinoma	PTGER3	Promote immunity	PGE2 signals through four different receptors (EP1-EP4) and targeting individual receptor(s) may avoid these side effects, while retaining significant anticancer benefits. This antitumor effect was associated with reduced Fas ligand expression and attenuated tumor-induced immune suppression. In particular, tumor infiltration by CD4(+) CD25(+) Foxp3(+) regulatory T cells was decreased, whereas the cytotoxic activity of isolated splenocytes against CT26 cells was increased.
23390011	Colon Carcinoma	PTGER2	Inhibit immunity (infiltration)	PGE2 signals through four different receptors (EP1-EP4) and targeting individual receptor(s) may avoid these side effects, while retaining significant anticancer benefits. This antitumor effect was associated with reduced Fas ligand expression and attenuated tumor-induced immune suppression. In particular, tumor infiltration by CD4(+) CD25(+) Foxp3(+) regulatory T cells was decreased, whereas the cytotoxic activity of isolated splenocytes against CT26 cells was increased.
23390011	Colon Carcinoma	PTGER1	Inhibit immunity (infiltration)	Targeting the EP1 receptor reduces Fas ligand expression and increases the antitumor immune response in an in vivo model of colon cancer. PGE2 signals through four different receptors (EP1-EP4) and targeting individual receptor(s) may avoid these side effects, while retaining significant anticancer benefits. This antitumor effect was associated with reduced Fas ligand expression and attenuated tumor-induced immune suppression. In particular, tumor infiltration by CD4(+) CD25(+) Foxp3(+) regulatory T cells was decreased, whereas the cytotoxic activity of isolated splenocytes against CT26 cells was increased.
23390011	Colon Carcinoma	FAS	Inhibit immunity (infiltration)	PGE2 signals through four different receptors (EP1-EP4) and targeting individual receptor(s) may avoid these side effects, while retaining significant anticancer benefits. This antitumor effect was associated with reduced Fas ligand expression and attenuated tumor-induced immune suppression. In particular, tumor infiltration by CD4(+) CD25(+) Foxp3(+) regulatory T cells was decreased, whereas the cytotoxic activity of isolated splenocytes against CT26 cells was increased.
23389942	Breast Carcinoma	IFNA1	Promote immunity (T cell function)	We previously reported that plasmacytoid dendritic cells (pDCs) infiltrating breast tumors are impaired for their interferon-α (IFN-α) production, resulting in local regulatory T cells amplification.
23389942	Breast Carcinoma	TGFB1	Inhibit immunity (T cell function)	We demonstrate that besides IFN-α, the production by Toll-like receptor (TLR)-activated healthy pDC of IFN-β and TNF-α but not IP-10/CXCL10 nor MIP1-α/CCL3 is impaired by the breast tumor environment. Indeed, recombinant TGF-β1 and TNF-α synergistically blocked IFN-α production of TLR-activated pDC, and neutralization of TGF-β and TNF-α in tumor-derived supernatants restored pDCs' IFN-α production.Importantly, we identified TGF-β and TNF-α as major soluble factors involved in TApDC functional alteration.
23389942	Breast Carcinoma	TNF	Promote immunity	We demonstrate that besides IFN-α, the production by Toll-like receptor (TLR)-activated healthy pDC of IFN-β and TNF-α but not IP-10/CXCL10 nor MIP1-α/CCL3 is impaired by the breast tumor environment. Indeed, recombinant TGF-β1 and TNF-α synergistically blocked IFN-α production of TLR-activated pDC, and neutralization of TGF-β and TNF-α in tumor-derived supernatants restored pDCs' IFN-α production.Importantly, we identified TGF-β and TNF-α as major soluble factors involved in TApDC functional alteration.
23389942	Breast Carcinoma	IRF7	Promote immunity (T cell function)	We demonstrate that besides IFN-α, the production by Toll-like receptor (TLR)-activated healthy pDC of IFN-β and TNF-α but not IP-10/CXCL10 nor MIP1-α/CCL3 is impaired by the breast tumor environment. Indeed, recombinant TGF-β1 and TNF-α synergistically blocked IFN-α production of TLR-activated pDC, and neutralization of TGF-β and TNF-α in tumor-derived supernatants restored pDCs' IFN-α production.Importantly, we identified TGF-β and TNF-α as major soluble factors involved in TApDC functional alteration. Mechanisms of type I IFN inhibition did not involve TLR downregulation but the inhibition of IRF-7 expression and nuclear translocation in pDC after their exposure to tumor-derived supernatants or recombinant TGF-β1 and TNF-α.
21292811	Colon Carcinoma; Lymphoma; Breast Carcinoma; Melanoma	NT5E	Inhibit immunity (T cell function)	We found that CD73 ablation significantly suppressed the growth of ovalbumin-expressing MC38 colon cancer, EG7 lymphoma, AT-3 mammary tumors, and B16F10 melanoma. The protective effect of CD73 deficiency on primary tumors was dependent on CD8(+) T cells and associated with an increased frequency of antigen-specific CD8(+) T cells in peripheral blood and tumors and increased antigen-specific IFN-γ production.
21292811	Colon Carcinoma; Lymphoma; Breast Carcinoma; Melanoma	IFNG	Promote immunity (T cell function)	We found that CD73 ablation significantly suppressed the growth of ovalbumin-expressing MC38 colon cancer, EG7 lymphoma, AT-3 mammary tumors, and B16F10 melanoma. The protective effect of CD73 deficiency on primary tumors was dependent on CD8(+) T cells and associated with an increased frequency of antigen-specific CD8(+) T cells in peripheral blood and tumors and increased antigen-specific IFN-γ production.
21288925	Colon Carcinoma; Gastric Neoplasm	IFNA1	Promote immunity (T cell function)	In this issue of Clinical Cancer Research, Zoglmeier and colleagues show that CpG, via the induction of IFN-α, matures myeloid-derived suppressor cells to abrogate immune suppression in 2 murine solid tumor models.
21282461	Bladder Carcinoma	CD40	Promote immunity	The immunostimulatory effects of CD40 ligation on malignant cells can be switched to apoptosis upon disruption of survival signals transduced by the binding of the adaptor protein TRAF6 to CD40.
21282461	Bladder Carcinoma	TRAF6	Promote immunity	The immunostimulatory effects of CD40 ligation on malignant cells can be switched to apoptosis upon disruption of survival signals transduced by the binding of the adaptor protein TRAF6 to CD40.
21282461	Bladder Carcinoma	TRAF2	Promote immunity	Apoptosis induction requires a TRAF2-interacting CD40 motif but is initiated within a cytosolic death-inducing signaling complex after mobilization of receptor-bound TRAF2 to the cytoplasm.
21282461	Bladder Carcinoma	RIPK1	Promote immunity	We demonstrate that receptor-interacting protein 1 (RIP1) is an integral component of this complex and is required for CD40 ligand-induced caspase-8 activation and tumor cell killing.
21282461	Bladder Carcinoma	CASP8	Promote immunity	We demonstrate that receptor-interacting protein 1 (RIP1) is an integral component of this complex and is required for CD40 ligand-induced caspase-8 activation and tumor cell killing.
21282461	Bladder Carcinoma	BIRC2	Inhibit immunity	Degradation of the RIP1 K63 ubiquitin ligases cIAP1/2 amplifies the CD40-mediated cytotoxic effect, whereas inhibition of CYLD, a RIP1 K63 deubiquitinating enzyme, reduces it.
21282461	Bladder Carcinoma	BIRC3	Inhibit immunity	Degradation of the RIP1 K63 ubiquitin ligases cIAP1/2 amplifies the CD40-mediated cytotoxic effect, whereas inhibition of CYLD, a RIP1 K63 deubiquitinating enzyme, reduces it.
21282461	Bladder Carcinoma	CYLD	Promote immunity	Degradation of the RIP1 K63 ubiquitin ligases cIAP1/2 amplifies the CD40-mediated cytotoxic effect, whereas inhibition of CYLD, a RIP1 K63 deubiquitinating enzyme, reduces it.
21282355	Lung Carcinoma	BIK	Promote immunity (T cell function)	Here, we found this cancer-targeted gene therapy, SV-BikDD, composed of the survivin promoter in the VP16-GAL4-WPRE integrated systemic amplifier system to drive the apoptotic gene BikDD, not only caused cytotoxic effects in cancer cells but also elicited a cancer-specific cytotoxic T lymphocyte response to synergistically increase the therapeutic effect and further develop an effective systemic antitumoral immunity against rechallenges of tumorigenic dose of parental tumor cells inoculated at distant sites in immunocompetent mice.
21282338	Lymphoma	IFNG	Promote immunity	The immunotherapeutic approach we developed utilizes a bifunctional fusion protein that binds tumor cells through NK (natural killer)-activating receptor NKG2D and that recruits and stimulates T cells through an anti-CD3 single-chain variable fragment (scFv-NKG2D). In vitro, this scFv-NKG2D fusion protein engaged both T cells and tumor cells, stimulating T cells to produce IFN-γ, and cytotoxicity against NKG2D ligand-positive tumor cells. In vivo, expression of scFv-NKG2D by NKG2D ligand-positive tumor cells reduced tumor burden and, in some cases, led to tumor-free survival.
21282337	Breast Carcinoma; Lung Carcinoma	IL2	Promote immunity	Anti-IL-23 monoclonal antibody synergizes in combination with targeted therapies or IL-2 to suppress tumor growth and metastases. More notably, combinatorial treatments of anti-IL-23 mAb with IL-2 or anti-erbB2 mAb significantly inhibited subcutaneous growth of established mammary carcinomas and suppressed established experimental and spontaneous lung metastases. Overall, our results suggest the potential of anti-human IL-23 mAbs to improve the immunostimulatory effects of IL-2 and trastuzumab in the current management of some advanced human cancers.
21282337	Breast Carcinoma; Lung Carcinoma	IL23R	Inhibit immunity	Anti-IL-23 monoclonal antibody synergizes in combination with targeted therapies or IL-2 to suppress tumor growth and metastases. More notably, combinatorial treatments of anti-IL-23 mAb with IL-2 or anti-erbB2 mAb significantly inhibited subcutaneous growth of established mammary carcinomas and suppressed established experimental and spontaneous lung metastases. Overall, our results suggest the potential of anti-human IL-23 mAbs to improve the immunostimulatory effects of IL-2 and trastuzumab in the current management of some advanced human cancers.
21278794	Breast Carcinoma	FAS	Promote immunity	Secretion of pro-inflammatory cytokines by the senescent cells, particularly TNF-α and IFN-γ, mediates Fas upregulation. Indeed, treatment of proliferating cancer cell lines with TNF-α and IFN-γ, upregulates Fas expression, while blocking TNF-α and IFN-γ by using neutralizing antibodies, decreases Fas expression in senescent cells. We also demonstrate that NF-κB has a central role in controlling the senescence-associated secretory phenotype (SASP) by the premature senescent cells, and that TNF-α and IFN-γ, transcriptionally controlled by NF-κB, are the main mediators of Fas upregulation. Our data suggest the existence of an NF-κB-dependent autocrine loop, mediated by TNF-α and IFN-γ, responsible for expression of Fas on the surface of senescent cells, and for their killing.
21278794	Breast Carcinoma	TNF	Promote immunity	Secretion of pro-inflammatory cytokines by the senescent cells, particularly TNF-α and IFN-γ, mediates Fas upregulation. Indeed, treatment of proliferating cancer cell lines with TNF-α and IFN-γ, upregulates Fas expression, while blocking TNF-α and IFN-γ by using neutralizing antibodies, decreases Fas expression in senescent cells. We also demonstrate that NF-κB has a central role in controlling the senescence-associated secretory phenotype (SASP) by the premature senescent cells, and that TNF-α and IFN-γ, transcriptionally controlled by NF-κB, are the main mediators of Fas upregulation. Our data suggest the existence of an NF-κB-dependent autocrine loop, mediated by TNF-α and IFN-γ, responsible for expression of Fas on the surface of senescent cells, and for their killing.
21278794	Breast Carcinoma	IFNG	Promote immunity	Secretion of pro-inflammatory cytokines by the senescent cells, particularly TNF-α and IFN-γ, mediates Fas upregulation. Indeed, treatment of proliferating cancer cell lines with TNF-α and IFN-γ, upregulates Fas expression, while blocking TNF-α and IFN-γ by using neutralizing antibodies, decreases Fas expression in senescent cells. We also demonstrate that NF-κB has a central role in controlling the senescence-associated secretory phenotype (SASP) by the premature senescent cells, and that TNF-α and IFN-γ, transcriptionally controlled by NF-κB, are the main mediators of Fas upregulation. Our data suggest the existence of an NF-κB-dependent autocrine loop, mediated by TNF-α and IFN-γ, responsible for expression of Fas on the surface of senescent cells, and for their killing.
21278794	Breast Carcinoma	NFKB1	Promote immunity	Secretion of pro-inflammatory cytokines by the senescent cells, particularly TNF-α and IFN-γ, mediates Fas upregulation. Indeed, treatment of proliferating cancer cell lines with TNF-α and IFN-γ, upregulates Fas expression, while blocking TNF-α and IFN-γ by using neutralizing antibodies, decreases Fas expression in senescent cells. We also demonstrate that NF-κB has a central role in controlling the senescence-associated secretory phenotype (SASP) by the premature senescent cells, and that TNF-α and IFN-γ, transcriptionally controlled by NF-κB, are the main mediators of Fas upregulation. Our data suggest the existence of an NF-κB-dependent autocrine loop, mediated by TNF-α and IFN-γ, responsible for expression of Fas on the surface of senescent cells, and for their killing.
21266358	Lung Carcinoma	TNFRSF9	Promote immunity (T cell function)	Agonist monoclonal antibodies (mAb) to the immune costimulatory molecule CD137, also known as 4-1BB, are presently in clinical trials for cancer treatment on the basis of their costimulatory effects on primed T cells and perhaps other cells of the immune system.
21263073	Colon Carcinoma	IFNA1	Inhibit immunity (T cell function)	IFN-α directly promotes programmed cell death-1 transcription and limits the duration of T cell-mediated immunity.
21263073	Colon Carcinoma	PDCD1	Inhibit immunity (T cell function)	IFN-α directly promotes programmed cell death-1 transcription and limits the duration of T cell-mediated immunity.
21263073	Colon Carcinoma	IRF9	Inhibit immunity (T cell function)	IFN-α directly promotes programmed cell death-1 transcription and limits the duration of T cell-mediated immunity. Consistent with this finding, activation by IFN-α enhanced both the induction and maintenance of PD-1 expression on TCR-engaged primary mouse T cells through an association IFN-responsive factor 9 (IRF9) to the IFN stimulation response element.
21258414	Kidney Neoplasm	VHL	Promote immunity	The RCC6 and RCC4 cell lines were transfected with the wild-type gene to restore the function of VHL. The presence of the gene in RCC cells downregulated hypoxia-inducible factor (HIF)-1α and subsequently decreased vascular endothelial growth factor (VEGF) production. Relative to control transfectants and parental cells, pVHL-transfected cell lines activated resting and IL2-activated NK cells less strongly, as assessed by IFNγ secretion, NK degranulation and cell lysis.
21258414	Kidney Neoplasm	KLRC1	Inhibit immunity	NKG2A, a human leukocyte antigen (HLA)-I-specific inhibitory NK receptor, controls the lysis of tumor targets. Blocking NKG2A/HLA-I interactions substantially increased lysis of RCC-pVHL, but had little effect on the lysis of VHL-mutated RCC cell lines.
21257710	Colorectal Carcinoma	STAT3	Inhibit immunity	In this study, we investigated the role of STAT3 in suppressing NK cell-mediated immunosurveillance. Using a colorectal cancer cell line (HT29) that can poorly activate NK, we neutralized STAT3 with pharmacologic inhibitors or siRNA and found that this led to an increase in NK degranulation and IFN-γ production in a TGF-β1-independent manner.
21257710	Colorectal Carcinoma	KLRK1	Promote immunity	Exposure to NKG2D-neutralizing antibodies partially restored STAT3 activity, suggesting that it prevented NKG2D-mediated NK cell activation.
21257710	Colorectal Carcinoma	MICA	Promote immunity	The NK cell recognition receptor MHC class I chain-related protein A (MICA) was upregulated following STAT3 neutralization, and a direct interaction between STAT3 and the MICA promoter was identified. We found that STAT3 negatively regulated MICA expression after irradiation or heat shock, including in lymphocytes activated by CD3/CD28 ligation.
21252114	Lymphoma	ERAP1	Inhibit immunity	The endoplasmic reticulum aminopeptidase ERAAP is involved in the final trimming of peptides for presentation by MHC class I (MHC-I) molecules. Herein, we show that ERAAP silencing results in MHC-I peptide-loading defects eliciting rejection of the murine T-cell lymphoma RMA in syngeneic mice. Because a large fraction of human tumors express high levels of the homologous ERAP1 and/or ERAP2, the present findings highlight a convenient, novel target for cancer immunotherapy.
21252114	Lymphoma	ERAP2	Promote immunity	The endoplasmic reticulum aminopeptidase ERAAP is involved in the final trimming of peptides for presentation by MHC class I (MHC-I) molecules. Herein, we show that ERAAP silencing results in MHC-I peptide-loading defects eliciting rejection of the murine T-cell lymphoma RMA in syngeneic mice. Because a large fraction of human tumors express high levels of the homologous ERAP1 and/or ERAP2, the present findings highlight a convenient, novel target for cancer immunotherapy.
21248250	Lung Carcinoma	CBLB	Inhibit immunity (T cell function)	The Casitas B-cell lymphoma (Cbl) family protein Cbl-b was the first E3 ubiquitin ligase directly implicated in the activation and tolerance of the peripheral T cell. In this study, we report that selective genetic inactivation of Cbl-b E3 ligase activity phenocopies the T cell responses observed when total Cbl-b is ablated, resulting in T cell hyperactivation, spontaneous autoimmunity, and impaired induction of T cell anergy in vivo. Moreover, mice carrying a Cbl-b E3 ligase-defective mutation spontaneously reject tumor cells that express human papilloma virus Ags. These data demonstrate for the first time, to our knowledge, that the catalytic function of an E3 ligase, Cbl-b, is essential for negative regulation of T cells in vivo.
21239696	Hodgkin Lymphoma	TNFRSF4	Promote immunity (T cell function)	The engagement of OX40L with the OX40 receptor is essential for the generation of antigen-specific memory T cells and for the induction of host antitumor immunity. Small interfering RNAs (siRNAs) that selectively inhibited HDAC11 expression, significantly up-regulated OX40L and induced apoptosis in HL cell lines, and silencing HDAC11 transcripts increased the production of tumor necrosis-α (TNF-α) and IL-17 in the supernatants of HL cells. Furthermore, HDACI-induced OX40L inhibited the generation of IL-10-producing type 1 T-reg cells. These results demonstrate for the first time that HDAC11 plays an essential role in regulating OX40L expression.
21239696	Hodgkin Lymphoma	HDAC11	Inhibit immunity (T cell function)	The engagement of OX40L with the OX40 receptor is essential for the generation of antigen-specific memory T cells and for the induction of host antitumor immunity. Small interfering RNAs (siRNAs) that selectively inhibited HDAC11 expression, significantly up-regulated OX40L and induced apoptosis in HL cell lines, and silencing HDAC11 transcripts increased the production of tumor necrosis-α (TNF-α) and IL-17 in the supernatants of HL cells. Furthermore, HDACI-induced OX40L inhibited the generation of IL-10-producing type 1 T-reg cells. These results demonstrate for the first time that HDAC11 plays an essential role in regulating OX40L expression.
21233400	Colon Carcinoma	TLR9	Promote immunity (T cell function)	We further show that TLR9 activation by CpG promotes maturation and differentiation of MDSC and strongly decreases the proportion of Ly6G(hi) MDSC in both tumor-bearing and tumor-free mice. We demonstrate that IFN-α produced by plasmacytoid dendritic cells upon CpG stimulation is a key effector for the induction of MDSC maturation in vitro and show that treatment of mice with recombinant IFN-α is sufficient to block MDSC suppressivity. We show here for the first time that TLR9 activation inhibits the regulatory function of MDSC in tumor-bearing mice and define a role for the antitumoral cytokine IFN-α in this process.
21233400	Colon Carcinoma	IFNA1	Promote immunity (T cell function)	We further show that TLR9 activation by CpG promotes maturation and differentiation of MDSC and strongly decreases the proportion of Ly6G(hi) MDSC in both tumor-bearing and tumor-free mice. We demonstrate that IFN-α produced by plasmacytoid dendritic cells upon CpG stimulation is a key effector for the induction of MDSC maturation in vitro and show that treatment of mice with recombinant IFN-α is sufficient to block MDSC suppressivity. We show here for the first time that TLR9 activation inhibits the regulatory function of MDSC in tumor-bearing mice and define a role for the antitumoral cytokine IFN-α in this process.
21232138	Breast Carcinoma	IFNG	Promote immunity (T cell function)	This finding was correlated with an increased ability of tumor-draining lymph node cells and splenocytes from α-TEA-treated mice to secrete interferon (IFN)-γ in response to CD3 or to mediate a cytolytic response in a tumor-specific fashion, respectively.
21232138	Breast Carcinoma	CD3G	Promote immunity (T cell function)	This finding was correlated with an increased ability of tumor-draining lymph node cells and splenocytes from α-TEA-treated mice to secrete interferon (IFN)-γ in response to CD3 or to mediate a cytolytic response in a tumor-specific fashion, respectively.
21224372	Melanoma	IL2	Promote immunity (T cell function)	A dynamic label free assay was used to determine the pathways involved in the lysis of melanoma cells by IL-2-activated NK cells. NKG2D, NCR (natural cytotoxicity receptor), and DNAM-1 are involved in the NK-mediated lysis of melanoma cells.
21224372	Melanoma	KLRK1	Promote immunity (NK cell function)	A dynamic label free assay was used to determine the pathways involved in the lysis of melanoma cells by IL-2-activated NK cells. NKG2D, NCR (natural cytotoxicity receptor), and DNAM-1 are involved in the NK-mediated lysis of melanoma cells.
21224372	Melanoma	NCR3	Promote immunity (T cell function)	A dynamic label free assay was used to determine the pathways involved in the lysis of melanoma cells by IL-2-activated NK cells. NKG2D, NCR (natural cytotoxicity receptor), and DNAM-1 are involved in the NK-mediated lysis of melanoma cells.
21224372	Melanoma	CD226	Promote immunity (T cell function)	A dynamic label free assay was used to determine the pathways involved in the lysis of melanoma cells by IL-2-activated NK cells. NKG2D, NCR (natural cytotoxicity receptor), and DNAM-1 are involved in the NK-mediated lysis of melanoma cells.
21217520	Pancreatic Carcinoma	CSF2	Promote immunity (T cell function)	We tested the safety and efficacy of a granulocyte-macrophage colony-stimulating factor (GM-CSF)-based immunotherapy administered in patients with resected pancreatic adenocarcinoma. The primary endpoint was disease free survival and secondary endpoints were overall survival and toxicity, and the induction of mesothelin specific T cell responses. In addition, the post-immunotherapy induction of mesothelin-specific CD8+ T cells in HLA-A1+ and HLA-A2+patients correlates with disease-free survival.
21216894	Melanoma	IFNG	Promote immunity (T cell function)	Melanoma cell lysis by the CTL was increased by IFN-γ treatment due to preferential processing of the antigenic peptide by the immunoproteasome.
21209070	Colon Carcinoma	VEGFA	Inhibit immunity (T cell function)	Antagonism of VEGF by genetically engineered dendritic cells is essential to induce antitumor immunity against malignant ascites. Using a murine model of MA with CT26 colon cancer cells, we here determined that the imbalance between the VEGF-A/vascular permeability factor and its decoy receptor, soluble fms-like tryrosine kinase receptor-1 (sFLT-1), was a major cause of MA resistance to dendritic cell (DC)-based immunotherapy. These findings were not seen in immunodeficient mice, indicating that a VEGF-A/sFLT-1 imbalance is critical for determining the antitumor immune response by DC-vaccination therapy against MA.
21209070	Colon Carcinoma	FLT1	Promote immunity (T cell function)	Antagonism of VEGF by genetically engineered dendritic cells is essential to induce antitumor immunity against malignant ascites. Using a murine model of MA with CT26 colon cancer cells, we here determined that the imbalance between the VEGF-A/vascular permeability factor and its decoy receptor, soluble fms-like tryrosine kinase receptor-1 (sFLT-1), was a major cause of MA resistance to dendritic cell (DC)-based immunotherapy. These findings were not seen in immunodeficient mice, indicating that a VEGF-A/sFLT-1 imbalance is critical for determining the antitumor immune response by DC-vaccination therapy against MA.
21207413	Melanoma	IFNG	Promote immunity (T cell function)	Tumor cells exposed to interferon-gamma (IFN-γ) were better recognized by the anti-MAGE-C2(42-50) CTL clone. Together, these results support the notion that the tumor regression of this patient was mediated by an antitumor response shaped by IFN-γ and dominated by CTL directed against peptides that are better produced by the immunoproteasome, such as the MAGE-C2 peptides.
21207371	Colon Carcinoma	ITGAE	Inhibit immunity (T cell function)	Here we show that CD103, an integrin mediating lymphocyte retention in epithelial tissues, is expressed at high levels on tumor-infiltrating FoxP3+ Treg in several types of murine cancer. In the CT26 model of colon cancer up to 90% of the intratumoral FoxP3+ cells expressed CD103 compared to less than 20% in lymphoid organs. CD103+ Treg suppressed T effector cell activation more strongly than CD103(neg) Treg.
21207371	Colon Carcinoma	TGFB1	Inhibit immunity (T cell function)	Here we show that CD103, an integrin mediating lymphocyte retention in epithelial tissues, is expressed at high levels on tumor-infiltrating FoxP3+ Treg in several types of murine cancer. In the CT26 model of colon cancer up to 90% of the intratumoral FoxP3+ cells expressed CD103 compared to less than 20% in lymphoid organs. CD103+ Treg suppressed T effector cell activation more strongly than CD103(neg) Treg. Expression of CD103 on Treg closely correlated with intratumoral levels of transforming growth factor β (TGF-β) and could be induced in a TGF-β-dependent manner by tumor cell lines. In vivo, gene silencing of TGF-β reduced the frequency of CD103+ Treg, demonstrating that CD103 expression on tumor-infiltrating Treg is driven by intratumoral TGF-β.
21194983	Lymphoma	SIGLEC1	Promote immunity (T cell function)	Here we show that CD169(+) macrophages phagocytose dead tumor cells transported via lymphatic flow and subsequently crosspresent tumor antigens to CD8(+) T?cells. However, tumor antigen-specific CD8(+) T?cell activation and subsequent antitumor immunity are severely impaired in mice depleted with CD169(+) macrophages. Thus, we have identified CD169(+) macrophages as lymph node-resident APCs dominating early activation of tumor antigen-specific CD8(+) T?cells.
22566819	Ovarian Carcinoma	IL10	Inhibit immunity (T cell function)	Here we identify a novel pathway in which the tumor-infiltrating MDSC are the predominant producers of IL-10 and, importantly, require it to develop their immunosuppressive function in vivo. Importantly, we demonstrate that the role of IL-10 is critical, and not redundant with other immunosuppressive molecules, to in vivo tumor progression: blockade of the IL-10 signaling network results in alleviation of MDSC-mediated immunosuppression, altered T cell phenotype and activity, and improved survival.
21191065	Lung Carcinoma	LGALS1	Inhibit immunity (T cell function)	We have shown that galectin-1 is highly expressed in lung cancer cell lines, together with the serum and surgical samples from lung cancer patients. Functionally, lung cancer-derived galectin-1 has been shown to alter the phenotypes of monocyte-derived DCs (MdDCs) and impair alloreactive T cell response, concomitant with the increase of CD4(+)CD25(+)FOXP3(+) regulatory T cells. The regulatory effect of galectin-1 is mediated, in part, through its ability to induce, in an Id3 (inhibitor of DNA binding 3)-dependent manner, the expression of IL-10 in monocytes and MdDCs. Of note, significant upregulation of IL-10 was seen in tumor-infiltrating CD11c(+) DCs in human lung cancer samples.
21191065	Lung Carcinoma	ID3	Inhibit immunity (T cell function)	We have shown that galectin-1 is highly expressed in lung cancer cell lines, together with the serum and surgical samples from lung cancer patients. Functionally, lung cancer-derived galectin-1 has been shown to alter the phenotypes of monocyte-derived DCs (MdDCs) and impair alloreactive T cell response, concomitant with the increase of CD4(+)CD25(+)FOXP3(+) regulatory T cells. The regulatory effect of galectin-1 is mediated, in part, through its ability to induce, in an Id3 (inhibitor of DNA binding 3)-dependent manner, the expression of IL-10 in monocytes and MdDCs. Of note, significant upregulation of IL-10 was seen in tumor-infiltrating CD11c(+) DCs in human lung cancer samples.
21191065	Lung Carcinoma	IL10	Inhibit immunity (T cell function)	We have shown that galectin-1 is highly expressed in lung cancer cell lines, together with the serum and surgical samples from lung cancer patients. Functionally, lung cancer-derived galectin-1 has been shown to alter the phenotypes of monocyte-derived DCs (MdDCs) and impair alloreactive T cell response, concomitant with the increase of CD4(+)CD25(+)FOXP3(+) regulatory T cells. The regulatory effect of galectin-1 is mediated, in part, through its ability to induce, in an Id3 (inhibitor of DNA binding 3)-dependent manner, the expression of IL-10 in monocytes and MdDCs. Of note, significant upregulation of IL-10 was seen in tumor-infiltrating CD11c(+) DCs in human lung cancer samples.
21178137	Bladder Carcinoma	CALR	Promote immunity	Here, we identified calreticulin as a pro-phagocytic signal that was highly expressed on the surface of several human cancers, but was minimally expressed on most normal cells. Increased CD47 expression correlated with high amounts of calreticulin on cancer cells and was necessary for protection from calreticulin-mediated phagocytosis.
21178137	Bladder Carcinoma	CD47	Inhibit immunity	Here, we identified calreticulin as a pro-phagocytic signal that was highly expressed on the surface of several human cancers, but was minimally expressed on most normal cells. Increased CD47 expression correlated with high amounts of calreticulin on cancer cells and was necessary for protection from calreticulin-mediated phagocytosis.
21178005	Choriocarcinoma; Breast Carcinoma; Ovarian Carcinoma	IL1B	Inhibit immunity	Tumor-associated a2 vacuolar ATPase acts as a key mediator of cancer-related inflammation by inducing pro-tumorigenic properties in monocytes. These included IL-1β and IL-10, which are important in promoting inflammation and immune escape by tumor cells.
21178005	Choriocarcinoma; Breast Carcinoma; Ovarian Carcinoma	IL10	Inhibit immunity	Tumor-associated a2 vacuolar ATPase acts as a key mediator of cancer-related inflammation by inducing pro-tumorigenic properties in monocytes. These included IL-1β and IL-10, which are important in promoting inflammation and immune escape by tumor cells.
21177380	Acute Lymphoblastic Leukemia	CD47	Inhibit immunity	CD47 was found to be more highly expressed on a subset of human ALL patient samples compared with normal cell counterparts and to be an independent predictor of survival and disease refractoriness in several ALL patient cohorts. In addition, a blocking monoclonal antibody against CD47 enabled phagocytosis of ALL cells by macrophages in vitro and inhibited tumor engraftment in vivo.
21173239	Melanoma	CTLA4	Inhibit immunity (T cell function); essential for immunotherapy	Clinical trials of CTLA-4-blocking antibodies to augment T-cell responses to malignant melanoma are at an advanced stage; however, little is known about the effects of CTLA-4 blockade on memory CD8(+) T-cell responses and the formation and maintenance of long-term CD8(+) T-cell memory. This is followed by an accumulation of memory cells that are capable of producing the effector cytokines IFN-γ and TNF-α.
21173239	Melanoma	IFNG	Promote immunity	Clinical trials of CTLA-4-blocking antibodies to augment T-cell responses to malignant melanoma are at an advanced stage; however, little is known about the effects of CTLA-4 blockade on memory CD8(+) T-cell responses and the formation and maintenance of long-term CD8(+) T-cell memory. This is followed by an accumulation of memory cells that are capable of producing the effector cytokines IFN-γ and TNF-α.
21173239	Melanoma	TNF	Promote immunity	Clinical trials of CTLA-4-blocking antibodies to augment T-cell responses to malignant melanoma are at an advanced stage; however, little is known about the effects of CTLA-4 blockade on memory CD8(+) T-cell responses and the formation and maintenance of long-term CD8(+) T-cell memory. This is followed by an accumulation of memory cells that are capable of producing the effector cytokines IFN-γ and TNF-α.
21172865	Melanoma	CD9	Promote immunity (T cell function)	CD9(pos)Siglec-H(low) pDC secrete IFN-α when stimulated with TLR agonists, induce CTLs, and promote protective antitumor immunity. By contrast, CD9(neg)Siglec-H(high) pDC secrete negligible amounts of IFN-α, induce Foxp3(+) CD4(+) T cells, and fail to promote antitumor immunity.
21172865	Melanoma	TLR9	Promote immunity (T cell function)	CD9(pos)Siglec-H(low) pDC secrete IFN-α when stimulated with TLR agonists, induce CTLs, and promote protective antitumor immunity. By contrast, CD9(neg)Siglec-H(high) pDC secrete negligible amounts of IFN-α, induce Foxp3(+) CD4(+) T cells, and fail to promote antitumor immunity.
21172865	Melanoma	IFNA1	Promote immunity (T cell function)	CD9(pos)Siglec-H(low) pDC secrete IFN-α when stimulated with TLR agonists, induce CTLs, and promote protective antitumor immunity. By contrast, CD9(neg)Siglec-H(high) pDC secrete negligible amounts of IFN-α, induce Foxp3(+) CD4(+) T cells, and fail to promote antitumor immunity.
21170961	Melanoma	VCAM1	Promote immunity (infiltration)	Enhanced Type-1 T cell infiltration of tumors was associated with treatment-induced expression of vascular cell adhesion molecule-1 (VCAM-1) and CXCR3 ligand chemokines in vascular/peri-vascular cells within the TME, with SUT/VAC therapy benefits conditionally negated upon adminsitration of CXCR3 or VCAM-1 blocking antibodies.
21170961	Melanoma	CXCR3	Promote immunity (infiltration)	Enhanced Type-1 T cell infiltration of tumors was associated with treatment-induced expression of vascular cell adhesion molecule-1 (VCAM-1) and CXCR3 ligand chemokines in vascular/peri-vascular cells within the TME, with SUT/VAC therapy benefits conditionally negated upon adminsitration of CXCR3 or VCAM-1 blocking antibodies.
21165950	Leukemia; Melanoma	IL2	Promote immunity (T cell function)	Here, we show that IL-2/S4B6 mAb immunocomplexes expand not only CD122(high) subsets and newly activated CD8(+) T cells but also natural killer T cells and γδ T cells. Further, we demonstrate that natural killer (NK) cells expanded by IL-2/S4B6 mAb immunocomplexes in vivo have high cytolytic activity, which can be further increased by coadministration of IL-12. We also demonstrate that IL-2/S4B6 mAb immunocomplexes possess noticeable antitumor activity in two syngeneic mouse tumor models, namely BCL1 leukemia and B16F10 melanoma, but only if administered early in tumor progression. To effectively treat established tumors, we administered the tumor-bearing mice first with N-(2-hydroxypropyl)methacrylamide copolymer-bound doxorubicin conjugate, and subsequently with IL-2/S4B6 mAb immunocomplexes alone or with IL-12 to induce an efficient antitumor immune response.
21165950	Leukemia; Melanoma	IL12A	Promote immunity (T cell function)	Here, we show that IL-2/S4B6 mAb immunocomplexes expand not only CD122(high) subsets and newly activated CD8(+) T cells but also natural killer T cells and γδ T cells. Further, we demonstrate that natural killer (NK) cells expanded by IL-2/S4B6 mAb immunocomplexes in vivo have high cytolytic activity, which can be further increased by coadministration of IL-12. We also demonstrate that IL-2/S4B6 mAb immunocomplexes possess noticeable antitumor activity in two syngeneic mouse tumor models, namely BCL1 leukemia and B16F10 melanoma, but only if administered early in tumor progression. To effectively treat established tumors, we administered the tumor-bearing mice first with N-(2-hydroxypropyl)methacrylamide copolymer-bound doxorubicin conjugate, and subsequently with IL-2/S4B6 mAb immunocomplexes alone or with IL-12 to induce an efficient antitumor immune response.
21159663	Melanoma	CCL2	Inhibit immunity	Induction of monocyte chemoattractant protein-1 and interleukin-10 by TGFbeta1 in melanoma enhances tumor infiltration and immunosuppression.
21159663	Melanoma	IL10	Inhibit immunity	Induction of monocyte chemoattractant protein-1 and interleukin-10 by TGFbeta1 in melanoma enhances tumor infiltration and immunosuppression.
21159663	Melanoma	TGFB1	Inhibit immunity	Induction of monocyte chemoattractant protein-1 and interleukin-10 by TGFbeta1 in melanoma enhances tumor infiltration and immunosuppression.
21159663	Melanoma	FGF2	Inhibit immunity	Induction of monocyte chemoattractant protein-1 and interleukin-10 by TGFbeta1 in melanoma enhances tumor infiltration and immunosuppression. Supernatants from TGFβ1-treated A375 cells enhanced MCP-1-dependent migration of monocytes, which, in turn, expressed high levels of TGF,β1, bFGF, and VEGF mRNA.
21159663	Melanoma	VEGFA	Inhibit immunity	Induction of monocyte chemoattractant protein-1 and interleukin-10 by TGFbeta1 in melanoma enhances tumor infiltration and immunosuppression. Supernatants from TGFβ1-treated A375 cells enhanced MCP-1-dependent migration of monocytes, which, in turn, expressed high levels of TGF,β1, bFGF, and VEGF mRNA.
21159663	Melanoma	IL10	Inhibit immunity	Induction of monocyte chemoattractant protein-1 and interleukin-10 by TGFbeta1 in melanoma enhances tumor infiltration and immunosuppression. Supernatants from TGFβ1-treated A375 cells enhanced MCP-1-dependent migration of monocytes, which, in turn, expressed high levels of TGF,β1, bFGF, and VEGF mRNA. Moreover, these supernatants also inhibited functional properties of dendritic cells through IL-10-dependent mechanisms.
21159663	Melanoma	SMAD3	Inhibit immunity	Induction of monocyte chemoattractant protein-1 and interleukin-10 by TGFbeta1 in melanoma enhances tumor infiltration and immunosuppression. Supernatants from TGFβ1-treated A375 cells enhanced MCP-1-dependent migration of monocytes, which, in turn, expressed high levels of TGF,β1, bFGF, and VEGF mRNA. Moreover, these supernatants also inhibited functional properties of dendritic cells through IL-10-dependent mechanisms. When using in vitro, the TGFβ1-blocking peptide P144, TGFβ1-dependent Smad3 phosphorylation, and expression of MCP-1 and IL-10 were inhibited.
21159663	Melanoma	CCL2	Inhibit immunity	Induction of monocyte chemoattractant protein-1 and interleukin-10 by TGFbeta1 in melanoma enhances tumor infiltration and immunosuppression. Supernatants from TGFβ1-treated A375 cells enhanced MCP-1-dependent migration of monocytes, which, in turn, expressed high levels of TGF,β1, bFGF, and VEGF mRNA. Moreover, these supernatants also inhibited functional properties of dendritic cells through IL-10-dependent mechanisms. When using in vitro, the TGFβ1-blocking peptide P144, TGFβ1-dependent Smad3 phosphorylation, and expression of MCP-1 and IL-10 were inhibited.
21159639	Lymphoma	CXCL12	Inhibit immunity (T cell function)	CXCL12 mediates immunosuppression in the lymphoma microenvironment after allogeneic transplantation of hematopoietic cells. In vivo blocking identified the CXCR4/CXCL12 axis as being critical for Treg attraction toward BCL. In contrast to Tregs, effector T cells displayed low levels of CXCR4 and were not affected by the pharmacologic blockade. Most important, blocking CXCR4 not only reduced Treg migration toward tumor tissue but also enhanced antitumor responses after alloHCT.
21159639	Lymphoma	CXCR4	Inhibit immunity (T cell function)	CXCL12 mediates immunosuppression in the lymphoma microenvironment after allogeneic transplantation of hematopoietic cells. In vivo blocking identified the CXCR4/CXCL12 axis as being critical for Treg attraction toward BCL. In contrast to Tregs, effector T cells displayed low levels of CXCR4 and were not affected by the pharmacologic blockade. Most important, blocking CXCR4 not only reduced Treg migration toward tumor tissue but also enhanced antitumor responses after alloHCT.
21159639	Lymphoma	IL2RA	Inhibit immunity (T cell function)	CXCL12 mediates immunosuppression in the lymphoma microenvironment after allogeneic transplantation of hematopoietic cells. In vivo blocking identified the CXCR4/CXCL12 axis as being critical for Treg attraction toward BCL. In contrast to Tregs, effector T cells displayed low levels of CXCR4 and were not affected by the pharmacologic blockade. Most important, blocking CXCR4 not only reduced Treg migration toward tumor tissue but also enhanced antitumor responses after alloHCT. CXCL12 production was dependent on antigen-presenting cells (APC) located in the lymphoma microenvironment, and their diphtheria-toxin receptor (DTR)-based depletion in CD11c.DTR-Tg mice significantly reduced Treg accumulation within BCL tissue.
21159639	Lymphoma	IRF8	Promote immunity (T cell function)	CXCL12 mediates immunosuppression in the lymphoma microenvironment after allogeneic transplantation of hematopoietic cells. In vivo blocking identified the CXCR4/CXCL12 axis as being critical for Treg attraction toward BCL. In contrast to Tregs, effector T cells displayed low levels of CXCR4 and were not affected by the pharmacologic blockade. Most important, blocking CXCR4 not only reduced Treg migration toward tumor tissue but also enhanced antitumor responses after alloHCT. CXCL12 production was dependent on antigen-presenting cells (APC) located in the lymphoma microenvironment, and their diphtheria-toxin receptor (DTR)-based depletion in CD11c.DTR-Tg mice significantly reduced Treg accumulation within BCL tissue.
21159638	Melanoma	NLRP3	Inhibit immunity (T cell function)	We concluded that Nlrp3 was critical for accumulation of MDSCs in tumors and for inhibition of antitumor T-cell immunity after dendritic cell vaccination. Our findings establish an unexpected role for Nlrp3 in impeding antitumor immune responses, suggesting novel approaches to improve the response to antitumor vaccines by limiting Nlrp3 signaling.
21159634	Breast Carcinoma	KLRK1	Promote immunity (NK cell function)	NKG2D ligands link the innate and adapative immune response by activating the receptors expressed on effector cells of both the innate (NK) and adaptive immune systems (CD8(+) T cells). Our findings demonstrate that administration of an antibody-NKG2D ligand fusion protein can enhance innate and adaptive immune antitumor responses, also evoking additional nontargeted antigens to enhance the potential clinical utility of this approach.
21123824	Leukemia	IFNG	Promote immunity (T cell function)	Herein we demonstrate that effector/memory CD4(+) T helper-1 (Th-1) lymphocytes, in addition to polarizing type-1 antitumor immune responses, impair tumor-induced CD4(+)CD25(+)FoxP3(+) regulatory T lymphocyte (Treg) immunosuppressive function in vitro and in vivo. Th-1 cells also inhibit the generation of FoxP3(+) Tregs from naive CD4(+)CD25(-)FoxP3(-) T cells by an interferon-γ-dependent mechanism.
21118964	Renal Cell Carcinoma; Melanoma	STAT3	Inhibit immunity (T cell function)	Sunitinib inhibited Stat3 in dendritic cells and T cells and reduced conversion of transferred FoxP3(-) T cells to tumor-associated regulatory T cells while increasing transferred CD8(+) T-cell infiltration and activation at the tumor site, leading to inhibition of primary tumor growth.
21106849	Melanoma	TNFRSF18	Promote immunity (T cell function)	Treatment of tumor-bearing mice with a stimulatory Ab to glucocorticoid-induced TNFR family-related receptor (GITR) has previously been shown to elicit protective T cell responses against poorly immunogenic tumors. We conclude that stimulation of GITR on effector CD8 T cells results in high-avidity T cell responses to tumor-specific Ags, thereby inducing potent antitumor immunity in the absence of autoimmunity.
21098714	Melanoma	ICOSLG	Inhibit immunity (T cell function)	Melanoma cells express ICOS ligand to promote the activation and expansion of T-regulatory cells. Here we show that human melanomas express inducible T-cell costimulator ligand (ICOS-L/B7H) that can provide costimulation through ICOS for the expansion of activated Tregs maintaining high Foxp3 and CD25 expression as well as a suppressive function.
21078911	Colon Carcinoma	IL10	Inhibit immunity (T cell function)	In this tumoral environment, these monocytes can differentiate into tolerogenic dendritic cells (DCs) that produce IL-10 and potently induce regulatory T cell responses in vivo. Moreover, diverting the differentiation of Gr-1(+) monocytes into tolerogenic DCs by forced expression of IL-10 soluble receptor and IL-3 in tumor cells improves host immunosurveillance by reducing the regulatory T cell frequency and by inducing immunogenic DCs in the tumor.
21078911	Colon Carcinoma	IL3	Promote immunity (T cell function)	In this tumoral environment, these monocytes can differentiate into tolerogenic dendritic cells (DCs) that produce IL-10 and potently induce regulatory T cell responses in vivo. Moreover, diverting the differentiation of Gr-1(+) monocytes into tolerogenic DCs by forced expression of IL-10 soluble receptor and IL-3 in tumor cells improves host immunosurveillance by reducing the regulatory T cell frequency and by inducing immunogenic DCs in the tumor.
19701890	Leukemia	TNFSF14	Promote immunity	The TNF member LIGHT also known as TL4 or TNFSF14) can play a major role in cancer control via its two receptors; it induces tumor cell death through lymphotoxin-beta receptor (LT-betaR) and ligation to the herpes virus entry mediator (HVEM) amplifies the immune response. By studying the effect of LIGHT in the transcriptional profile of a lymphoid malignancy, we found that HVEM, but not LT-betaR, stimulation induces a significant increase in the expression of chemokine genes such as IL-8, and an unexpected upregulation of apoptotic genes. This had functional consequences, since LIGHT, or HVEM mAb, thus far known to costimulate T- and B-cell activation, induced chronic lymphocytic leukemia cell death. Many of the mediators involved were identified here, with an apoptotic pathway as demonstrated by caspases activation, decrease in mitochondrial membrane potential, upregulation of the pro-apoptotic protein Bax, but also a role of TRAIL. HVEM Moreover, HVEM induced endogenous TNF-alpha production and TNF-alpha enhanced HVEM-mediated cell death.
19701890	Leukemia	TNFRSF14	Promote immunity	The TNF member LIGHT also known as TL4 or TNFSF14) can play a major role in cancer control via its two receptors; it induces tumor cell death through lymphotoxin-beta receptor (LT-betaR) and ligation to the herpes virus entry mediator (HVEM) amplifies the immune response. By studying the effect of LIGHT in the transcriptional profile of a lymphoid malignancy, we found that HVEM, but not LT-betaR, stimulation induces a significant increase in the expression of chemokine genes such as IL-8, and an unexpected upregulation of apoptotic genes. This had functional consequences, since LIGHT, or HVEM mAb, thus far known to costimulate T- and B-cell activation, induced chronic lymphocytic leukemia cell death. Many of the mediators involved were identified here, with an apoptotic pathway as demonstrated by caspases activation, decrease in mitochondrial membrane potential, upregulation of the pro-apoptotic protein Bax, but also a role of TRAIL. HVEM Moreover, HVEM induced endogenous TNF-alpha production and TNF-alpha enhanced HVEM-mediated cell death.
19701890	Leukemia	CXCL8	Promote immunity	The TNF member LIGHT also known as TL4 or TNFSF14) can play a major role in cancer control via its two receptors; it induces tumor cell death through lymphotoxin-beta receptor (LT-betaR) and ligation to the herpes virus entry mediator (HVEM) amplifies the immune response. By studying the effect of LIGHT in the transcriptional profile of a lymphoid malignancy, we found that HVEM, but not LT-betaR, stimulation induces a significant increase in the expression of chemokine genes such as IL-8, and an unexpected upregulation of apoptotic genes. This had functional consequences, since LIGHT, or HVEM mAb, thus far known to costimulate T- and B-cell activation, induced chronic lymphocytic leukemia cell death. Many of the mediators involved were identified here, with an apoptotic pathway as demonstrated by caspases activation, decrease in mitochondrial membrane potential, upregulation of the pro-apoptotic protein Bax, but also a role of TRAIL. HVEM Moreover, HVEM induced endogenous TNF-alpha production and TNF-alpha enhanced HVEM-mediated cell death.
19701890	Leukemia	TNF	Promote immunity	The TNF member LIGHT also known as TL4 or TNFSF14) can play a major role in cancer control via its two receptors; it induces tumor cell death through lymphotoxin-beta receptor (LT-betaR) and ligation to the herpes virus entry mediator (HVEM) amplifies the immune response. By studying the effect of LIGHT in the transcriptional profile of a lymphoid malignancy, we found that HVEM, but not LT-betaR, stimulation induces a significant increase in the expression of chemokine genes such as IL-8, and an unexpected upregulation of apoptotic genes. This had functional consequences, since LIGHT, or HVEM mAb, thus far known to costimulate T- and B-cell activation, induced chronic lymphocytic leukemia cell death. Many of the mediators involved were identified here, with an apoptotic pathway as demonstrated by caspases activation, decrease in mitochondrial membrane potential, upregulation of the pro-apoptotic protein Bax, but also a role of TRAIL. HVEM Moreover, HVEM induced endogenous TNF-alpha production and TNF-alpha enhanced HVEM-mediated cell death.
19692638	Head and Neck Squamous Cell Carcinoma	FAS	Inhibit immunity (T cell function)	Sera of patients with cancer contain membraneous microvesicles (MV) able to induce apoptosis of activated T cells by activating the Fas/Fas ligand pathway.
19692638	Head and Neck Squamous Cell Carcinoma	FASLG	Inhibit immunity (T cell function)	Sera of patients with cancer contain membraneous microvesicles (MV) able to induce apoptosis of activated T cells by activating the Fas/Fas ligand pathway.
19690146	Renal Cell Carcinoma	HSP90AA1	Inhibit immunity (T cell function)	In the current study, we show that treatment of EphA2(+) tumor cells with the irreversible heat shock protein 90 inhibitor, 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), similarly enhances their recognition by EphA2-specific CD8(+) T-cell lines and clones in vitro via a mechanism that is dependent on proteasome and transporter-associated protein function as well as the retrotranslocation of EphA2 into the tumor cytoplasm.
19688743	Melanoma	GADD45B	Inhibit immunity	Gadd45b, a signaling molecule highly up-regulated during Th1 type responses, is studied for its role in limiting tumor growth. Mouse B16 melanoma cells implanted into Gadd45b(-/-) mice grew faster than those in WT or Gadd45b(+/-) littermate controls. The defect of Gadd45b(-/-) mice in tumor immunosurveillance was attributed to the reduced expression of IFN-gamma, granzyme B, and CCR5 in Gadd45b(-/-) CD8(+) T cells at the tumor site.
19688743	Melanoma	GADD45G	Promote immunity (T cell function)	Gadd45b and Gadd45g are important for anti-tumor immune responses.
19688743	Melanoma	IFNG	Promote immunity (T cell function)	Gadd45b, a signaling molecule highly up-regulated during Th1 type responses, is studied for its role in limiting tumor growth. Mouse B16 melanoma cells implanted into Gadd45b(-/-) mice grew faster than those in WT or Gadd45b(+/-) littermate controls. The defect of Gadd45b(-/-) mice in tumor immunosurveillance was attributed to the reduced expression of IFN-gamma, granzyme B, and CCR5 in Gadd45b(-/-) CD8(+) T cells at the tumor site.
19688743	Melanoma	GZMB	Promote immunity (T cell function)	Gadd45b, a signaling molecule highly up-regulated during Th1 type responses, is studied for its role in limiting tumor growth. Mouse B16 melanoma cells implanted into Gadd45b(-/-) mice grew faster than those in WT or Gadd45b(+/-) littermate controls. The defect of Gadd45b(-/-) mice in tumor immunosurveillance was attributed to the reduced expression of IFN-gamma, granzyme B, and CCR5 in Gadd45b(-/-) CD8(+) T cells at the tumor site.
19688743	Melanoma	CCR5	Promote immunity (T cell function)	Gadd45b, a signaling molecule highly up-regulated during Th1 type responses, is studied for its role in limiting tumor growth. Mouse B16 melanoma cells implanted into Gadd45b(-/-) mice grew faster than those in WT or Gadd45b(+/-) littermate controls. The defect of Gadd45b(-/-) mice in tumor immunosurveillance was attributed to the reduced expression of IFN-gamma, granzyme B, and CCR5 in Gadd45b(-/-) CD8(+) T cells at the tumor site.
19688743	Melanoma	MAPK14	Promote immunity (T cell function)	Gadd45b, a signaling molecule highly up-regulated during Th1 type responses, is studied for its role in limiting tumor growth. Mouse B16 melanoma cells implanted into Gadd45b(-/-) mice grew faster than those in WT or Gadd45b(+/-) littermate controls. The defect of Gadd45b(-/-) mice in tumor immunosurveillance was attributed to the reduced expression of IFN-gamma, granzyme B, and CCR5 in Gadd45b(-/-) CD8(+) T cells at the tumor site. Activation of p38 MAP kinase, but not ERK or JNK, by either TCR-stimuli or IL-12 and IL-18 is diminished in Gadd45b(-/-) CD8(+) T cells, resulting in reduced production of IFN-gamma.
19688743	Melanoma	IL12A	Promote immunity (T cell function)	Gadd45b, a signaling molecule highly up-regulated during Th1 type responses, is studied for its role in limiting tumor growth. Mouse B16 melanoma cells implanted into Gadd45b(-/-) mice grew faster than those in WT or Gadd45b(+/-) littermate controls. The defect of Gadd45b(-/-) mice in tumor immunosurveillance was attributed to the reduced expression of IFN-gamma, granzyme B, and CCR5 in Gadd45b(-/-) CD8(+) T cells at the tumor site. Activation of p38 MAP kinase, but not ERK or JNK, by either TCR-stimuli or IL-12 and IL-18 is diminished in Gadd45b(-/-) CD8(+) T cells, resulting in reduced production of IFN-gamma.
19688743	Melanoma	IL18	Promote immunity (T cell function)	Gadd45b, a signaling molecule highly up-regulated during Th1 type responses, is studied for its role in limiting tumor growth. Mouse B16 melanoma cells implanted into Gadd45b(-/-) mice grew faster than those in WT or Gadd45b(+/-) littermate controls. The defect of Gadd45b(-/-) mice in tumor immunosurveillance was attributed to the reduced expression of IFN-gamma, granzyme B, and CCR5 in Gadd45b(-/-) CD8(+) T cells at the tumor site. Activation of p38 MAP kinase, but not ERK or JNK, by either TCR-stimuli or IL-12 and IL-18 is diminished in Gadd45b(-/-) CD8(+) T cells, resulting in reduced production of IFN-gamma.
19688743	Melanoma	TBX21	Promote immunity (T cell function)	Gadd45b, a signaling molecule highly up-regulated during Th1 type responses, is studied for its role in limiting tumor growth. Mouse B16 melanoma cells implanted into Gadd45b(-/-) mice grew faster than those in WT or Gadd45b(+/-) littermate controls. The defect of Gadd45b(-/-) mice in tumor immunosurveillance was attributed to the reduced expression of IFN-gamma, granzyme B, and CCR5 in Gadd45b(-/-) CD8(+) T cells at the tumor site. Activation of p38 MAP kinase, but not ERK or JNK, by either TCR-stimuli or IL-12 and IL-18 is diminished in Gadd45b(-/-) CD8(+) T cells, resulting in reduced production of IFN-gamma. In addition, mRNA of T-bet and Eomes were reduced in Gadd45b(-/-) CD8(+) T cells, supporting a critical role of Gadd45b in shaping the Th1 fate.
19688743	Melanoma	EOMES	Promote immunity (T cell function)	Gadd45b, a signaling molecule highly up-regulated during Th1 type responses, is studied for its role in limiting tumor growth. Mouse B16 melanoma cells implanted into Gadd45b(-/-) mice grew faster than those in WT or Gadd45b(+/-) littermate controls. The defect of Gadd45b(-/-) mice in tumor immunosurveillance was attributed to the reduced expression of IFN-gamma, granzyme B, and CCR5 in Gadd45b(-/-) CD8(+) T cells at the tumor site. Activation of p38 MAP kinase, but not ERK or JNK, by either TCR-stimuli or IL-12 and IL-18 is diminished in Gadd45b(-/-) CD8(+) T cells, resulting in reduced production of IFN-gamma. In addition, mRNA of T-bet and Eomes were reduced in Gadd45b(-/-) CD8(+) T cells, supporting a critical role of Gadd45b in shaping the Th1 fate.
19672905	Prostate Carcinoma	TNFRSF4	Promote immunity (T cell function)	These data demonstrate that OX40 ligation can rescue the function of anergic self- or tumor-reactive CD8 T cells in vivo and suggests that OX40-mediated therapy may provide a novel means of boosting anti-tumor immunity by restoring the responsiveness of previously anergic tumor-specific CD8 T cells.
19671844	Hodgkin Lymphoma	HSP90AA1	Inhibit immunity	Heat shock protein 90 inhibitor BIIB021 (CNF2024) depletes NF-kappaB and sensitizes Hodgkin's lymphoma cells for natural killer cell-mediated cytotoxicity.
19671844	Hodgkin Lymphoma	NFKB1	Inhibit immunity	Heat shock protein 90 inhibitor BIIB021 (CNF2024) depletes NF-kappaB and sensitizes Hodgkin's lymphoma cells for natural killer cell-mediated cytotoxicity.
19665763	Ovarian Carcinoma	IDO1	Inhibit immunity (infiltration)	IDO expression was immunohistochemically scored in surgically-resected ovarian cancer tissues (n=60), and its association with tumor-infiltrating lymphocyte (TIL) count or patient survival was analyzed. Next, IDO cDNA was transfected into the human ovarian carcinoma cell line SKOV3, establishing stable clones of IDO-overexpressing cells (SK-IDO). High IDO expression in tumor cells was found in 34 (56.7%) cases and was correlated with a reduced number of CD8+ TIL.
19658097	Cervical Carcinoma	RAET1L	Promote immunity	ULBP6 had a more restricted expression profile in cell lines and primary human tissues than other NKG2D ligands, but expression was detected in several human papillomavirus-positive cervical carcinoma cell lines and was inducible on infection with human CMV. Expression of ULBP6 on target cells induced a significant increase in NK-cell killing.
19658092	Fibrosarcoma	SELL	Promote immunity (T cell function)	HP of CD8(+) T cells is dependent on host IL-7, IL-15, and MHC-class I and has been shown to prevent T-cell tolerance, reverse T-cell anergy and support T-cell-mediated tumor control in vivo. Since we observed that the earliest detectable HP occurs within LN and that T cells undergoing HP retain a CD62L(bright) phenotype, we investigated the functional role of CD62L for this process. We found that CD62L-expression on T cells is required for optimal HP and HP was impaired in lymphotoxin-alphabeta(-/-) mice, indicating the necessity for intact host secondary lymphoid organ structures.
19654302	Renal Cell Carcinoma	FASLG	Promote immunity (T cell function)	The biological relevance of the perforin and Fas ligand (FasL) cytolytic pathways of CD8(+) T lymphocytes (CTL) for cancer immunotherapy is controversial. Blocking FasL in vivo inhibited tumor rejection in these mice. Strikingly, a range of mouse tumor cells presenting low concentrations of immunogenic peptide were all preferentially lysed by the FasL but not the Pfp-mediated effector pathway of CTL, whereas at higher peptide concentrations, the preference in effector pathway usage by CTL was lost. Therefore, the FasL cytolytic pathway may be particularly important for eradicating Fas-sensitive tumors presenting low levels of MHC class I-associated antigens following adoptive T-cell therapy.
19641184	Lymphoma	TNFRSF9	Promote immunity (T cell function)	Anti-CD137 agonistic mAb has demonstrated antitumor efficacy in various tumor models and has now entered clinical trials for the treatment of solid tumors. The antitumor effect of anti-CD137 therapy was mediated by both natural killer (NK) and CD8 T cells and induced long-lasting immunity.
19638467	Neuroblastoma; Leukemia	CD244	Promote immunity (T cell function)	2B4 (CD244) signaling by recombinant antigen-specific chimeric receptors costimulates natural killer cell activation to leukemia and neuroblastoma cells. The signaling lymphocyte activation molecule-related receptor 2B4 (CD244) is an important regulator of NK cell activation.
19620771	Ovarian Carcinoma	TLR5	Promote immunity	Here we demonstrated that linear polyethylenimine-based (PEI-based) nanoparticles encapsulating siRNA were preferentially and avidly engulfed by regulatory DCs expressing CD11c and programmed cell death 1-ligand 1 (PD-L1) at ovarian cancer locations in mice. PEI triggered robust and selective TLR5 activation in vitro and elicited the production of hallmark TLR5-inducible cytokines in WT mice, but not in Tlr5-/- littermates. Our results demonstrate that the intrinsic TLR5 and TLR7 stimulation of siRNA-PEI nanoparticles synergizes with the gene-specific silencing activity of siRNA to transform tumor-infiltrating regulatory DCs into DCs capable of promoting therapeutic antitumor immunity.
19620771	Ovarian Carcinoma	TLR7	Promote immunity	Here we demonstrated that linear polyethylenimine-based (PEI-based) nanoparticles encapsulating siRNA were preferentially and avidly engulfed by regulatory DCs expressing CD11c and programmed cell death 1-ligand 1 (PD-L1) at ovarian cancer locations in mice. PEI triggered robust and selective TLR5 activation in vitro and elicited the production of hallmark TLR5-inducible cytokines in WT mice, but not in Tlr5-/- littermates. Our results demonstrate that the intrinsic TLR5 and TLR7 stimulation of siRNA-PEI nanoparticles synergizes with the gene-specific silencing activity of siRNA to transform tumor-infiltrating regulatory DCs into DCs capable of promoting therapeutic antitumor immunity.
19602595	Ovarian Carcinoma	CCL5	Promote immunity (T cell function)	CCL5-mediated endogenous antitumor immunity elicited by adoptively transferred lymphocytes and dendritic cell depletion. Importantly, these shortly primed T cells secreted large amounts of CCL5, which was required for their therapeutic benefit. Accordingly, transferred T cells recruited CCR5(+) DCs into the tumor, where they showed distinct immunostimulatory attributes. Activated CCR5(+) host T cells with antitumor activity also accumulated at tumor locations, and endogenous tumor-specific memory T cells remained elevated after the disappearance of transferred lymphocytes.
19588506	Colon Carcinoma	HGF	Inhibit immunity (T cell function)	Gene transfer of NK4, an angiogenesis inhibitor, induces CT26 tumor regression via tumor-specific T lymphocyte activation. Hepatocyte growth factor (HGF) has been shown to be involved in malignant behaviors, such as invasion and metastasis, in different tumors. Hepatocyte growth factor (HGF) has been shown to be involved in malignant behaviors, such as invasion and metastasis, in different tumors. NK4 is a competitive antagonist for HGF and exerts an antitumor activity, not only by HGF antagonism but also by antiangiogenesis. Depletion of CD8+ T lymphocytes markedly abrogated the antitumor activity of NK4.
19584290	Neuroblastoma	CD276	Inhibit immunity (T cell function)	B7-H3 protein expression was inversely correlated with miR-29 levels in both cell lines and tumor tissues tested. Using luciferase reporter assay, miR-29a was shown to directly target B7-H3 3' untranslated region, and knock-in and knockdown of miR-29a led to down-regulation and up-regulation, respectively, of B7-H3 protein expression. The ability of miR-29 to control B7-H3 protein expression has implications in immune escape by solid tumors.
19581407	Melanoma	CTLA4	Inhibit immunity (T cell function); essential for immunotherapy	Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. We conclude that the combination of direct enhancement of T(eff) cell function and concomitant inhibition of T reg cell activity through blockade of CTLA-4 on both cell types is essential for mediating the full therapeutic effects of anti-CTLA-4 antibodies during cancer immunotherapy.
19549909	Breast Carcinoma; Head and Neck Squamous Cell Carcinoma	IL27RA	Promote immunity	Expression of exogenous WSX1 in epithelial tumor cells suppresses tumorigenicity in vitro and inhibits tumor growth in vivo. Different from the role of WSX1 in immune cells, the antitumor activity of WSX1 in epithelial tumor cells is independent of IL-27 signaling but is mainly dependent on natural killer (NK) cell surveillance. Deficiency of either the IL-27 subunit EBV-induced gene 3 or the IL-27 receptor WSX1 in the host animals had no effect on tumor growth inhibition induced by WSX1 expression in tumor cells. Expression of WSX1 in epithelial tumor cells enhances NK cell cytolytic activity against tumor cells, whereas the absence of functional NK cells impairs the WSX1-mediated inhibition of epithelial tumor growth. Our results reveal an IL-27-independent function of WSX1: sensitizing NK cell-mediated antitumor surveillance via a NKG2D-dependent mechanism.
19549909	Breast Carcinoma; Head and Neck Squamous Cell Carcinoma	KLRK1	Promote immunity	Expression of exogenous WSX1 in epithelial tumor cells suppresses tumorigenicity in vitro and inhibits tumor growth in vivo. Different from the role of WSX1 in immune cells, the antitumor activity of WSX1 in epithelial tumor cells is independent of IL-27 signaling but is mainly dependent on natural killer (NK) cell surveillance. Deficiency of either the IL-27 subunit EBV-induced gene 3 or the IL-27 receptor WSX1 in the host animals had no effect on tumor growth inhibition induced by WSX1 expression in tumor cells. Expression of WSX1 in epithelial tumor cells enhances NK cell cytolytic activity against tumor cells, whereas the absence of functional NK cells impairs the WSX1-mediated inhibition of epithelial tumor growth. Our results reveal an IL-27-independent function of WSX1: sensitizing NK cell-mediated antitumor surveillance via a NKG2D-dependent mechanism.
19549770	Melanoma	IL10	Inhibit immunity (T cell function)	DCs from melanoma-bearing mice secreted significantly more interleukin 10 and less interleukin 12p70, and showed a decreased capacity to activate T cells compared with DCs from tumor-free animals.
19549770	Melanoma	IL12A	Promote immunity (T cell function)	DCs from melanoma-bearing mice secreted significantly more interleukin 10 and less interleukin 12p70, and showed a decreased capacity to activate T cells compared with DCs from tumor-free animals.
19549768	Cervical Carcinoma	IL10	Inhibit immunity (T cell function)	We used the HPV16 E6- and E7-expressing TC-1 mouse tumor model to study the effect of TAM on T-cell function in vitro, and depleted TAM, using clodronate-containing liposomes, to characterize its role in vivo. TAM displayed high basal Arginase I activity, producing interleukin-10 (IL-10); they were resistant to iNOSII activity induction, therefore reversion to M1 phenotype, when stimulated in vitro with lipopolysaccharide/IFNgamma, indicating an M2 phentoype. In cultures of isolated TAM, TAM induced regulatory phenotype, characterized by IL-10 and Foxp3 expression, and inhibited proliferation of CD8 lymphocytes.
19549768	Cervical Carcinoma	FOXP3	Inhibit immunity (T cell function)	We used the HPV16 E6- and E7-expressing TC-1 mouse tumor model to study the effect of TAM on T-cell function in vitro, and depleted TAM, using clodronate-containing liposomes, to characterize its role in vivo. TAM displayed high basal Arginase I activity, producing interleukin-10 (IL-10); they were resistant to iNOSII activity induction, therefore reversion to M1 phenotype, when stimulated in vitro with lipopolysaccharide/IFNgamma, indicating an M2 phentoype. In cultures of isolated TAM, TAM induced regulatory phenotype, characterized by IL-10 and Foxp3 expression, and inhibited proliferation of CD8 lymphocytes.
19542426	Breast Carcinoma	IRF8	Promote immunity (T cell function)	CD11b(+)Gr-1(+)-expressing cells, termed myeloid-derived suppressor cells, can mediate immunosuppression and tumor progression. Despite limited differences in phenotype, tumor-induced CD11b(+)Gr-1(+) cells were found to produce a more immunosuppressive cytokine profile than that observed by Cnt CD11b(+)Gr-1(+) cells. Furthermore, when admixed with tumor cells, CD11b(+)Gr-1(+) cells from tumor-bearing mice significantly enhanced neoplastic growth compared with counterpart cells from Cnt mice. However, the protumorigenic behavior of these tumor-induced CD11b(+)Gr-1(+) cells was significantly diminished when the expression of IFN regulatory factor 8, a key myeloid-associated transcription factor, was enhanced.
19520829	Glioma	ICAM1	Promote immunity (T cell function)	Dicer-regulated microRNAs 222 and 339 promote resistance of cancer cells to cytotoxic T-lymphocytes by down-regulation of ICAM-1. Taken together, Dicer is responsible for the generation of the mature miR-222 and -339, which suppress ICAM-1 expression on tumor cells, thereby down-regulating the susceptibility of tumor cells to CTL-mediated cytolysis.
19494278	Colon Carcinoma; Prostate Carcinoma	HPGD	Promote immunity	PGDH-mediated antitumor effect was associated with attenuated tumor-induced immune suppression and substantially reduced secretion of immunosuppressive mediators and cytokines such as PGE(2), IL-10, IL-13, and IL-6 by intratumoral CD11b cells. We show also that introduction of 15-PGDH gene in tumor tissue is sufficient to redirect the differentiation of intratumoral CD11b cells from immunosuppressive M2-oriented F4/80(+) tumor-associated macrophages (TAM) into M1-oriented CD11c(+) MHC class II-positive myeloid APCs.
19494278	Colon Carcinoma; Prostate Carcinoma	PTGES2	Inhibit immunity	PGDH-mediated antitumor effect was associated with attenuated tumor-induced immune suppression and substantially reduced secretion of immunosuppressive mediators and cytokines such as PGE(2), IL-10, IL-13, and IL-6 by intratumoral CD11b cells. We show also that introduction of 15-PGDH gene in tumor tissue is sufficient to redirect the differentiation of intratumoral CD11b cells from immunosuppressive M2-oriented F4/80(+) tumor-associated macrophages (TAM) into M1-oriented CD11c(+) MHC class II-positive myeloid APCs.
19494278	Colon Carcinoma; Prostate Carcinoma	IL10	Inhibit immunity	PGDH-mediated antitumor effect was associated with attenuated tumor-induced immune suppression and substantially reduced secretion of immunosuppressive mediators and cytokines such as PGE(2), IL-10, IL-13, and IL-6 by intratumoral CD11b cells. We show also that introduction of 15-PGDH gene in tumor tissue is sufficient to redirect the differentiation of intratumoral CD11b cells from immunosuppressive M2-oriented F4/80(+) tumor-associated macrophages (TAM) into M1-oriented CD11c(+) MHC class II-positive myeloid APCs.
19494278	Colon Carcinoma; Prostate Carcinoma	IL13	Inhibit immunity	PGDH-mediated antitumor effect was associated with attenuated tumor-induced immune suppression and substantially reduced secretion of immunosuppressive mediators and cytokines such as PGE(2), IL-10, IL-13, and IL-6 by intratumoral CD11b cells. We show also that introduction of 15-PGDH gene in tumor tissue is sufficient to redirect the differentiation of intratumoral CD11b cells from immunosuppressive M2-oriented F4/80(+) tumor-associated macrophages (TAM) into M1-oriented CD11c(+) MHC class II-positive myeloid APCs.
19494278	Colon Carcinoma; Prostate Carcinoma	IL6	Inhibit immunity	PGDH-mediated antitumor effect was associated with attenuated tumor-induced immune suppression and substantially reduced secretion of immunosuppressive mediators and cytokines such as PGE(2), IL-10, IL-13, and IL-6 by intratumoral CD11b cells. We show also that introduction of 15-PGDH gene in tumor tissue is sufficient to redirect the differentiation of intratumoral CD11b cells from immunosuppressive M2-oriented F4/80(+) tumor-associated macrophages (TAM) into M1-oriented CD11c(+) MHC class II-positive myeloid APCs.
19494262	Melanoma	IFNA1	Promote immunity (T cell function)	IFN-alpha synergized with peptide vaccination in a dose-dependent manner by boosting relative and absolute numbers of gp100-specific T cells that suppressed B16 melanoma growth. IFN-alpha dramatically increased the accumulation of gp100-specific, IFN-gamma-secreting, CD8(+) T cells in the tumor through reduced apoptosis and enhanced proliferation of Ag-specific CD8(+) T cells. IFN-alpha treatment also greatly increased the long-term maintenance of pmel-1 CD8(+) T cells with an effector memory phenotype, a process that required expression of IFN-alpha receptor on the T cells and IL-15 in the host.
19491278	Lymphoma	TGFB1	Inhibit immunity (T cell function)	For inhibition of TGF-beta-mediated immunosuppression in DLNs, C57BL/6 mice subcutaneously bearing E.G7 tumors were administered plasmid DNA encoding the extracellular domain of TGF-beta type II receptor fused to the human IgG heavy chain (TGFR DNA) i.m. In DLNs, inhibition of TGF-beta suppressed the proliferation of regulatory T cells and increased the number of tumor antigen-specific CD4(+) or CD8(+) cells producing IFN-gamma.
19471017	Melanoma; Fibrosarcoma	IL17A	Promote immunity	We skewed CD8(+) T cells to secrete IL-17 through priming in Th17-polarizing conditions. This improved antitumor immunity was associated with increased expression of IL-7R-alpha, decreased expression of killer cell lectin-like receptor G1, and enhanced persistence of the transferred cells.
19471017	Melanoma; Fibrosarcoma	IL7R	Promote immunity	We skewed CD8(+) T cells to secrete IL-17 through priming in Th17-polarizing conditions. This improved antitumor immunity was associated with increased expression of IL-7R-alpha, decreased expression of killer cell lectin-like receptor G1, and enhanced persistence of the transferred cells.
19471017	Melanoma; Fibrosarcoma	KLRG1	Inhibit immunity	We skewed CD8(+) T cells to secrete IL-17 through priming in Th17-polarizing conditions. This improved antitumor immunity was associated with increased expression of IL-7R-alpha, decreased expression of killer cell lectin-like receptor G1, and enhanced persistence of the transferred cells.
19470694	Ovarian Carcinoma	IL17A	Promote immunity (infiltration)	Furthermore, through synergistic action between IL-17 and interferon-gamma, Th17 cells stimulate CXCL9 and CXCL10 production to recruit effector T cells to the tumor microenvironment. The levels of CXCL9 and CXCL10 are associated with tumor-infiltrating effector T cells. The levels of tumor-infiltrating Th17 cells and the levels of ascites IL-17 are reduced in more advanced diseases and positively predict patient outcome.
19470694	Ovarian Carcinoma	IFNG	Promote immunity (infiltration)	Furthermore, through synergistic action between IL-17 and interferon-gamma, Th17 cells stimulate CXCL9 and CXCL10 production to recruit effector T cells to the tumor microenvironment. The levels of CXCL9 and CXCL10 are associated with tumor-infiltrating effector T cells. The levels of tumor-infiltrating Th17 cells and the levels of ascites IL-17 are reduced in more advanced diseases and positively predict patient outcome.
19470694	Ovarian Carcinoma	CXCL9	Promote immunity (infiltration)	Furthermore, through synergistic action between IL-17 and interferon-gamma, Th17 cells stimulate CXCL9 and CXCL10 production to recruit effector T cells to the tumor microenvironment. The levels of CXCL9 and CXCL10 are associated with tumor-infiltrating effector T cells. The levels of tumor-infiltrating Th17 cells and the levels of ascites IL-17 are reduced in more advanced diseases and positively predict patient outcome.
19470694	Ovarian Carcinoma	CXCL10	Promote immunity (infiltration)	Furthermore, through synergistic action between IL-17 and interferon-gamma, Th17 cells stimulate CXCL9 and CXCL10 production to recruit effector T cells to the tumor microenvironment. The levels of CXCL9 and CXCL10 are associated with tumor-infiltrating effector T cells. The levels of tumor-infiltrating Th17 cells and the levels of ascites IL-17 are reduced in more advanced diseases and positively predict patient outcome.
19455675	Embryonal Carcinoma	TNFRSF4	Promote immunity (T cell function)	OX40 costimulation can abrogate Foxp3+ regulatory T cell-mediated suppression of antitumor immunity. Our data indicate that, in addition to controlling effector T-cell function, OX40 costimulation directly controls Treg-mediated suppression in tumor immunity.
19454669	Lymphoma	BCL2L1	Promote immunity (T cell function)	In vivo, with response to tumor-expressed Ag following adoptive T cell transfer, Ag-reactive CD8(+) T cells expressing both Bcl-x(L) and survivin displayed greatly enhanced tumor protective activity compared with CD8(+) T cells expressing either molecule introduced separately. These results indicate that Bcl-x(L) and survivin can critically contribute in a cooperative, nonredundant manner to augment the accumulation and persistence of CD8(+) T cells following encounter with Ag.
19454669	Lymphoma	BIRC5	Promote immunity (T cell function)	In vivo, with response to tumor-expressed Ag following adoptive T cell transfer, Ag-reactive CD8(+) T cells expressing both Bcl-x(L) and survivin displayed greatly enhanced tumor protective activity compared with CD8(+) T cells expressing either molecule introduced separately. These results indicate that Bcl-x(L) and survivin can critically contribute in a cooperative, nonredundant manner to augment the accumulation and persistence of CD8(+) T cells following encounter with Ag.
29090321	Hepatocellular Carcinoma	JAK1	Inhibit immunity (T cell function)	In the present study, we asked whether TNF-α can promote the expression of B7-H1 induced by IFN-γ in HCC cells. We found that JAK/STAT1/IRF1 was the primary pathway responsible for induction of B7-H1 expression by IFN-γ in human HCC cell lines. TNF-α and IFN-γ synergistically induced the expression of B7-H1 in the HCC cells. Moreover, the mechanism of the synergy was that TNF-α enhanced IFN-γ signaling by upregulating the expression of IFN-γ receptors.
29090321	Hepatocellular Carcinoma	STAT1	Inhibit immunity (T cell function)	In the present study, we asked whether TNF-α can promote the expression of B7-H1 induced by IFN-γ in HCC cells. We found that JAK/STAT1/IRF1 was the primary pathway responsible for induction of B7-H1 expression by IFN-γ in human HCC cell lines. TNF-α and IFN-γ synergistically induced the expression of B7-H1 in the HCC cells. Moreover, the mechanism of the synergy was that TNF-α enhanced IFN-γ signaling by upregulating the expression of IFN-γ receptors.
29090321	Hepatocellular Carcinoma	IRF1	Inhibit immunity (T cell function)	In the present study, we asked whether TNF-α can promote the expression of B7-H1 induced by IFN-γ in HCC cells. We found that JAK/STAT1/IRF1 was the primary pathway responsible for induction of B7-H1 expression by IFN-γ in human HCC cell lines. TNF-α and IFN-γ synergistically induced the expression of B7-H1 in the HCC cells. Moreover, the mechanism of the synergy was that TNF-α enhanced IFN-γ signaling by upregulating the expression of IFN-γ receptors.
29090321	Hepatocellular Carcinoma	IFNG	Inhibit immunity (T cell function)	In the present study, we asked whether TNF-α can promote the expression of B7-H1 induced by IFN-γ in HCC cells. We found that JAK/STAT1/IRF1 was the primary pathway responsible for induction of B7-H1 expression by IFN-γ in human HCC cell lines. TNF-α and IFN-γ synergistically induced the expression of B7-H1 in the HCC cells. Moreover, the mechanism of the synergy was that TNF-α enhanced IFN-γ signaling by upregulating the expression of IFN-γ receptors.
29090321	Hepatocellular Carcinoma	TNF	Inhibit immunity (T cell function)	In the present study, we asked whether TNF-α can promote the expression of B7-H1 induced by IFN-γ in HCC cells. We found that JAK/STAT1/IRF1 was the primary pathway responsible for induction of B7-H1 expression by IFN-γ in human HCC cell lines. TNF-α and IFN-γ synergistically induced the expression of B7-H1 in the HCC cells. Moreover, the mechanism of the synergy was that TNF-α enhanced IFN-γ signaling by upregulating the expression of IFN-γ receptors.
29090321	Hepatocellular Carcinoma	IFNGR1	Inhibit immunity (T cell function)	In the present study, we asked whether TNF-α can promote the expression of B7-H1 induced by IFN-γ in HCC cells. We found that JAK/STAT1/IRF1 was the primary pathway responsible for induction of B7-H1 expression by IFN-γ in human HCC cell lines. TNF-α and IFN-γ synergistically induced the expression of B7-H1 in the HCC cells. Moreover, the mechanism of the synergy was that TNF-α enhanced IFN-γ signaling by upregulating the expression of IFN-γ receptors.
29090321	Hepatocellular Carcinoma	CD274	Inhibit immunity (T cell function)	In the present study, we asked whether TNF-α can promote the expression of B7-H1 induced by IFN-γ in HCC cells. We found that JAK/STAT1/IRF1 was the primary pathway responsible for induction of B7-H1 expression by IFN-γ in human HCC cell lines. TNF-α and IFN-γ synergistically induced the expression of B7-H1 in the HCC cells. Moreover, the mechanism of the synergy was that TNF-α enhanced IFN-γ signaling by upregulating the expression of IFN-γ receptors.
29036438	Gastric Carcinoma	S1PR1	Inhibit immunity (T cell function)	We generated a xenograft mouse model and used SEW-2871, a S1P1 specific agonist to activate S1P1 signalling. SEW-2871 promoted tumor growth in our mouse model, and induced a higher level of MDSC and a reduced level of CD8+CD69+ T cells within tumor. Additionally, SEW-2871 enhanced expression of several MDSC recruitment-associated chemokines (CXCL12, CXCL5 and CCL2) in tumor cells. These chemokines facilitated MDSC migration by interaction with CCR2, CXCR2 and CXCR4. S1P1 signalling promoted gastric cancer by enhancing chemokine expression in tumor cells and recruiting MDSC to tumor microenvironment, which impaired anti-tumoral function of TILs.
29036438	Gastric Carcinoma	CXCL12	Inhibit immunity (T cell function)	We generated a xenograft mouse model and used SEW-2871, a S1P1 specific agonist to activate S1P1 signalling. SEW-2871 promoted tumor growth in our mouse model, and induced a higher level of MDSC and a reduced level of CD8+CD69+ T cells within tumor. Additionally, SEW-2871 enhanced expression of several MDSC recruitment-associated chemokines (CXCL12, CXCL5 and CCL2) in tumor cells. These chemokines facilitated MDSC migration by interaction with CCR2, CXCR2 and CXCR4. S1P1 signalling promoted gastric cancer by enhancing chemokine expression in tumor cells and recruiting MDSC to tumor microenvironment, which impaired anti-tumoral function of TILs.
29036438	Gastric Carcinoma	CXCL5	Inhibit immunity (T cell function)	We generated a xenograft mouse model and used SEW-2871, a S1P1 specific agonist to activate S1P1 signalling. SEW-2871 promoted tumor growth in our mouse model, and induced a higher level of MDSC and a reduced level of CD8+CD69+ T cells within tumor. Additionally, SEW-2871 enhanced expression of several MDSC recruitment-associated chemokines (CXCL12, CXCL5 and CCL2) in tumor cells. These chemokines facilitated MDSC migration by interaction with CCR2, CXCR2 and CXCR4. S1P1 signalling promoted gastric cancer by enhancing chemokine expression in tumor cells and recruiting MDSC to tumor microenvironment, which impaired anti-tumoral function of TILs.
29036438	Gastric Carcinoma	CCL2	Inhibit immunity (T cell function)	We generated a xenograft mouse model and used SEW-2871, a S1P1 specific agonist to activate S1P1 signalling. SEW-2871 promoted tumor growth in our mouse model, and induced a higher level of MDSC and a reduced level of CD8+CD69+ T cells within tumor. Additionally, SEW-2871 enhanced expression of several MDSC recruitment-associated chemokines (CXCL12, CXCL5 and CCL2) in tumor cells. These chemokines facilitated MDSC migration by interaction with CCR2, CXCR2 and CXCR4. S1P1 signalling promoted gastric cancer by enhancing chemokine expression in tumor cells and recruiting MDSC to tumor microenvironment, which impaired anti-tumoral function of TILs.
29036438	Gastric Carcinoma	CCR2	Inhibit immunity (T cell function)	We generated a xenograft mouse model and used SEW-2871, a S1P1 specific agonist to activate S1P1 signalling. SEW-2871 promoted tumor growth in our mouse model, and induced a higher level of MDSC and a reduced level of CD8+CD69+ T cells within tumor. Additionally, SEW-2871 enhanced expression of several MDSC recruitment-associated chemokines (CXCL12, CXCL5 and CCL2) in tumor cells. These chemokines facilitated MDSC migration by interaction with CCR2, CXCR2 and CXCR4. S1P1 signalling promoted gastric cancer by enhancing chemokine expression in tumor cells and recruiting MDSC to tumor microenvironment, which impaired anti-tumoral function of TILs.
29036438	Gastric Carcinoma	CXCR2	Inhibit immunity (T cell function)	We generated a xenograft mouse model and used SEW-2871, a S1P1 specific agonist to activate S1P1 signalling. SEW-2871 promoted tumor growth in our mouse model, and induced a higher level of MDSC and a reduced level of CD8+CD69+ T cells within tumor. Additionally, SEW-2871 enhanced expression of several MDSC recruitment-associated chemokines (CXCL12, CXCL5 and CCL2) in tumor cells. These chemokines facilitated MDSC migration by interaction with CCR2, CXCR2 and CXCR4. S1P1 signalling promoted gastric cancer by enhancing chemokine expression in tumor cells and recruiting MDSC to tumor microenvironment, which impaired anti-tumoral function of TILs.
29036438	Gastric Carcinoma	CXCR4	Inhibit immunity (T cell function)	We generated a xenograft mouse model and used SEW-2871, a S1P1 specific agonist to activate S1P1 signalling. SEW-2871 promoted tumor growth in our mouse model, and induced a higher level of MDSC and a reduced level of CD8+CD69+ T cells within tumor. Additionally, SEW-2871 enhanced expression of several MDSC recruitment-associated chemokines (CXCL12, CXCL5 and CCL2) in tumor cells. These chemokines facilitated MDSC migration by interaction with CCR2, CXCR2 and CXCR4. S1P1 signalling promoted gastric cancer by enhancing chemokine expression in tumor cells and recruiting MDSC to tumor microenvironment, which impaired anti-tumoral function of TILs.
29034589	Colon Carcinoma	AGTR1	Inhibit immunity (T cell function)	Giving angiotensin II receptor blockers (ARB) to C57BL/6 mice bearing murine colon cancer cell line MC38 resulted in significant enhancement of tumor antigen gp70 specific T cells. ARB administration did not change the numbers of CD11b+ myeloid cells in tumors, but significantly reduced their T-cell inhibitory ability along with decreased production of various immunosuppressive factors including interleukin (IL)-6, IL-10, vascular endothelial growth factor (VEGF), and arginase by CD11b+ cells in tumors.
29034589	Colon Carcinoma	IL6	Inhibit immunity (T cell function)	Giving angiotensin II receptor blockers (ARB) to C57BL/6 mice bearing murine colon cancer cell line MC38 resulted in significant enhancement of tumor antigen gp70 specific T cells. ARB administration did not change the numbers of CD11b+ myeloid cells in tumors, but significantly reduced their T-cell inhibitory ability along with decreased production of various immunosuppressive factors including interleukin (IL)-6, IL-10, vascular endothelial growth factor (VEGF), and arginase by CD11b+ cells in tumors.
29034589	Colon Carcinoma	IL10	Inhibit immunity (T cell function)	Giving angiotensin II receptor blockers (ARB) to C57BL/6 mice bearing murine colon cancer cell line MC38 resulted in significant enhancement of tumor antigen gp70 specific T cells. ARB administration did not change the numbers of CD11b+ myeloid cells in tumors, but significantly reduced their T-cell inhibitory ability along with decreased production of various immunosuppressive factors including interleukin (IL)-6, IL-10, vascular endothelial growth factor (VEGF), and arginase by CD11b+ cells in tumors.
29034589	Colon Carcinoma	VEGFA	Inhibit immunity (T cell function)	Giving angiotensin II receptor blockers (ARB) to C57BL/6 mice bearing murine colon cancer cell line MC38 resulted in significant enhancement of tumor antigen gp70 specific T cells. ARB administration did not change the numbers of CD11b+ myeloid cells in tumors, but significantly reduced their T-cell inhibitory ability along with decreased production of various immunosuppressive factors including interleukin (IL)-6, IL-10, vascular endothelial growth factor (VEGF), and arginase by CD11b+ cells in tumors.
29034589	Colon Carcinoma	ARG1	Inhibit immunity (T cell function)	Giving angiotensin II receptor blockers (ARB) to C57BL/6 mice bearing murine colon cancer cell line MC38 resulted in significant enhancement of tumor antigen gp70 specific T cells. ARB administration did not change the numbers of CD11b+ myeloid cells in tumors, but significantly reduced their T-cell inhibitory ability along with decreased production of various immunosuppressive factors including interleukin (IL)-6, IL-10, vascular endothelial growth factor (VEGF), and arginase by CD11b+ cells in tumors.
29034543	Gastric Carcinoma	IFNG	Inhibit immunity (T cell function)	PD-L1 expression is mainly regulated by interferon gamma associated with JAK-STAT pathway in gastric cancer. Our in?vitro findings showed that interferon gamma upregulated programmed death ligand-1 expression on solid tumor cells through the JAK-signal transducer and activator of transcription pathway, and impaired the cytotoxicity of tumor antigen-specific CTL against tumor cells.
29034543	Gastric Carcinoma	JAK1	Inhibit immunity (T cell function)	PD-L1 expression is mainly regulated by interferon gamma associated with JAK-STAT pathway in gastric cancer. Our in?vitro findings showed that interferon gamma upregulated programmed death ligand-1 expression on solid tumor cells through the JAK-signal transducer and activator of transcription pathway, and impaired the cytotoxicity of tumor antigen-specific CTL against tumor cells.
29034543	Gastric Carcinoma	STAT1	Inhibit immunity (T cell function)	PD-L1 expression is mainly regulated by interferon gamma associated with JAK-STAT pathway in gastric cancer. Our in?vitro findings showed that interferon gamma upregulated programmed death ligand-1 expression on solid tumor cells through the JAK-signal transducer and activator of transcription pathway, and impaired the cytotoxicity of tumor antigen-specific CTL against tumor cells.
28868628	Ovarian Carcinoma	CCL5	Inhibit immunity (T cell function)	Ovarian cancer stem cells promote tumour immune privilege and invasion via CCL5 and regulatory T cells. The expression of its receptor, C-C motif chemokine receptor 5 (CCR5), was also increased on the surface of Tregs in ovarian cancer patients. This receptor-ligand expression profile indicated that ovarian CSCs recruit Tregs via CCL5-CCR5 interactions.
28868628	Ovarian Carcinoma	CCR5	Inhibit immunity (T cell function)	Ovarian cancer stem cells promote tumour immune privilege and invasion via CCL5 and regulatory T cells. The expression of its receptor, C-C motif chemokine receptor 5 (CCR5), was also increased on the surface of Tregs in ovarian cancer patients. This receptor-ligand expression profile indicated that ovarian CSCs recruit Tregs via CCL5-CCR5 interactions.
28868628	Ovarian Carcinoma	IL10	Inhibit immunity (T cell function)	Ovarian cancer stem cells promote tumour immune privilege and invasion via CCL5 and regulatory T cells. The expression of its receptor, C-C motif chemokine receptor 5 (CCR5), was also increased on the surface of Tregs in ovarian cancer patients. This receptor-ligand expression profile indicated that ovarian CSCs recruit Tregs via CCL5-CCR5 interactions. Tregs cultured in conditioned medium (CM) from ovarian CD133+ cells expressed a higher level of IL-10 than Tregs cultured in CM from CD133- cells, indicating that Tregs exert pronounced immune-inhibitory functions in CSC-rich environments.
16788095	Leukemia	IL15	Inhibit immunity (T cell function)	CD8+ memory T cells, as defined by CD44(hi) surface expression, are dependent on IL-15 as a positive regulator of their homeostatic maintenance. Manipulation of IL-15 signaling through gene aberration, overexpression, or receptor alterations has been shown to dramatically affect T-cell homeostasis, with overexpression leading to fatal leukemia. Here we show that TGF-beta is the critical negative regulator of murine CD8+ memory T-cell homeostasis with direct opposition to the positive effects of IL-15.
16788095	Leukemia	TGFB1	Promote immunity (T cell function)	CD8+ memory T cells, as defined by CD44(hi) surface expression, are dependent on IL-15 as a positive regulator of their homeostatic maintenance. Manipulation of IL-15 signaling through gene aberration, overexpression, or receptor alterations has been shown to dramatically affect T-cell homeostasis, with overexpression leading to fatal leukemia. Here we show that TGF-beta is the critical negative regulator of murine CD8+ memory T-cell homeostasis with direct opposition to the positive effects of IL-15.
16785526	Melanoma	IL2	Promote immunity (T cell function)	Here we show that a widely used neutralizing anti-murine IL-2 mAb (S4B6) exhibits unexpected activities that enhance the treatment effects of IL-2 in vivo. A 5-day treatment with the anti-IL-2 mAb alone gradually increased the CD44(high)CD8+ population, and the increased population was maintained for >300 days, suggesting that the mAb can gradually maintain and potentially enhance the bioactivity of endogenous IL-2 for extended periods. 16785526-7 IL2 IL-2 These results demonstrated IL-2-enhancing effects of the anti-IL-2 mAb in vivo and suggest that combining a neutralizing anti-IL-2 Ab with IL-2 gene delivery might be used effectively to enhance IL-2 functions in clinical applications.
16778987	Melanoma	CSF2	Promote immunity (T cell function)	CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells. We examined the mechanisms of action of anti-CTLA4 and a GM-CSF-transduced tumor cell vaccine (Gvax) and their impact on the balance of effector T cells (Teffs) and Tregs in an in vivo model of B16/BL6 melanoma. Tumor challenge increased the frequency of Tregs in lymph nodes, and untreated tumors became infiltrated by CD4+Foxp3- and CD4+Foxp3+ T cells but few CD8+ T cells. While Gvax primed the tumor-reactive Teff compartment, inducing activation, tumor infiltration, and a delay in tumor growth, the combination with CTLA4 blockade induced greater infiltration and a striking change in the intratumor balance of Tregs and Teffs that directly correlated with tumor rejection.
16778987	Melanoma	CTLA4	Inhibit immunity (T cell function); essential for immunotherapy	CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells. We examined the mechanisms of action of anti-CTLA4 and a GM-CSF-transduced tumor cell vaccine (Gvax) and their impact on the balance of effector T cells (Teffs) and Tregs in an in vivo model of B16/BL6 melanoma. Tumor challenge increased the frequency of Tregs in lymph nodes, and untreated tumors became infiltrated by CD4+Foxp3- and CD4+Foxp3+ T cells but few CD8+ T cells. While Gvax primed the tumor-reactive Teff compartment, inducing activation, tumor infiltration, and a delay in tumor growth, the combination with CTLA4 blockade induced greater infiltration and a striking change in the intratumor balance of Tregs and Teffs that directly correlated with tumor rejection.
16778218	Melanoma	IL23A	Promote immunity (T cell function)	In vivo depletion assay revealed that the antitumor effect of B16/IL-23 was mainly mediated by CD8+ T cells and IFN-gamma whereas that of B16/IL-27 mainly involved natural killer cells and was independent of IFN-gamma. We also found that antitumor effects of B16/IL-23 and B16/IL-27 were synergistically enhanced by treatment with IL-18 and IL-12, respectively. Our data support that IL-23 and IL-27 might play a role in future cytokine-based immunotherapy against poorly immunogenic tumors.
16778218	Melanoma	IFNG	Promote immunity (T cell function)	In vivo depletion assay revealed that the antitumor effect of B16/IL-23 was mainly mediated by CD8+ T cells and IFN-gamma whereas that of B16/IL-27 mainly involved natural killer cells and was independent of IFN-gamma. We also found that antitumor effects of B16/IL-23 and B16/IL-27 were synergistically enhanced by treatment with IL-18 and IL-12, respectively. Our data support that IL-23 and IL-27 might play a role in future cytokine-based immunotherapy against poorly immunogenic tumors.
16778218	Melanoma	IL27	Promote immunity (T cell function)	In vivo depletion assay revealed that the antitumor effect of B16/IL-23 was mainly mediated by CD8+ T cells and IFN-gamma whereas that of B16/IL-27 mainly involved natural killer cells and was independent of IFN-gamma. We also found that antitumor effects of B16/IL-23 and B16/IL-27 were synergistically enhanced by treatment with IL-18 and IL-12, respectively. Our data support that IL-23 and IL-27 might play a role in future cytokine-based immunotherapy against poorly immunogenic tumors.
16778218	Melanoma	IL18	Promote immunity (T cell function)	In vivo depletion assay revealed that the antitumor effect of B16/IL-23 was mainly mediated by CD8+ T cells and IFN-gamma whereas that of B16/IL-27 mainly involved natural killer cells and was independent of IFN-gamma. We also found that antitumor effects of B16/IL-23 and B16/IL-27 were synergistically enhanced by treatment with IL-18 and IL-12, respectively. Our data support that IL-23 and IL-27 might play a role in future cytokine-based immunotherapy against poorly immunogenic tumors.
16778218	Melanoma	IL12A	Promote immunity (T cell function)	In vivo depletion assay revealed that the antitumor effect of B16/IL-23 was mainly mediated by CD8+ T cells and IFN-gamma whereas that of B16/IL-27 mainly involved natural killer cells and was independent of IFN-gamma. We also found that antitumor effects of B16/IL-23 and B16/IL-27 were synergistically enhanced by treatment with IL-18 and IL-12, respectively. Our data support that IL-23 and IL-27 might play a role in future cytokine-based immunotherapy against poorly immunogenic tumors.
16778191	Breast Carcinoma	PTGES2	Inhibit immunity (T cell function)	Different progression of tumor xenografts between mucin-producing and mucin-non-producing mammary adenocarcinoma-bearing mice. tumor formation by using mucin-producing (TA3-Ha) and mucin-non-producing (TA3-St) cloned variants of mouse mammary adenocarcinomas. IFN-gamma-producing CD4 T cells in spleens obtained from TA3-Ha tumor-bearing mice were significantly reduced compared with TA3-St tumor-bearing mice, suggesting that mucins cause PGE2-mediated immune suppression.
16778191	Breast Carcinoma	MUC5AC	Inhibit immunity (T cell function)	Different progression of tumor xenografts between mucin-producing and mucin-non-producing mammary adenocarcinoma-bearing mice. tumor formation by using mucin-producing (TA3-Ha) and mucin-non-producing (TA3-St) cloned variants of mouse mammary adenocarcinomas. IFN-gamma-producing CD4 T cells in spleens obtained from TA3-Ha tumor-bearing mice were significantly reduced compared with TA3-St tumor-bearing mice, suggesting that mucins cause PGE2-mediated immune suppression.
16767155	Lymphoma	FASLG	Promote immunity (T cell function)	CD95 ligand mediates T-cell receptor-induced apoptosis of a CD4+ CD8+ double positive thymic lymphoma.
16754847	Melanoma	KLRK1	Promote immunity (NK cell function)	Therapy-induced antibodies to MHC class I chain-related protein A antagonize immune suppression and stimulate antitumor cytotoxicity. The activation of NKG2D on innate and adaptive cytotoxic lymphocytes contributes to immune-mediated tumor destruction. Nonetheless, tumor cell shedding of NKG2D ligands, such as MHC class I chain-related protein A (MICA), results in immune suppression through down-regulation of NKG2D surface expression. Together, these findings establish a key role for the NKG2D pathway in the clinical activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade and granulocyte-macrophage colony-stimulating factor secreting tumor cell vaccines.
16754847	Melanoma	MICA	Promote immunity	Therapy-induced antibodies to MHC class I chain-related protein A antagonize immune suppression and stimulate antitumor cytotoxicity. The activation of NKG2D on innate and adaptive cytotoxic lymphocytes contributes to immune-mediated tumor destruction. Nonetheless, tumor cell shedding of NKG2D ligands, such as MHC class I chain-related protein A (MICA), results in immune suppression through down-regulation of NKG2D surface expression. Together, these findings establish a key role for the NKG2D pathway in the clinical activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade and granulocyte-macrophage colony-stimulating factor secreting tumor cell vaccines.
16751420	Melanoma	IL2	Promote immunity (T cell function)	Incubation in vitro with high doses of IL-2 (3,000 IU/ml) or administration of IL-2 in vivo resulted in substantial up-regulation of CD70 expression and the concomitant loss of cell surface CD27 expression on CD8(+) cells. Withdrawal of IL-2 from activated CD8(+) T cells that had been maintained in IL-2 resulted in a reversal of the expression of these two markers, whereas reciprocal changes were seen following treatment of PBMCs with IL-2. The proliferation observed in cells stimulated with IL-2 primarily occurred in a subset of the CD70(+)CD8(+) T cells that up-regulated IL-2 receptor expression but did not occur in CD70(-)CD8(+) T cells. Blocking CD70 resulted in a significant reduction of T cell proliferation induced by high-dose IL-2, indicating that the interaction of CD70 with CD27 played a direct role in T cell activation mediated by IL-2. Finally, studies conducted on tumor-infiltrating lymphocyte (TIL) samples that were administered to melanoma patients indicated that the size of the pool of CD27(+)CD8(+) T cells in bulk TILs was highly associated (p = 0.004) with the ability of these TILs to mediate tumor regression following adoptive transfer.
16751420	Melanoma	CD70	Promote immunity (T cell function)	Incubation in vitro with high doses of IL-2 (3,000 IU/ml) or administration of IL-2 in vivo resulted in substantial up-regulation of CD70 expression and the concomitant loss of cell surface CD27 expression on CD8(+) cells. Withdrawal of IL-2 from activated CD8(+) T cells that had been maintained in IL-2 resulted in a reversal of the expression of these two markers, whereas reciprocal changes were seen following treatment of PBMCs with IL-2. The proliferation observed in cells stimulated with IL-2 primarily occurred in a subset of the CD70(+)CD8(+) T cells that up-regulated IL-2 receptor expression but did not occur in CD70(-)CD8(+) T cells. Blocking CD70 resulted in a significant reduction of T cell proliferation induced by high-dose IL-2, indicating that the interaction of CD70 with CD27 played a direct role in T cell activation mediated by IL-2. Finally, studies conducted on tumor-infiltrating lymphocyte (TIL) samples that were administered to melanoma patients indicated that the size of the pool of CD27(+)CD8(+) T cells in bulk TILs was highly associated (p = 0.004) with the ability of these TILs to mediate tumor regression following adoptive transfer.
16751420	Melanoma	CD27	Promote immunity (T cell function)	Incubation in vitro with high doses of IL-2 (3,000 IU/ml) or administration of IL-2 in vivo resulted in substantial up-regulation of CD70 expression and the concomitant loss of cell surface CD27 expression on CD8(+) cells. Withdrawal of IL-2 from activated CD8(+) T cells that had been maintained in IL-2 resulted in a reversal of the expression of these two markers, whereas reciprocal changes were seen following treatment of PBMCs with IL-2. The proliferation observed in cells stimulated with IL-2 primarily occurred in a subset of the CD70(+)CD8(+) T cells that up-regulated IL-2 receptor expression but did not occur in CD70(-)CD8(+) T cells. Blocking CD70 resulted in a significant reduction of T cell proliferation induced by high-dose IL-2, indicating that the interaction of CD70 with CD27 played a direct role in T cell activation mediated by IL-2. Finally, studies conducted on tumor-infiltrating lymphocyte (TIL) samples that were administered to melanoma patients indicated that the size of the pool of CD27(+)CD8(+) T cells in bulk TILs was highly associated (p = 0.004) with the ability of these TILs to mediate tumor regression following adoptive transfer.
16751420	Melanoma	IL2RA	Promote immunity (T cell function)	Incubation in vitro with high doses of IL-2 (3,000 IU/ml) or administration of IL-2 in vivo resulted in substantial up-regulation of CD70 expression and the concomitant loss of cell surface CD27 expression on CD8(+) cells. Withdrawal of IL-2 from activated CD8(+) T cells that had been maintained in IL-2 resulted in a reversal of the expression of these two markers, whereas reciprocal changes were seen following treatment of PBMCs with IL-2. The proliferation observed in cells stimulated with IL-2 primarily occurred in a subset of the CD70(+)CD8(+) T cells that up-regulated IL-2 receptor expression but did not occur in CD70(-)CD8(+) T cells. Blocking CD70 resulted in a significant reduction of T cell proliferation induced by high-dose IL-2, indicating that the interaction of CD70 with CD27 played a direct role in T cell activation mediated by IL-2. Finally, studies conducted on tumor-infiltrating lymphocyte (TIL) samples that were administered to melanoma patients indicated that the size of the pool of CD27(+)CD8(+) T cells in bulk TILs was highly associated (p = 0.004) with the ability of these TILs to mediate tumor regression following adoptive transfer.
16751376	Breast Carcinoma	IL12A	Promote immunity (T cell function)	A single intratumoral injection of IL-12 and GM-CSF-encapsulated microspheres induces the complete regression of advanced spontaneous tumors in her-2/neu transgenic mice. Posttherapy molecular analysis of immune activation/suppression markers within the tumor microenvironment demonstrated a dramatic up-regulation of IFN-gamma and a concomitant down-regulation of Forkhead/winged-helix protein 3 (Foxp3), TGFbeta, and IL-10 expression.
16751376	Breast Carcinoma	CSF2	Promote immunity (T cell function)	A single intratumoral injection of IL-12 and GM-CSF-encapsulated microspheres induces the complete regression of advanced spontaneous tumors in her-2/neu transgenic mice. Posttherapy molecular analysis of immune activation/suppression markers within the tumor microenvironment demonstrated a dramatic up-regulation of IFN-gamma and a concomitant down-regulation of Forkhead/winged-helix protein 3 (Foxp3), TGFbeta, and IL-10 expression.
16751376	Breast Carcinoma	IFNG	Promote immunity (T cell function)	A single intratumoral injection of IL-12 and GM-CSF-encapsulated microspheres induces the complete regression of advanced spontaneous tumors in her-2/neu transgenic mice. Posttherapy molecular analysis of immune activation/suppression markers within the tumor microenvironment demonstrated a dramatic up-regulation of IFN-gamma and a concomitant down-regulation of Forkhead/winged-helix protein 3 (Foxp3), TGFbeta, and IL-10 expression.
16751376	Breast Carcinoma	FOXP3	Inhibit immunity (T cell function)	A single intratumoral injection of IL-12 and GM-CSF-encapsulated microspheres induces the complete regression of advanced spontaneous tumors in her-2/neu transgenic mice. Posttherapy molecular analysis of immune activation/suppression markers within the tumor microenvironment demonstrated a dramatic up-regulation of IFN-gamma and a concomitant down-regulation of Forkhead/winged-helix protein 3 (Foxp3), TGFbeta, and IL-10 expression.
16751376	Breast Carcinoma	TGFB1	Inhibit immunity (T cell function)	A single intratumoral injection of IL-12 and GM-CSF-encapsulated microspheres induces the complete regression of advanced spontaneous tumors in her-2/neu transgenic mice. Posttherapy molecular analysis of immune activation/suppression markers within the tumor microenvironment demonstrated a dramatic up-regulation of IFN-gamma and a concomitant down-regulation of Forkhead/winged-helix protein 3 (Foxp3), TGFbeta, and IL-10 expression.
16751376	Breast Carcinoma	IL10	Inhibit immunity (T cell function)	A single intratumoral injection of IL-12 and GM-CSF-encapsulated microspheres induces the complete regression of advanced spontaneous tumors in her-2/neu transgenic mice. Posttherapy molecular analysis of immune activation/suppression markers within the tumor microenvironment demonstrated a dramatic up-regulation of IFN-gamma and a concomitant down-regulation of Forkhead/winged-helix protein 3 (Foxp3), TGFbeta, and IL-10 expression.
16751375	Lung Carcinoma	IL27	Promote immunity	Similar antitumor and antimetastatic activities of IL-27 were also observed in IFN-gamma knockout mice. Immunohistochemical analyses with Abs against vascular endothelial growth factor and CD31 revealed that B16F10 + IL-27 cells markedly suppressed tumor-induced neovascularization in lung metastases. IL-27 was revealed to directly act on HUVECs and induce production of the antiangiogenic chemokines, IFN-gamma-inducible protein (IP-10) and monokine induced by IFN-gamma. Finally, augmented mRNA expression of IP-10 and monokine induced by IFN-gamma was detected at the s.c.
16751375	Lung Carcinoma	IFNG	Promote immunity	Similar antitumor and antimetastatic activities of IL-27 were also observed in IFN-gamma knockout mice. Immunohistochemical analyses with Abs against vascular endothelial growth factor and CD31 revealed that B16F10 + IL-27 cells markedly suppressed tumor-induced neovascularization in lung metastases. IL-27 was revealed to directly act on HUVECs and induce production of the antiangiogenic chemokines, IFN-gamma-inducible protein (IP-10) and monokine induced by IFN-gamma. Finally, augmented mRNA expression of IP-10 and monokine induced by IFN-gamma was detected at the s.c.
16751375	Lung Carcinoma	CXCL10	Promote immunity	Similar antitumor and antimetastatic activities of IL-27 were also observed in IFN-gamma knockout mice. Immunohistochemical analyses with Abs against vascular endothelial growth factor and CD31 revealed that B16F10 + IL-27 cells markedly suppressed tumor-induced neovascularization in lung metastases. IL-27 was revealed to directly act on HUVECs and induce production of the antiangiogenic chemokines, IFN-gamma-inducible protein (IP-10) and monokine induced by IFN-gamma. Finally, augmented mRNA expression of IP-10 and monokine induced by IFN-gamma was detected at the s.c.
16709808	Melanoma	CTSD	Inhibit immunity	Our studies suggest that CCL20 processing in the extracellular environment of melanoma cells is exclusively mediated by cathepsin D. Thus, we propose a model where cathepsin D inactivates CCL20 and possibly prevents the establishment of an effective antitumoral immune response in melanomas.
16709808	Melanoma	CCL20	Promote immunity	Our studies suggest that CCL20 processing in the extracellular environment of melanoma cells is exclusively mediated by cathepsin D. Thus, we propose a model where cathepsin D inactivates CCL20 and possibly prevents the establishment of an effective antitumoral immune response in melanomas.
16709800	Melanoma	TNFRSF18	Promote immunity (T cell function)	Thus, we conclude that overall, GITR stimulation overcomes self-tolerance/ignorance and enhances T cell-mediated antitumor activity with minimal autoimmunity.
16680149	Breast Carcinoma; Renal Cell Carcinoma; Colon Carcinoma; Lung Carcinoma	TNFRSF10B	Promote immunity	Here we show that induction of tumor-cell apoptosis by an agonistic monoclonal antibody to DR5, the apoptosis-inducing receptor for TNF-related apoptosis-inducing ligand (TRAIL), combined with T-cell activation by agonistic monoclonal antibodies to the costimulatory molecules CD40 and CD137, potently and rapidly stimulated tumor-specific effector CD8+ T cells capable of eradicating preestablished tumors. This combination therapy of three monoclonal antibodies (trimAb) rapidly induced tumor-specific CD8+ T cells producing interferon (IFN)-gamma in the tumor-draining lymph node, consistent with a crucial requirement for CD8+ T cells and IFN-gamma in the tumor rejection process.
16680149	Breast Carcinoma; Renal Cell Carcinoma; Colon Carcinoma; Lung Carcinoma	TNFSF10	Promote immunity	Here we show that induction of tumor-cell apoptosis by an agonistic monoclonal antibody to DR5, the apoptosis-inducing receptor for TNF-related apoptosis-inducing ligand (TRAIL), combined with T-cell activation by agonistic monoclonal antibodies to the costimulatory molecules CD40 and CD137, potently and rapidly stimulated tumor-specific effector CD8+ T cells capable of eradicating preestablished tumors. This combination therapy of three monoclonal antibodies (trimAb) rapidly induced tumor-specific CD8+ T cells producing interferon (IFN)-gamma in the tumor-draining lymph node, consistent with a crucial requirement for CD8+ T cells and IFN-gamma in the tumor rejection process.
16680149	Breast Carcinoma; Renal Cell Carcinoma; Colon Carcinoma; Lung Carcinoma	CD40	Promote immunity (T cell function)	Here we show that induction of tumor-cell apoptosis by an agonistic monoclonal antibody to DR5, the apoptosis-inducing receptor for TNF-related apoptosis-inducing ligand (TRAIL), combined with T-cell activation by agonistic monoclonal antibodies to the costimulatory molecules CD40 and CD137, potently and rapidly stimulated tumor-specific effector CD8+ T cells capable of eradicating preestablished tumors. This combination therapy of three monoclonal antibodies (trimAb) rapidly induced tumor-specific CD8+ T cells producing interferon (IFN)-gamma in the tumor-draining lymph node, consistent with a crucial requirement for CD8+ T cells and IFN-gamma in the tumor rejection process.
16680149	Breast Carcinoma; Renal Cell Carcinoma; Colon Carcinoma; Lung Carcinoma	TNFRSF9	Promote immunity (T cell function)	Here we show that induction of tumor-cell apoptosis by an agonistic monoclonal antibody to DR5, the apoptosis-inducing receptor for TNF-related apoptosis-inducing ligand (TRAIL), combined with T-cell activation by agonistic monoclonal antibodies to the costimulatory molecules CD40 and CD137, potently and rapidly stimulated tumor-specific effector CD8+ T cells capable of eradicating preestablished tumors. This combination therapy of three monoclonal antibodies (trimAb) rapidly induced tumor-specific CD8+ T cells producing interferon (IFN)-gamma in the tumor-draining lymph node, consistent with a crucial requirement for CD8+ T cells and IFN-gamma in the tumor rejection process.
16680149	Breast Carcinoma; Renal Cell Carcinoma; Colon Carcinoma; Lung Carcinoma	IFNG	Promote immunity (T cell function)	Here we show that induction of tumor-cell apoptosis by an agonistic monoclonal antibody to DR5, the apoptosis-inducing receptor for TNF-related apoptosis-inducing ligand (TRAIL), combined with T-cell activation by agonistic monoclonal antibodies to the costimulatory molecules CD40 and CD137, potently and rapidly stimulated tumor-specific effector CD8+ T cells capable of eradicating preestablished tumors. This combination therapy of three monoclonal antibodies (trimAb) rapidly induced tumor-specific CD8+ T cells producing interferon (IFN)-gamma in the tumor-draining lymph node, consistent with a crucial requirement for CD8+ T cells and IFN-gamma in the tumor rejection process.
16651452	Melanoma	IFNA1	Promote immunity (T cell function)	The use of IFN-alpha in clinical oncology has generally been based on the rationale of exploiting its antiproliferative and antiangiogenic activities. However, IFN-alpha also exhibits enhancing effects on T-cell and dendritic cell functions, which may suggest a novel use as a vaccine adjuvant. We have carried out a pilot phase I-II trial to determine the effects of IFN-alpha, administered as an adjuvant of Melan-A/MART-1:26-35(27L) and gp100:209-217(210M) peptides, on immune responses in stage IV melanoma patients. In five of the seven evaluable patients, a consistent enhancement of CD8(+) T cells recognizing modified and native MART-1 and gp100 peptides and MART-1(+)gp100(+) melanoma cells was observed.
16651448	Leukemia	IL12A	Promote immunity (T cell function)	The cytokine interleukin (IL)-12 promotes CD8(+) T-cell cytotoxicity and, with IL-18, synergistically up-regulates IFN-gamma release. We have shown that culturing CD8(+) T cells ex vivo with IL-12 and IL-18 enhanced antitumor responses in vivo and in vitro using a model of C1498/ovalbumin, a murine acute myeloid leukemia cell line expressing the antigen ovalbumin. Maximal IFN-gamma release occurred after T-cell culture with IL-12 and IL-18. Tumor-specific in vitro cytotoxicity was enhanced by IL-12, unaffected by addition of IL-18, and abrogated in perforin-deficient T cells irrespective of cytokine exposure.
16651448	Leukemia	IL18	Promote immunity (T cell function)	The cytokine interleukin (IL)-12 promotes CD8(+) T-cell cytotoxicity and, with IL-18, synergistically up-regulates IFN-gamma release. We have shown that culturing CD8(+) T cells ex vivo with IL-12 and IL-18 enhanced antitumor responses in vivo and in vitro using a model of C1498/ovalbumin, a murine acute myeloid leukemia cell line expressing the antigen ovalbumin. Maximal IFN-gamma release occurred after T-cell culture with IL-12 and IL-18. Tumor-specific in vitro cytotoxicity was enhanced by IL-12, unaffected by addition of IL-18, and abrogated in perforin-deficient T cells irrespective of cytokine exposure.
16651448	Leukemia	IFNG	Promote immunity (T cell function)	The cytokine interleukin (IL)-12 promotes CD8(+) T-cell cytotoxicity and, with IL-18, synergistically up-regulates IFN-gamma release. We have shown that culturing CD8(+) T cells ex vivo with IL-12 and IL-18 enhanced antitumor responses in vivo and in vitro using a model of C1498/ovalbumin, a murine acute myeloid leukemia cell line expressing the antigen ovalbumin. Maximal IFN-gamma release occurred after T-cell culture with IL-12 and IL-18. Tumor-specific in vitro cytotoxicity was enhanced by IL-12, unaffected by addition of IL-18, and abrogated in perforin-deficient T cells irrespective of cytokine exposure.
16651448	Leukemia	PRF1	Promote immunity (T cell function)	The cytokine interleukin (IL)-12 promotes CD8(+) T-cell cytotoxicity and, with IL-18, synergistically up-regulates IFN-gamma release. We have shown that culturing CD8(+) T cells ex vivo with IL-12 and IL-18 enhanced antitumor responses in vivo and in vitro using a model of C1498/ovalbumin, a murine acute myeloid leukemia cell line expressing the antigen ovalbumin. Maximal IFN-gamma release occurred after T-cell culture with IL-12 and IL-18. Tumor-specific in vitro cytotoxicity was enhanced by IL-12, unaffected by addition of IL-18, and abrogated in perforin-deficient T cells irrespective of cytokine exposure.
16651447	Melanoma	TNFRSF18	Promote immunity (T cell function)	We sought to improve on this strategy by combining xenogeneic DNA vaccination with an agonist anti-glucocorticoid-induced tumor necrosis factor receptor family-related gene (GITR) monoclonal antibody (mAb), DTA-1, which has been shown previously both to costimulate activated effector CD4(+) and CD8(+) T cells and to inhibit the suppressive activity of CD4(+)CD25(+) regulatory T cells. We found that ligation of GITR with DTA-1 just before the second, but not the first, of 3 weekly DNA immunizations enhanced primary CD8(+) T-cell responses against the melanoma differentiation antigens gp100 and tyrosinase-related protein 2/dopachrome tautomerase and increased protection from a lethal challenge with B16 melanoma.
16651446	Sarcoma	FLT3LG	Promote immunity (infiltration)	We have observed that the treatment of BALB/c mice bearing syngeneic CMS4 sarcomas with the combination of recombinant Flt3 ligand and recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) for five sequential days is sufficient to optimize the number of tumor-infiltrating dendritic cells (TIDC).
16651446	Sarcoma	CSF2	Promote immunity (infiltration)	We have observed that the treatment of BALB/c mice bearing syngeneic CMS4 sarcomas with the combination of recombinant Flt3 ligand and recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) for five sequential days is sufficient to optimize the number of tumor-infiltrating dendritic cells (TIDC).
16644201	Melanoma	CCR10	Promote immunity	Aim of this study was to investigate using immunohistochemistry techniques the interrelation between T immunoreactive cells and the expression of CCR10 and its ligand CCL27 in 59 cutaneous melanocytic lesions. CCR10 expression was found both in benign and malignant lesions and it was directly correlated with the Breslow depth (P=0.0298) and inversely with T lymphocyte density (P=0.0231). Moreover, cases with positive sentinel lymph node tended to have a higher CCR10 expression compared to cases with negative sentinel lymph node (P=0.0281). When CCR10 and CCL27 expression were evaluated together, CCR10-/CCL27-melanomas tended to have a higher mean density of CD3+ and CD8+ lymphocytes. Our results suggest that in human melanomas CCR10 and CCL27 may act to increase the ability of neoplastic cells to grow, invade tissue, disseminate to lymph nodes and to escape the host immune response.
16644201	Melanoma	CCL27	Inhibit immunity	Aim of this study was to investigate using immunohistochemistry techniques the interrelation between T immunoreactive cells and the expression of CCR10 and its ligand CCL27 in 59 cutaneous melanocytic lesions. CCR10 expression was found both in benign and malignant lesions and it was directly correlated with the Breslow depth (P=0.0298) and inversely with T lymphocyte density (P=0.0231). Moreover, cases with positive sentinel lymph node tended to have a higher CCR10 expression compared to cases with negative sentinel lymph node (P=0.0281). When CCR10 and CCL27 expression were evaluated together, CCR10-/CCL27-melanomas tended to have a higher mean density of CD3+ and CD8+ lymphocytes. Our results suggest that in human melanomas CCR10 and CCL27 may act to increase the ability of neoplastic cells to grow, invade tissue, disseminate to lymph nodes and to escape the host immune response.
16638868	Fibrosarcoma; Colon Carcinoma	TNF	Promote immunity (T cell function)	Targeted delivery of tumor necrosis factor-alpha to tumor vessels induces a therapeutic T cell-mediated immune response that protects the host against syngeneic tumors of different histologic origin.
16621991	Melanoma	IL2	Inhibit immunity (T cell function)	IL-2 is a critical T cell growth factor in vitro, but predominantly mediates tolerance in vivo. IL-2 is mainly produced by CD4(+) Th cells, but the role of Th cell-derived IL-2 in vivo is controversial. We demonstrate that during immunity to a tumor/self-Ag, the predominant role of Th cell-derived IL-2 was to maintain IL-2Ralpha (CD25) on CD4(+) T regulatory cells (T(reg)), which resulted in their maintenance of the T(reg) cell lineage factor, Forkhead/winged helix transcription factor (Foxp3), and tolerance. Lastly, administration of anti-IL-2 plus exogenous IL-15 to tumor-bearing mice enhanced the adoptive immunotherapy of cancer.
16621991	Melanoma	IL15	Promote immunity (T cell function)	IL-2 is a critical T cell growth factor in vitro, but predominantly mediates tolerance in vivo. IL-2 is mainly produced by CD4(+) Th cells, but the role of Th cell-derived IL-2 in vivo is controversial. We demonstrate that during immunity to a tumor/self-Ag, the predominant role of Th cell-derived IL-2 was to maintain IL-2Ralpha (CD25) on CD4(+) T regulatory cells (T(reg)), which resulted in their maintenance of the T(reg) cell lineage factor, Forkhead/winged helix transcription factor (Foxp3), and tolerance. Lastly, administration of anti-IL-2 plus exogenous IL-15 to tumor-bearing mice enhanced the adoptive immunotherapy of cancer.
16621962	Lymphoma	IL15	Promote immunity (T cell function)	ULBPs, human ligands of the NKG2D receptor, stimulate tumor immunity with enhancement by IL-15. ULBPs are human ligands for NKG2D, an activating receptor expressed on natural killer (NK) cells, NK1.1(+) T cells, and T cells. We report that ectopic expression of ULBP1 or ULBP2 on murine EL4 or RMA tumor cells elicits potent antitumor responses in syngeneic C57BL/6 and SCID mice. Although binding of ULBP3 to murine NKG2D could not be demonstrated in vitro, ULBP3 can also stimulate antitumor responses, suggesting that ULBP3 binds to murine NKG2D or possibly another receptor in vivo. IL-15 was found to strongly enhance the immune response directed against ULBP-expressing tumors.
16621962	Lymphoma	KLRK1	Promote immunity (NK cell function)	ULBPs, human ligands of the NKG2D receptor, stimulate tumor immunity with enhancement by IL-15. ULBPs are human ligands for NKG2D, an activating receptor expressed on natural killer (NK) cells, NK1.1(+) T cells, and T cells. We report that ectopic expression of ULBP1 or ULBP2 on murine EL4 or RMA tumor cells elicits potent antitumor responses in syngeneic C57BL/6 and SCID mice. Although binding of ULBP3 to murine NKG2D could not be demonstrated in vitro, ULBP3 can also stimulate antitumor responses, suggesting that ULBP3 binds to murine NKG2D or possibly another receptor in vivo. IL-15 was found to strongly enhance the immune response directed against ULBP-expressing tumors.
16621962	Lymphoma	ULBP1	Promote immunity (T and NK cell function)	ULBPs, human ligands of the NKG2D receptor, stimulate tumor immunity with enhancement by IL-15. ULBPs are human ligands for NKG2D, an activating receptor expressed on natural killer (NK) cells, NK1.1(+) T cells, and T cells. We report that ectopic expression of ULBP1 or ULBP2 on murine EL4 or RMA tumor cells elicits potent antitumor responses in syngeneic C57BL/6 and SCID mice. Although binding of ULBP3 to murine NKG2D could not be demonstrated in vitro, ULBP3 can also stimulate antitumor responses, suggesting that ULBP3 binds to murine NKG2D or possibly another receptor in vivo. IL-15 was found to strongly enhance the immune response directed against ULBP-expressing tumors.
16621962	Lymphoma	ULBP2	Promote immunity (T and NK cell function)	ULBPs, human ligands of the NKG2D receptor, stimulate tumor immunity with enhancement by IL-15. ULBPs are human ligands for NKG2D, an activating receptor expressed on natural killer (NK) cells, NK1.1(+) T cells, and T cells. We report that ectopic expression of ULBP1 or ULBP2 on murine EL4 or RMA tumor cells elicits potent antitumor responses in syngeneic C57BL/6 and SCID mice. Although binding of ULBP3 to murine NKG2D could not be demonstrated in vitro, ULBP3 can also stimulate antitumor responses, suggesting that ULBP3 binds to murine NKG2D or possibly another receptor in vivo. IL-15 was found to strongly enhance the immune response directed against ULBP-expressing tumors.
16621962	Lymphoma	ULBP3	Promote immunity (T and NK cell function)	ULBPs, human ligands of the NKG2D receptor, stimulate tumor immunity with enhancement by IL-15. ULBPs are human ligands for NKG2D, an activating receptor expressed on natural killer (NK) cells, NK1.1(+) T cells, and T cells. We report that ectopic expression of ULBP1 or ULBP2 on murine EL4 or RMA tumor cells elicits potent antitumor responses in syngeneic C57BL/6 and SCID mice. Although binding of ULBP3 to murine NKG2D could not be demonstrated in vitro, ULBP3 can also stimulate antitumor responses, suggesting that ULBP3 binds to murine NKG2D or possibly another receptor in vivo. IL-15 was found to strongly enhance the immune response directed against ULBP-expressing tumors.
16598185	Lung Carcinoma	CCL19	Promote immunity (infiltration)	We evaluated the antitumour efficacy of CCL19 in a murine model of spontaneous bronchoalveolar cell carcinoma. CCL19 treatment led to a marked reduction in tumour burden with extensive mononuclear infiltration of the tumours compared to diluent treated controls.
16585609	Leukemia	KLRK1	Promote immunity (NK cell function)	MHC class I chain-related molecules (MIC) participate in immune surveillance of cancer through engagement of the NKG2D-activating receptor on NK and T cells. Decreased NKG2D expression and function upon chronic exposure to NKG2D ligands and/or soluble forms of MIC (sMIC) may participate in immune escape. At diagnosis, chronic myeloid leukemia patients had abnormally high serum levels of sMICA and weak NKG2D expression on NK and CD8+ T cells, which were restored by imatinib mesylate (IM) therapy.
16585565	Lung Carcinoma	IFNG	Promote immunity (T cell function)	IFN-gamma acts on T cells to induce NK cell mobilization and accumulation in target organs. Intraperitoneal administration of IFN-gamma stimulates the mobilization of NK cells into the circulation, but not their cell death or proliferation. Moreover, mobilization and migration of spleen NK cells in response to IFN-gamma treatment is dependent on the chemokine receptor CXCR3.
16585565	Lung Carcinoma	CXCR3	Promote immunity	IFN-gamma acts on T cells to induce NK cell mobilization and accumulation in target organs. Intraperitoneal administration of IFN-gamma stimulates the mobilization of NK cells into the circulation, but not their cell death or proliferation. Moreover, mobilization and migration of spleen NK cells in response to IFN-gamma treatment is dependent on the chemokine receptor CXCR3.
16585215	Osteosarcoma	CD1D	Inhibit immunity	CD1d-restricted natural killer T cells can down-regulate tumor immunosurveillance independent of interleukin-4 receptor-signal transducer and activator of transcription 6 or transforming growth factor-beta.
16585213	Glioma	ATP6V0A2	Inhibit immunity (T cell function)	Suppression of RTF expression by RNA interference promotes the lysis of glioma cells by natural killer (NK) and T cells in vitro.
16565324	Neuroblastoma	CD40	Promote immunity	In vivo CD40 ligation can induce T-cell-independent antitumor effects that involve macrophages.
16540672	Lung Carcinoma	CCL21	Promote immunity (infiltration)	A single intratracheal administration of CCL21 gene-modified dendritic cells (DC-AdCCL21) led to a marked reduction in tumor burden with extensive mononuclear cell infiltration of the tumors. The reduction in tumor burden was accompanied by the enhanced elaboration of type 1 cytokines [IFN-gamma, interleukin (IL)-12, and granulocyte macrophage colony-stimulating factor] and antiangiogenic chemokines (CXCL9 and CXCL10) but a concomitant decrease in the immunosuppressive molecules (IL-10, transforming growth factor-beta, prostaglandin E(2)) in the tumor microenvironment. The DC-AdCCL21 therapy group revealed a significantly greater frequency of tumor-specific T cells releasing IFN-gamma compared with the controls.
16540672	Lung Carcinoma	IFNG	Promote immunity	A single intratracheal administration of CCL21 gene-modified dendritic cells (DC-AdCCL21) led to a marked reduction in tumor burden with extensive mononuclear cell infiltration of the tumors. The reduction in tumor burden was accompanied by the enhanced elaboration of type 1 cytokines [IFN-gamma, interleukin (IL)-12, and granulocyte macrophage colony-stimulating factor] and antiangiogenic chemokines (CXCL9 and CXCL10) but a concomitant decrease in the immunosuppressive molecules (IL-10, transforming growth factor-beta, prostaglandin E(2)) in the tumor microenvironment. The DC-AdCCL21 therapy group revealed a significantly greater frequency of tumor-specific T cells releasing IFN-gamma compared with the controls.
16540672	Lung Carcinoma	IL12A	Promote immunity	A single intratracheal administration of CCL21 gene-modified dendritic cells (DC-AdCCL21) led to a marked reduction in tumor burden with extensive mononuclear cell infiltration of the tumors. The reduction in tumor burden was accompanied by the enhanced elaboration of type 1 cytokines [IFN-gamma, interleukin (IL)-12, and granulocyte macrophage colony-stimulating factor] and antiangiogenic chemokines (CXCL9 and CXCL10) but a concomitant decrease in the immunosuppressive molecules (IL-10, transforming growth factor-beta, prostaglandin E(2)) in the tumor microenvironment. The DC-AdCCL21 therapy group revealed a significantly greater frequency of tumor-specific T cells releasing IFN-gamma compared with the controls.
16540672	Lung Carcinoma	CSF2	Promote immunity	A single intratracheal administration of CCL21 gene-modified dendritic cells (DC-AdCCL21) led to a marked reduction in tumor burden with extensive mononuclear cell infiltration of the tumors. The reduction in tumor burden was accompanied by the enhanced elaboration of type 1 cytokines [IFN-gamma, interleukin (IL)-12, and granulocyte macrophage colony-stimulating factor] and antiangiogenic chemokines (CXCL9 and CXCL10) but a concomitant decrease in the immunosuppressive molecules (IL-10, transforming growth factor-beta, prostaglandin E(2)) in the tumor microenvironment. The DC-AdCCL21 therapy group revealed a significantly greater frequency of tumor-specific T cells releasing IFN-gamma compared with the controls.
16540672	Lung Carcinoma	IL10	Inhibit immunity	A single intratracheal administration of CCL21 gene-modified dendritic cells (DC-AdCCL21) led to a marked reduction in tumor burden with extensive mononuclear cell infiltration of the tumors. The reduction in tumor burden was accompanied by the enhanced elaboration of type 1 cytokines [IFN-gamma, interleukin (IL)-12, and granulocyte macrophage colony-stimulating factor] and antiangiogenic chemokines (CXCL9 and CXCL10) but a concomitant decrease in the immunosuppressive molecules (IL-10, transforming growth factor-beta, prostaglandin E(2)) in the tumor microenvironment. The DC-AdCCL21 therapy group revealed a significantly greater frequency of tumor-specific T cells releasing IFN-gamma compared with the controls.
16540672	Lung Carcinoma	TGFB1	Inhibit immunity	A single intratracheal administration of CCL21 gene-modified dendritic cells (DC-AdCCL21) led to a marked reduction in tumor burden with extensive mononuclear cell infiltration of the tumors. The reduction in tumor burden was accompanied by the enhanced elaboration of type 1 cytokines [IFN-gamma, interleukin (IL)-12, and granulocyte macrophage colony-stimulating factor] and antiangiogenic chemokines (CXCL9 and CXCL10) but a concomitant decrease in the immunosuppressive molecules (IL-10, transforming growth factor-beta, prostaglandin E(2)) in the tumor microenvironment. The DC-AdCCL21 therapy group revealed a significantly greater frequency of tumor-specific T cells releasing IFN-gamma compared with the controls.
16540672	Lung Carcinoma	PTGS2	Inhibit immunity	A single intratracheal administration of CCL21 gene-modified dendritic cells (DC-AdCCL21) led to a marked reduction in tumor burden with extensive mononuclear cell infiltration of the tumors. The reduction in tumor burden was accompanied by the enhanced elaboration of type 1 cytokines [IFN-gamma, interleukin (IL)-12, and granulocyte macrophage colony-stimulating factor] and antiangiogenic chemokines (CXCL9 and CXCL10) but a concomitant decrease in the immunosuppressive molecules (IL-10, transforming growth factor-beta, prostaglandin E(2)) in the tumor microenvironment. The DC-AdCCL21 therapy group revealed a significantly greater frequency of tumor-specific T cells releasing IFN-gamma compared with the controls.
16525992	Melanoma; Colon Carcinoma	CX3CR1	Promote immunity (infiltration)	Dendritic cells modified to express fractalkine/CX3CL1 in the treatment of preexisting tumors. Fractalkine (CX3CL1) is a unique membrane-bound CX3C chemokine that serves as a potent chemoattractant for lymphocytes. Consistent with the finding, the intratumoral administration of Ad-FKN-transduced DC evoked tumor-specific cytotoxic T lymphocytes, which ensued from in vivo priming of Th1 immune responses in the treated host.
27593937	Hepatocellular Carcinoma	IL6	Inhibit immunity (T cell function); immunotherapy target	Tumor-associated fibroblasts (TAFs) attracted monocytes by the stromal cell-derived factor (SDF)-1a/CXCR4 pathway and induced their differentiation into MDSCs through interleukin (IL)-6-mediated STAT3 activation. Together, our results are the first to show that TAF-derived cytokines, such as IL-6 and SDF-1a, can induce MDSC generation and activation and then impair human anti-tumor immune responses, which create favorable conditions for HCC progression. Consequently, methods in which immunotherapy is combined with IL-6, SDF-1a or STAT3 inhibition may offer an improved option to eliminate suppressive CD11b+ myeloid cells in HCC patients.
27593937	Hepatocellular Carcinoma	CXCL12	Inhibit immunity (T cell function); immunotherapy target	Tumor-associated fibroblasts (TAFs) attracted monocytes by the stromal cell-derived factor (SDF)-1a/CXCR4 pathway and induced their differentiation into MDSCs through interleukin (IL)-6-mediated STAT3 activation. Together, our results are the first to show that TAF-derived cytokines, such as IL-6 and SDF-1a, can induce MDSC generation and activation and then impair human anti-tumor immune responses, which create favorable conditions for HCC progression. Consequently, methods in which immunotherapy is combined with IL-6, SDF-1a or STAT3 inhibition may offer an improved option to eliminate suppressive CD11b+ myeloid cells in HCC patients.
27593937	Hepatocellular Carcinoma	STAT3	Inhibit immunity (T cell function); immunotherapy target	Tumor-associated fibroblasts (TAFs) attracted monocytes by the stromal cell-derived factor (SDF)-1a/CXCR4 pathway and induced their differentiation into MDSCs through interleukin (IL)-6-mediated STAT3 activation. These data also suggest an important role for STAT3 activation in TAF-mediated MDSC generation and MDSC-mediated immune suppression. Consequently, methods in which immunotherapy is combined with IL-6, SDF-1a or STAT3 inhibition may offer an improved option to eliminate suppressive CD11b+ myeloid cells in HCC patients.
27575718	Colorectal Carcinoma	IDO1	Inhibit immunity (infiltration)	We detected increased T cell infiltration in the tumor microenvironment after activation of the immune system with the combination of IDO inhibition by the small-molecule immunotherapy agent and immunogenic cell death induced by PDT.
27572267	Basal-Like Breast Carcinoma	EGF	Inhibit immunity	We also demonstrate that epidermal growth factor (EGF) stabilizes PD-L1 via GSK3β inactivation in basal-like breast cancer. Inhibition of EGF signalling by gefitinib destabilizes PD-L1, enhances antitumour T-cell immunity and therapeutic efficacy of PD-1 blockade in syngeneic mouse models.
27572267	Basal-Like Breast Carcinoma	GSK3B	Promote immunity (T cell function)	We also demonstrate that epidermal growth factor (EGF) stabilizes PD-L1 via GSK3β inactivation in basal-like breast cancer. Inhibition of EGF signalling by gefitinib destabilizes PD-L1, enhances antitumour T-cell immunity and therapeutic efficacy of PD-1 blockade in syngeneic mouse models.
27571406	B Acute Lymphoblastic Leukemia	CD19	Promote immunity (T cell function); essential for immunotherapy	Finally, we devised a dual CAR-expressing construct that combined CD19- and CD123-mediated T cell activation and demonstrated that it provides superior in vivo activity against B-ALL compared with single-expressing CART or pooled combination CART. In conclusion, these findings indicate that targeting CD19 and CD123 on leukemic blasts represents an effective strategy for treating and preventing antigen-loss relapses occurring after CD19-directed therapies.
27571406	B Acute Lymphoblastic Leukemia	IL3RA	Promote immunity (T cell function); essential for immunotherapy	Finally, we devised a dual CAR-expressing construct that combined CD19- and CD123-mediated T cell activation and demonstrated that it provides superior in vivo activity against B-ALL compared with single-expressing CART or pooled combination CART. In conclusion, these findings indicate that targeting CD19 and CD123 on leukemic blasts represents an effective strategy for treating and preventing antigen-loss relapses occurring after CD19-directed therapies.
27568523	Leukemia	TREM1	Inhibit immunity	Forced expression of the downregulated DNA repair genes, Rad51c or Trp53i13, in the Fanca-/-?pre-LSCs partially rescues DDR but has no effect on leukemia, whereas shRNA knockdown of the upregulated immune receptor genes Trem1 or Pilrb improves leukemia-related survival, but not DDR or genomic instability. Furthermore, Trem1 cooperates with diminished DDR in vivo to promote Fanca-/-?pre-LSC expansion and leukemia development.
27568523	Leukemia	PILRB	Promote immunity	Forced expression of the downregulated DNA repair genes, Rad51c or Trp53i13, in the Fanca-/-?pre-LSCs partially rescues DDR but has no effect on leukemia, whereas shRNA knockdown of the upregulated immune receptor genes Trem1 or Pilrb improves leukemia-related survival, but not DDR or genomic instability. Furthermore, Trem1 cooperates with diminished DDR in vivo to promote Fanca-/-?pre-LSC expansion and leukemia development.
27553831	Non-Small Cell Lung Carcinoma	HHLA2	Inhibit immunity (T cell function); immunotherapy target	By regulating T-cell function, HHLA2 could contribute to tumor immune suppression and thus be a novel target for cancer immunotherapy. HHLA2 is widely expressed in NSCLC and is associated with EGFR mutation and high TILs in lung adenocarcinoma. Overall, HHLA2 was not detected in most of normal lung tissue but expressed in 66% of NSCLC across different subtypes.
27550451	Lung Carcinoma	IL34	Inhibit immunity (T cell function); immunotherapy target	In particular, we found that IL34 modulated the functions of tumor-associated macrophages to enhance local immunosuppression and to promote the survival of chemoresistant cancer cells by activating AKT signaling. Targeting IL34 in chemoresistant tumors resulted in a remarkable inhibition of tumor growth when accompanied with chemotherapy.
27550451	Lung Carcinoma	AKT1	Inhibit immunity (T cell function)	In particular, we found that IL34 modulated the functions of tumor-associated macrophages to enhance local immunosuppression and to promote the survival of chemoresistant cancer cells by activating AKT signaling. Targeting IL34 in chemoresistant tumors resulted in a remarkable inhibition of tumor growth when accompanied with chemotherapy.
27549124	Sarcoma; Neuroblastoma	CD28	Promote immunity (T cell function); essential for immunotherapy	T cells engineered to express a third-generation GD2-CAR incorporating the 14g2a-scFv with the CD28, OX40, and CD3ζ signaling domains (14g2a.CD28.OX40.ζ) mediated efficient and comparable lysis of both GD2+ sarcoma and neuroblastoma cell lines in vitro
27549124	Sarcoma; Neuroblastoma	TNFRSF4	Promote immunity (T cell function); essential for immunotherapy	T cells engineered to express a third-generation GD2-CAR incorporating the 14g2a-scFv with the CD28, OX40, and CD3ζ signaling domains (14g2a.CD28.OX40.ζ) mediated efficient and comparable lysis of both GD2+ sarcoma and neuroblastoma cell lines in vitro
27549124	Sarcoma; Neuroblastoma	CD247	Promote immunity (T cell function); essential for immunotherapy	T cells engineered to express a third-generation GD2-CAR incorporating the 14g2a-scFv with the CD28, OX40, and CD3ζ signaling domains (14g2a.CD28.OX40.ζ) mediated efficient and comparable lysis of both GD2+ sarcoma and neuroblastoma cell lines in vitro
27546622	Pancreatic Ductal Adenocarcinoma	YAP1	Inhibit immunity (T cell function)	Within Kras:p53 mutant pancreatic ductal cells, Yap drives the expression and secretion of multiple cytokines/chemokines, which in turn promote the differentiation and accumulation of myeloid-derived suppressor cells (MDSCs) both in vitro and in vivo. Pancreas-specific knockout of Yap or antibody-mediated depletion of MDSCs promoted macrophage reprogramming, reactivation of T cells, apoptosis of Kras mutant neoplastic ductal cells and pancreatic regeneration after acute pancreatitis.
27535994	Chronic Lymphocytic Leukemia	FCMR	Promote immunity	We identified the immunoglobulin M Fc receptor (FcμR), also known as the Fas apoptotic inhibitory molecule-3 or TOSO, as a target for a more selective treatment of CLL by CAR T cells. FcμR is highly and consistently expressed by CLL cells; only minor levels are detected on healthy B cells or other hematopoietic cells. T cells with a CAR specific for FcμR efficiently responded toward CLL cells, released a panel of proinflammatory cytokines and lytic factors, like soluble FasL and granzyme B, and eliminated the leukemic cells. In contrast to CD19 CAR T cells, anti-FcμR CAR T cells did not attack healthy B cells.
27535994	Chronic Lymphocytic Leukemia	FASLG	Promote immunity (T cell function); increase the efficacy of immunotherapy	We identified the immunoglobulin M Fc receptor (FcμR), also known as the Fas apoptotic inhibitory molecule-3 or TOSO, as a target for a more selective treatment of CLL by CAR T cells. FcμR is highly and consistently expressed by CLL cells; only minor levels are detected on healthy B cells or other hematopoietic cells. T cells with a CAR specific for FcμR efficiently responded toward CLL cells, released a panel of proinflammatory cytokines and lytic factors, like soluble FasL and granzyme B, and eliminated the leukemic cells. In contrast to CD19 CAR T cells, anti-FcμR CAR T cells did not attack healthy B cells.
27535994	Chronic Lymphocytic Leukemia	GZMB	Promote immunity (T cell function); increase the efficacy of immunotherapy	We identified the immunoglobulin M Fc receptor (FcμR), also known as the Fas apoptotic inhibitory molecule-3 or TOSO, as a target for a more selective treatment of CLL by CAR T cells. FcμR is highly and consistently expressed by CLL cells; only minor levels are detected on healthy B cells or other hematopoietic cells. T cells with a CAR specific for FcμR efficiently responded toward CLL cells, released a panel of proinflammatory cytokines and lytic factors, like soluble FasL and granzyme B, and eliminated the leukemic cells. In contrast to CD19 CAR T cells, anti-FcμR CAR T cells did not attack healthy B cells.
27530322	Glioblastoma	CCL20	Inhibit immunity (T cell function)	CCL2 Produced by the Glioma Microenvironment Is Essential for the Recruitment of Regulatory T Cells and Myeloid-Derived Suppressor Cells. In many aggressive cancers, such as glioblastoma multiforme, progression is enabled by local immunosuppression driven by the accumulation of regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC). Here we report that macrophages and microglia within the glioma microenvironment produce CCL2, a chemokine that is critical for recruiting both CCR4+?Treg and CCR2+Ly-6C+?monocytic MDSCs in this disease setting. In murine gliomas, we established novel roles for tumor-derived CCL20 and osteoprotegerin in inducing CCL2 production from macrophages and microglia.
27530322	Glioblastoma	TNFRSF11B	Inhibit immunity (T cell function)	CCL2 Produced by the Glioma Microenvironment Is Essential for the Recruitment of Regulatory T Cells and Myeloid-Derived Suppressor Cells. In many aggressive cancers, such as glioblastoma multiforme, progression is enabled by local immunosuppression driven by the accumulation of regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC). Here we report that macrophages and microglia within the glioma microenvironment produce CCL2, a chemokine that is critical for recruiting both CCR4+?Treg and CCR2+Ly-6C+?monocytic MDSCs in this disease setting. In murine gliomas, we established novel roles for tumor-derived CCL20 and osteoprotegerin in inducing CCL2 production from macrophages and microglia.
27530322	Glioblastoma	CCL2	Inhibit immunity (T cell function)	CCL2 Produced by the Glioma Microenvironment Is Essential for the Recruitment of Regulatory T Cells and Myeloid-Derived Suppressor Cells. In many aggressive cancers, such as glioblastoma multiforme, progression is enabled by local immunosuppression driven by the accumulation of regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC). Here we report that macrophages and microglia within the glioma microenvironment produce CCL2, a chemokine that is critical for recruiting both CCR4+?Treg and CCR2+Ly-6C+?monocytic MDSCs in this disease setting. In murine gliomas, we established novel roles for tumor-derived CCL20 and osteoprotegerin in inducing CCL2 production from macrophages and microglia.
27520877	Hepatocellular Carcinoma	PDCD1	Inhibit immunity (T cell function); immunotherapy target	Treg accumulation and upregulation of PD-1 provide two independent mechanisms to induce profound immune tolerance in HCC. Chemoimmunotherapy using Food and Drug Administration-approved sunitinib with anti-PD-1 antibodies achieved significant tumor control, supporting translation of this approach for the treatment of HCC patients.
27511870	B-Cell Non-Hodgkin Lymphoma	MS4A1	Promote immunity	Here, we describe the use of the anti-CD20 monoclonal antibody (mAb), rituximab-IR700 APC for NIR-PIT of B-cell lymphoma in two CD20-expressing lymphoma mouse models. Rituximab-IR700 showed high tumor accumulation and high target-to-background ratio in?vivo. Tumor growth was significantly inhibited by NIR-PIT in comparison with the other groups. In conclusion, anti-CD20 rituximab-IR700 works as a highly effective APC for NIR-PIT against B-cell lymphoma.
27505670	Diffuse Large B Cell Lymphoma	EZH2	Inhibit immunity; immunotherapy target	Herein we show that the actions of EZH2 in driving GC formation and lymphoma precursor lesions require site-specific binding by the BCL6 transcriptional repressor and the presence of a non-canonical PRC1-BCOR-CBX8 complex. The chromodomain protein CBX8 is induced in GC B cells, binds to H3K27me3 at bivalent promoters, and is required for stable association of the complex and the resulting histone modifications. Moreover, oncogenic BCL6 and EZH2 cooperate to accelerate diffuse large B cell lymphoma (DLBCL) development and combinatorial targeting of these repressors results in enhanced anti-lymphoma activity in DLBCLs.
27505670	Diffuse Large B Cell Lymphoma	BCL6	Inhibit immunity; immunotherapy target	Herein we show that the actions of EZH2 in driving GC formation and lymphoma precursor lesions require site-specific binding by the BCL6 transcriptional repressor and the presence of a non-canonical PRC1-BCOR-CBX8 complex. The chromodomain protein CBX8 is induced in GC B cells, binds to H3K27me3 at bivalent promoters, and is required for stable association of the complex and the resulting histone modifications. Moreover, oncogenic BCL6 and EZH2 cooperate to accelerate diffuse large B cell lymphoma (DLBCL) development and combinatorial targeting of these repressors results in enhanced anti-lymphoma activity in DLBCLs.
27505670	Diffuse Large B Cell Lymphoma	PRC1	Inhibit immunity	Herein we show that the actions of EZH2 in driving GC formation and lymphoma precursor lesions require site-specific binding by the BCL6 transcriptional repressor and the presence of a non-canonical PRC1-BCOR-CBX8 complex. The chromodomain protein CBX8 is induced in GC B cells, binds to H3K27me3 at bivalent promoters, and is required for stable association of the complex and the resulting histone modifications. Moreover, oncogenic BCL6 and EZH2 cooperate to accelerate diffuse large B cell lymphoma (DLBCL) development and combinatorial targeting of these repressors results in enhanced anti-lymphoma activity in DLBCLs.
27505670	Diffuse Large B Cell Lymphoma	BCOR	Inhibit immunity	Herein we show that the actions of EZH2 in driving GC formation and lymphoma precursor lesions require site-specific binding by the BCL6 transcriptional repressor and the presence of a non-canonical PRC1-BCOR-CBX8 complex. The chromodomain protein CBX8 is induced in GC B cells, binds to H3K27me3 at bivalent promoters, and is required for stable association of the complex and the resulting histone modifications. Moreover, oncogenic BCL6 and EZH2 cooperate to accelerate diffuse large B cell lymphoma (DLBCL) development and combinatorial targeting of these repressors results in enhanced anti-lymphoma activity in DLBCLs.
27505670	Diffuse Large B Cell Lymphoma	CBX8	Inhibit immunity	Herein we show that the actions of EZH2 in driving GC formation and lymphoma precursor lesions require site-specific binding by the BCL6 transcriptional repressor and the presence of a non-canonical PRC1-BCOR-CBX8 complex. The chromodomain protein CBX8 is induced in GC B cells, binds to H3K27me3 at bivalent promoters, and is required for stable association of the complex and the resulting histone modifications. Moreover, oncogenic BCL6 and EZH2 cooperate to accelerate diffuse large B cell lymphoma (DLBCL) development and combinatorial targeting of these repressors results in enhanced anti-lymphoma activity in DLBCLs.
27497761	Castration-Resistant Prostate Carcinoma	AR	Inhibit immunity (infiltration)	Accordingly, infiltration of CD3+ and CD68+ cells was lower in AR-driven than in non-AR-driven metastases, and tumor cell HLA class I ABC immunoreactivity was inversely correlated with nuclear AR immunoreactivity. Most CRPC bone metastases show high AR and metabolic activities and low immune responses.
27496866	Head and Neck Carcinoma	EGFR	Inhibit immunity (NK cell function); immunotherapy target	Cetuximab, an EGFR-specific antibody (mAb), modestly improves clinical outcome in patients with head and neck cancer (HNC). Cetuximab mediates natural killer (NK) cell:dendritic cell (DC) cross-talk by cross-linking FcγRIIIa, which is important for inducing antitumor cellular immunity. Cetuximab-activated NK cells upregulate the costimulatory receptor CD137 (4-1BB), which, when triggered by agonistic mAb urelumab, might enhance NK-cell functions, to promote T-cell-based immunity.
27496866	Head and Neck Carcinoma	FCGR3A	Promote immunity (NK cell function); essential for immunotherapy	Cetuximab, an EGFR-specific antibody (mAb), modestly improves clinical outcome in patients with head and neck cancer (HNC). Cetuximab mediates natural killer (NK) cell:dendritic cell (DC) cross-talk by cross-linking FcγRIIIa, which is important for inducing antitumor cellular immunity. Cetuximab-activated NK cells upregulate the costimulatory receptor CD137 (4-1BB), which, when triggered by agonistic mAb urelumab, might enhance NK-cell functions, to promote T-cell-based immunity.
27496866	Head and Neck Carcinoma	TNFRSF9	Promote immunity (NK cell function)	CD137 agonist mAb urelumab enhanced cetuximab-activated NK-cell survival, DC maturation, and tumor antigen cross-presentation. Urelumab boosted DC maturation markers, CD86 and HLA DR, and antigen-processing machinery (APM) components TAP1/2, leading to increased tumor antigen cross-presentation. These results suggest a beneficial effect of combination immunotherapy using cetuximab and CD137 agonist in HNC.
27496866	Head and Neck Carcinoma	CD86	Promote immunity (T cell function); essential for immunotherapy	CD137 agonist mAb urelumab enhanced cetuximab-activated NK-cell survival, DC maturation, and tumor antigen cross-presentation. Urelumab boosted DC maturation markers, CD86 and HLA DR, and antigen-processing machinery (APM) components TAP1/2, leading to increased tumor antigen cross-presentation. These results suggest a beneficial effect of combination immunotherapy using cetuximab and CD137 agonist in HNC.
27496866	Head and Neck Carcinoma	HLA-DRA	Promote immunity (T cell function); essential for immunotherapy	CD137 agonist mAb urelumab enhanced cetuximab-activated NK-cell survival, DC maturation, and tumor antigen cross-presentation. Urelumab boosted DC maturation markers, CD86 and HLA DR, and antigen-processing machinery (APM) components TAP1/2, leading to increased tumor antigen cross-presentation. These results suggest a beneficial effect of combination immunotherapy using cetuximab and CD137 agonist in HNC.
27496866	Head and Neck Carcinoma	TAP1	Promote immunity (T cell function); essential for immunotherapy	CD137 agonist mAb urelumab enhanced cetuximab-activated NK-cell survival, DC maturation, and tumor antigen cross-presentation. Urelumab boosted DC maturation markers, CD86 and HLA DR, and antigen-processing machinery (APM) components TAP1/2, leading to increased tumor antigen cross-presentation. These results suggest a beneficial effect of combination immunotherapy using cetuximab and CD137 agonist in HNC.
27496866	Head and Neck Carcinoma	TAP2	Promote immunity (T cell function); essential for immunotherapy	CD137 agonist mAb urelumab enhanced cetuximab-activated NK-cell survival, DC maturation, and tumor antigen cross-presentation. Urelumab boosted DC maturation markers, CD86 and HLA DR, and antigen-processing machinery (APM) components TAP1/2, leading to increased tumor antigen cross-presentation. These results suggest a beneficial effect of combination immunotherapy using cetuximab and CD137 agonist in HNC.
27489285	Melanoma; Head and Neck Carcinoma; Bladder Carcinoma; Triple-negative Breast Carcinoma	MAGEC2	Promote immunity	Pretreatment of tumor cells upregulated MC2 gene expression and enhanced recognition by T cells. One of the tested TCRs consistently recognized pretreated MC2(+) cell lines from melanoma, head and neck, bladder, and triple-negative breast cancers but showed no response to MHC-eluted peptides or peptides highly similar to MC2. We conclude that targeting MC2 Ag, combined with epigenetic drug-enhanced antigenicity, allows for significant and tumor-selective T cell responses.
27488528	Chronic Lymphocytic Leukemia	TGFB1	Promote immunity	Notably, in progressive CLL, splenic neutrophils were observed to differentiate toward a B-cell helper phenotype, a process promoted by the induction of leukemia-associated IL10 and TGFβ. Our results suggest that targeting aberrant neutrophil differentiation and restoring myeloid cell homeostasis could limit the formation of survival niches for CLL cells.
27481844	Non-Small Cell Lung Carcinoma	TERT	Promote immunity (T cell function); essential for immunotherapy	Telomerase is a prototype-shared tumor Ag and represents an attractive target for anticancer immunotherapy. We have previously described promiscuous and immunogenic HLA-DR-restricted peptides derived from human telomerase reverse transcriptase (hTERT) and referred as universal cancer peptide (UCP). In nonsmall cell lung cancer, the presence of spontaneous UCP-specific CD4 T cell responses increases the survival of chemotherapy-responding patients. Altogether, our findings provide a novel mechanism of tumor-specific CD4 T cell activation and will be useful for the development of novel cancer immunotherapies that harness CD4 T cells.
27479183	Acute Myeloid Leukemia	HLA-DPB1	Promote immunity (T cell function); essential for immunotherapy	HLA-DPB1 mismatch alleles represent powerful leukemia rejection antigens in CD4 T-cell immunotherapy after allogeneic stem-cell transplantation. In conclusion, we show strong immunogenicity of HLA-DPB1 mismatch alleles in CD45RA-selected CD4 T cells of stem-cell donors and introduce a novel strategy to reliably generate HLA-DPB1-specific CD4 CTL that might be powerful cellular therapeutics in relapsed or refractory AML after HSCT.
27479178	Chronic Lymphocytic Leukemia	PDCD1	Inhibit immunity; immunotherapy target	Furthermore, we report that CLL monocytes express Bruton's tyrosine kinase (BTK). Our observations suggest that using BTK inhibitors in CLL might further aggravate the observed immune metabolic defects in monocytes. Triggering the programmed cell death-1 (PD-1) checkpoint on monocytes hampers glycolysis, phagocytosis and BTK signaling. Conversely, disrupting PD-1/PD-L1 signaling reverses these immune metabolic dysfunctions. Taken together, our findings imply a novel metabolic interplay between CLL cells and monocytes and that blocking PD-1/PD-L1 might restore metabolic together with antitumor activity of CLL monocytes/macrophages.
27479178	Chronic Lymphocytic Leukemia	CD274	Inhibit immunity; immunotherapy target	Furthermore, we report that CLL monocytes express Bruton's tyrosine kinase (BTK). Our observations suggest that using BTK inhibitors in CLL might further aggravate the observed immune metabolic defects in monocytes. Triggering the programmed cell death-1 (PD-1) checkpoint on monocytes hampers glycolysis, phagocytosis and BTK signaling. Conversely, disrupting PD-1/PD-L1 signaling reverses these immune metabolic dysfunctions. Taken together, our findings imply a novel metabolic interplay between CLL cells and monocytes and that blocking PD-1/PD-L1 might restore metabolic together with antitumor activity of CLL monocytes/macrophages.
27479178	Chronic Lymphocytic Leukemia	BTK	Promote immunity	Furthermore, we report that CLL monocytes express Bruton's tyrosine kinase (BTK). Our observations suggest that using BTK inhibitors in CLL might further aggravate the observed immune metabolic defects in monocytes. Triggering the programmed cell death-1 (PD-1) checkpoint on monocytes hampers glycolysis, phagocytosis and BTK signaling. Conversely, disrupting PD-1/PD-L1 signaling reverses these immune metabolic dysfunctions. Taken together, our findings imply a novel metabolic interplay between CLL cells and monocytes and that blocking PD-1/PD-L1 might restore metabolic together with antitumor activity of CLL monocytes/macrophages.
27475305	Colorectal Carcinoma	PTGS2	Inhibit immunity (T cell function)	Aspirin use reduces colorectal cancer?risk. Aspirin, a nonsteroidal anti-inflammatory drug, inhibits prostaglandin-endoperoxide synthase 2 (PTGS2 or cyclooxygenase-2); PTGS2 promotes inflammation and suppresses T-cell-mediated adaptive immunity. Compared with nonregular use, regular aspirin use was associated with a lower risk of tumors that had low levels of TILs (relative risk, 0.72; 95% confidence interval, 0.63-0.81), and strength of the association depended on aspirin dose and duration (both Ptrend < .001).
27470968	Gastrointestinal Stromal Tumor	PDCD1	Inhibit immunity (T cell function)	The inhibitory receptors PD-1, lymphocyte activation gene 3, and T-cell immunoglobulin mucin-3 were upregulated on tumor-infiltrating T cells compared with T cells from matched blood. In human GIST cell lines, treatment with imatinib abrogated the IFNγ-induced upregulation of PD-L1 via STAT1 inhibition. In KitV558Δ/+?mice, imatinib downregulated IFNγ-related genes and reduced PD-L1 expression on tumor cells. PD-1 and PD-L1 blockade in vivo each had no efficacy alone but enhanced the antitumor effects of imatinib by increasing T-cell effector function in the presence of KIT and IDO inhibition.
27470968	Gastrointestinal Stromal Tumor	LAG3	Inhibit immunity (T cell function)	The inhibitory receptors PD-1, lymphocyte activation gene 3, and T-cell immunoglobulin mucin-3 were upregulated on tumor-infiltrating T cells compared with T cells from matched blood. In human GIST cell lines, treatment with imatinib abrogated the IFNγ-induced upregulation of PD-L1 via STAT1 inhibition. In KitV558Δ/+?mice, imatinib downregulated IFNγ-related genes and reduced PD-L1 expression on tumor cells. PD-1 and PD-L1 blockade in vivo each had no efficacy alone but enhanced the antitumor effects of imatinib by increasing T-cell effector function in the presence of KIT and IDO inhibition.
27470968	Gastrointestinal Stromal Tumor	IFNG	Inhibit immunity (T cell function)	The inhibitory receptors PD-1, lymphocyte activation gene 3, and T-cell immunoglobulin mucin-3 were upregulated on tumor-infiltrating T cells compared with T cells from matched blood. In human GIST cell lines, treatment with imatinib abrogated the IFNγ-induced upregulation of PD-L1 via STAT1 inhibition. In KitV558Δ/+?mice, imatinib downregulated IFNγ-related genes and reduced PD-L1 expression on tumor cells. PD-1 and PD-L1 blockade in vivo each had no efficacy alone but enhanced the antitumor effects of imatinib by increasing T-cell effector function in the presence of KIT and IDO inhibition.
27470968	Gastrointestinal Stromal Tumor	STAT1	Promote immunity	In human GIST cell lines, treatment with imatinib abrogated the IFNγ-induced upregulation of PD-L1 via STAT1 inhibition.
27466285	Melanoma	TP53	Inhibit immunity (T cell function); essential for immunotherapy	Lack of p53 Augments Antitumor Functions in Cytolytic T Cells. This increased effector function correlated to the improved control of subcutaneously established murine melanoma after adoptive transfer of p53-KO T cells. Pharmacological inhibition of human TCR-transduced T cells using a combination of p53 inhibitors also potentiated the T-cell effector function and improved persistence.
27465917	B-cell Lymphoma	IL15	Promote immunity (T cell function)	IL-15 augmented mammalian target of rapamycin (mTOR) signaling, which correlated with increased expression of genes related to cell metabolism and respiration. Moreover, mTOR-independent STAT-5 signaling contributed to improved NK-cell function during cytokine activation but not following cytokine withdrawal. Finally, expression of IL-15 correlated with cytolytic immune functions in patients with B-cell lymphoma and favorable clinical outcome. These findings highlight the importance of mTOR-regulated metabolic processes for immune cell functions and argue for implementation of IL-15 in adoptive NK-cell cancer therapy.
27465917	B-cell Lymphoma	STAT5A	Promote immunity (NK cell function)	IL-15 augmented mammalian target of rapamycin (mTOR) signaling, which correlated with increased expression of genes related to cell metabolism and respiration. Moreover, mTOR-independent STAT-5 signaling contributed to improved NK-cell function during cytokine activation but not following cytokine withdrawal. Finally, expression of IL-15 correlated with cytolytic immune functions in patients with B-cell lymphoma and favorable clinical outcome. These findings highlight the importance of mTOR-regulated metabolic processes for immune cell functions and argue for implementation of IL-15 in adoptive NK-cell cancer therapy.
27465528	Melanoma	LTB4R	Promote immunity (infiltration)	Significant accelerations in tumor growth and reduced survival were observed in both BLT1(-/-) and CXCR3(-/-) mice as compared with wild-type (WT) mice. The loss of efficacy correlated with failure of the knockout CTLs to infiltrate into tumors upon anti-PD-1 treatment, suggesting an obligate requirement for both BLT1 and CXCR3 in mediating anti-PD-1 based antitumor immune response. These results demonstrate a critical role for both BLT1 and CXCR3 in CTL migration to tumors and thus may be targeted to enhance efficacy of CTL-based immunotherapies.
27465528	B16 Malignant Melanoma	CXCR3	Promote immunity (infiltration)	Significant accelerations in tumor growth and reduced survival were observed in both BLT1(-/-) and CXCR3(-/-) mice as compared with wild-type (WT) mice. The loss of efficacy correlated with failure of the knockout CTLs to infiltrate into tumors upon anti-PD-1 treatment, suggesting an obligate requirement for both BLT1 and CXCR3 in mediating anti-PD-1 based antitumor immune response. These results demonstrate a critical role for both BLT1 and CXCR3 in CTL migration to tumors and thus may be targeted to enhance efficacy of CTL-based immunotherapies.
27463676	Medulloblastoma	CDK5	Inhibit immunity (T cell function)	Cdk5 disruption attenuates tumor PD-L1 expression and promotes antitumor immunity. Interferon-γ (IFN-γ)-induced PD-L1 up-regulation on MB requires Cdk5, and disruption of Cdk5 expression in a mouse model of MB results in potent CD4(+) T cell-mediated tumor rejection.
27463676	Medulloblastoma	IFNG	Inhibit immunity (T cell function)	Interferon-γ (IFN-γ)-induced PD-L1 up-regulation on MB requires Cdk5, and disruption of Cdk5 expression in a mouse model of MB results in potent CD4(+) T cell-mediated tumor rejection. Loss of Cdk5 results in persistent expression of the PD-L1 transcriptional repressors, the interferon regulatory factors IRF2 and IRF2BP2, which likely leads to reduced PD-L1 expression on tumors. Our finding highlights a central role for Cdk5 in immune checkpoint regulation by tumor cells.
27463676	Medulloblastoma	IRF2	Promote immunity (T cell function)	Interferon-γ (IFN-γ)-induced PD-L1 up-regulation on MB requires Cdk5, and disruption of Cdk5 expression in a mouse model of MB results in potent CD4(+) T cell-mediated tumor rejection. Loss of Cdk5 results in persistent expression of the PD-L1 transcriptional repressors, the interferon regulatory factors IRF2 and IRF2BP2, which likely leads to reduced PD-L1 expression on tumors. Our finding highlights a central role for Cdk5 in immune checkpoint regulation by tumor cells.
27463676	Medulloblastoma	IRF2BP2	Promote immunity (T cell function)	Interferon-γ (IFN-γ)-induced PD-L1 up-regulation on MB requires Cdk5, and disruption of Cdk5 expression in a mouse model of MB results in potent CD4(+) T cell-mediated tumor rejection. Loss of Cdk5 results in persistent expression of the PD-L1 transcriptional repressors, the interferon regulatory factors IRF2 and IRF2BP2, which likely leads to reduced PD-L1 expression on tumors. Our finding highlights a central role for Cdk5 in immune checkpoint regulation by tumor cells.
27460500	Pre-B Acute Lymphoblastic Leukemia	CD19	Promote immunity (T cell function); essential for immunotherapy	Adoptive immunotherapy using chimeric antigen receptor (CAR) expressing T cells targeting the CD19 B lineage receptor has demonstrated marked success in relapsed pre-B-cell acute lymphoblastic leukaemia (ALL). Using murine ALL models we study the long-term effects of CD19 CAR-T cells and demonstrate partial or complete lineage switch as a consistent mechanism of CAR resistance depending on the underlying genetic oncogenic driver. Deletion of Pax5 or Ebf1 recapitulates lineage reprogramming occurring during CD19 CAR pressure. Our findings establish lineage switch as a mechanism of CAR resistance exposing inherent plasticity in genetic subtypes of pre-B-cell ALL.
27458246	Lymphoma; Glioblastoma	PDCD1	Inhibit immunity (T cell function); immunotherapy target	The injection of anti-PD-1 antibody reduced by more 50% the size of SCC-3 and U87 tumors. In addition, induction of CTLs against SCC-3 cells and upregulation of natural killer cell activity was observed in the antibody-treated group. A greater number of CD8+?and granzyme-producing T cells infiltrated the tumor in mice treated with the anti-PD-1 antibody. These results suggest that NOG-dKO mice might serve as a good humanized immunotherapy model to evaluate the efficacy of anti-PD-1 antibody prior to the clinical treatment.
27458013	Hepatocellular Carcinoma	SQSTM1	Inhibit immunity	Innate immune responses are important for pathogen elimination and adaptive immune response activation. However, excess inflammation may contribute to immunopathology and disease progression (e.g. inflammation-associated hepatocellular carcinoma). Blockade of autophagy restored the immunosuppressive activity of patulin, and pharmacological activation of p62-dependent mitophagy directly reduced RIG-I-like receptor-dependent inflammatory cytokine production. These results demonstrated that p62-dependent mitophagy has an immunosuppressive role to innate immune response and might serve as a potential immunomodulatory target for inflammation-associated diseases.
27445334	Ovarian Carcinoma	FOLR1	Essential for immunotherapy	As a proof of concept, we chemically programmed h38C2 × v9 with hapten-folate and demonstrated its selectivity and potency against folate receptor 1 (FOLR1)-expressing ovarian cancer cells in vitro and in vivo Unlike conventional biAbs, chemically programmed biAbs in DART format are highly modular with broad utility in terms of both target and effector cell engagement. Most importantly, they provide tumor-targeting compounds access to the power of cancer immunotherapy.
27435394	Ovarian Carcinoma	FSHR	Promote immunity (T cell function); essential for immunotherapy	FSHR is expressed in gynecologic malignancies of different histologic types but not in nonovarian healthy tissues. T cells redirected against FSHR+ tumor cells with full-length FSH represent a promising therapeutic alternative against a broad range of ovarian malignancies, with negligible toxicity even in the presence of cognate targets in tumor-free ovaries.
27435394	Ovarian Carcinoma	CGA	Promote immunity	FSHR is expressed in gynecologic malignancies of different histologic types but not in nonovarian healthy tissues. T cells redirected against FSHR+ tumor cells with full-length FSH represent a promising therapeutic alternative against a broad range of ovarian malignancies, with negligible toxicity even in the presence of cognate targets in tumor-free ovaries.
23838315	Childhood acute lymphoblastic leukemia	WT1	Promote immunity (T cell function); essential for immunotherapy	Peripheral blood mononuclear cells were stimulated with autologous dendritic cells pulsed with complete peptide libraries of WT1, Survivin, MAGE-A3, and PRAME, antigens frequently expressed on ALL blasts. Antigen-specificity was observed in more than 50% of patients after the initial stimulation and increased to more than 90% after three stimulations as assessed in IFN-γ-enzyme-linked immunospot (ELISpot) and (51)Cr-release assays. This study supports the use of immunotherapy with adoptively transferred autologous tumor antigen-specific T cells to prevent relapse and improve the prognosis of patients with high-risk ALL.
23838315	Childhood acute lymphoblastic leukemia	BIRC5	Promote immunity (T cell function); essential for immunotherapy	Peripheral blood mononuclear cells were stimulated with autologous dendritic cells pulsed with complete peptide libraries of WT1, Survivin, MAGE-A3, and PRAME, antigens frequently expressed on ALL blasts. Antigen-specificity was observed in more than 50% of patients after the initial stimulation and increased to more than 90% after three stimulations as assessed in IFN-γ-enzyme-linked immunospot (ELISpot) and (51)Cr-release assays. This study supports the use of immunotherapy with adoptively transferred autologous tumor antigen-specific T cells to prevent relapse and improve the prognosis of patients with high-risk ALL.
23838315	Childhood acute lymphoblastic leukemia	MAGEA3	Promote immunity (T cell function); essential for immunotherapy	Peripheral blood mononuclear cells were stimulated with autologous dendritic cells pulsed with complete peptide libraries of WT1, Survivin, MAGE-A3, and PRAME, antigens frequently expressed on ALL blasts. Antigen-specificity was observed in more than 50% of patients after the initial stimulation and increased to more than 90% after three stimulations as assessed in IFN-γ-enzyme-linked immunospot (ELISpot) and (51)Cr-release assays. This study supports the use of immunotherapy with adoptively transferred autologous tumor antigen-specific T cells to prevent relapse and improve the prognosis of patients with high-risk ALL.
23838315	Childhood acute lymphoblastic leukemia	PRAME	Promote immunity (T cell function); essential for immunotherapy	Peripheral blood mononuclear cells were stimulated with autologous dendritic cells pulsed with complete peptide libraries of WT1, Survivin, MAGE-A3, and PRAME, antigens frequently expressed on ALL blasts. Antigen-specificity was observed in more than 50% of patients after the initial stimulation and increased to more than 90% after three stimulations as assessed in IFN-γ-enzyme-linked immunospot (ELISpot) and (51)Cr-release assays. This study supports the use of immunotherapy with adoptively transferred autologous tumor antigen-specific T cells to prevent relapse and improve the prognosis of patients with high-risk ALL.
23821660	Non-Hodgkin Lymphoma; Systemic Lupus Erythematosus	CD22	Promote immunity	Epratuzumab, a humanized anti-CD22 antibody, is currently in clinical trials of B-cell lymphomas and autoimmune diseases, demonstrating therapeutic activity in non-Hodgkin lymphoma (NHL) and systemic lupus erythematosus (SLE). Here we report for the first time that epratuzumab promptly induces a marked decrease of CD22 (>80%), CD19 (>50%), CD21 (>50%), and CD79b (>30%) on the surface of B cells in peripheral blood mononuclear cells (PBMCs) obtained from normal donors or SLE patients, and of NHL cells (Daudi and Raji) spiked into normal PBMCs.
23820258	Acute Myeloid Leukemia; Adenocarcinoma	MICA	Promote immunity (NK cell function); essential for immunotherapy	NKG2D recognises several ligands, including polymorphic major histocompatibility complex class I chain-related chain-related proteins A and B (MICA/B) and unique long 16-binding proteins (ULBPs). These ligands are present on cancer cells and are recognised by NKG2D in a cell-structure-sensing manner, triggering natural killer (NK) cell cytotoxicity. Treatment with 1,25(OH)2D3 enhanced the susceptibility of both the haematological tumour cell line Kasumi-1 and solid tumour cell line MDA-MB-231 to NK92 cells. 1,25(OH)2D3 facilitates the immuno-attack of NK cells against malignant cells partly through downregulation of miR-302c and miR-520c and hence upregulation of the NKG2D ligands MICA/B and ULBP2.
23820258	Acute Myeloid Leukemia; Adenocarcinoma	MICB	Promote immunity (NK cell function); essential for immunotherapy	NKG2D recognises several ligands, including polymorphic major histocompatibility complex class I chain-related chain-related proteins A and B (MICA/B) and unique long 16-binding proteins (ULBPs). These ligands are present on cancer cells and are recognised by NKG2D in a cell-structure-sensing manner, triggering natural killer (NK) cell cytotoxicity. Treatment with 1,25(OH)2D3 enhanced the susceptibility of both the haematological tumour cell line Kasumi-1 and solid tumour cell line MDA-MB-231 to NK92 cells. 1,25(OH)2D3 facilitates the immuno-attack of NK cells against malignant cells partly through downregulation of miR-302c and miR-520c and hence upregulation of the NKG2D ligands MICA/B and ULBP2.
23820258	Acute Myeloid Leukemia; Adenocarcinoma	ULBP2	Promote immunity (NK cell function); essential for immunotherapy	NKG2D recognises several ligands, including polymorphic major histocompatibility complex class I chain-related chain-related proteins A and B (MICA/B) and unique long 16-binding proteins (ULBPs). These ligands are present on cancer cells and are recognised by NKG2D in a cell-structure-sensing manner, triggering natural killer (NK) cell cytotoxicity. Treatment with 1,25(OH)2D3 enhanced the susceptibility of both the haematological tumour cell line Kasumi-1 and solid tumour cell line MDA-MB-231 to NK92 cells. 1,25(OH)2D3 facilitates the immuno-attack of NK cells against malignant cells partly through downregulation of miR-302c and miR-520c and hence upregulation of the NKG2D ligands MICA/B and ULBP2.
23820258	Acute Myeloid Leukemia; Adenocarcinoma	KLRK1	Promote immunity (NK cell function); essential for immunotherapy	These ligands are present on cancer cells and are recognised by NKG2D in a cell-structure-sensing manner, triggering natural killer (NK) cell cytotoxicity. 1,25(OH)2D3 facilitates the immuno-attack of NK cells against malignant cells partly through downregulation of miR-302c and miR-520c and hence upregulation of the NKG2D ligands MICA/B and ULBP2.
23807163	Ovarian carcinoma	SCGB2A1	Promote immunity T cell function); essential for immunotherapy	We studied the genetic fingerprints of ovarian cancer and validated the potential of Mammaglobin b (SCGB2A1), one of the top differentially expressed genes found in our analysis, as a novel ovarian tumour rejection antigen. The CD8+ CTL populations generated against SCGB2A1 were able to consistently induce lysis of autologous primary (chemo-naive) and metastatic/recurrent (chemo-resistant) target tumour cells expressing SCGB2A1, whereas autologous HLA-identical noncancerous cells were not lysed. Cytotoxicity against autologous tumour cells was significantly inhibited by anti-HLA-class I (W6/32) monoclonal antibody.
23807163	Ovarian carcinoma	HLA-A	Promote immunity (T cell function)	We studied the genetic fingerprints of ovarian cancer and validated the potential of Mammaglobin b (SCGB2A1), one of the top differentially expressed genes found in our analysis, as a novel ovarian tumour rejection antigen. The CD8+ CTL populations generated against SCGB2A1 were able to consistently induce lysis of autologous primary (chemo-naive) and metastatic/recurrent (chemo-resistant) target tumour cells expressing SCGB2A1, whereas autologous HLA-identical noncancerous cells were not lysed. Cytotoxicity against autologous tumour cells was significantly inhibited by anti-HLA-class I (W6/32) monoclonal antibody.
23804711	Chronic Lymphocytic Leukemia	CXCL12	Inhibit immunity	Transendothelial migration (TEM) of normal lymphocytes into lymph nodes requires the chemokine-induced activation of Rap1 and αLβ2 integrin. However, in most cases of CLL, Rap1 is refractory to chemokine stimulation, resulting in failed αLβ2 activation and TEM unless α4β1 is coexpressed. In this study, we show that the inability of CXCL12 to induce Rap1 GTP loading in CLL cells results from failure of Rap1-containing endosomes to translocate to the plasma membrane. Taken together, our findings indicate that chemokine unresponsiveness in CLL lymphocytes results from failure of Arf1/phospholipase D1-mediated translocation of Rap1 to the plasma membrane for GTP loading and may be a specific feature of anergy induced by DNA Ags.
23804711	Chronic Lymphocytic Leukemia	RAP1A	Inhibit immunity	Transendothelial migration (TEM) of normal lymphocytes into lymph nodes requires the chemokine-induced activation of Rap1 and αLβ2 integrin. However, in most cases of CLL, Rap1 is refractory to chemokine stimulation, resulting in failed αLβ2 activation and TEM unless α4β1 is coexpressed. In this study, we show that the inability of CXCL12 to induce Rap1 GTP loading in CLL cells results from failure of Rap1-containing endosomes to translocate to the plasma membrane. Taken together, our findings indicate that chemokine unresponsiveness in CLL lymphocytes results from failure of Arf1/phospholipase D1-mediated translocation of Rap1 to the plasma membrane for GTP loading and may be a specific feature of anergy induced by DNA Ags.
23804711	Chronic Lymphocytic Leukemia	PLD1	Promote immunity	Transendothelial migration (TEM) of normal lymphocytes into lymph nodes requires the chemokine-induced activation of Rap1 and αLβ2 integrin. However, in most cases of CLL, Rap1 is refractory to chemokine stimulation, resulting in failed αLβ2 activation and TEM unless α4β1 is coexpressed. In this study, we show that the inability of CXCL12 to induce Rap1 GTP loading in CLL cells results from failure of Rap1-containing endosomes to translocate to the plasma membrane. Taken together, our findings indicate that chemokine unresponsiveness in CLL lymphocytes results from failure of Arf1/phospholipase D1-mediated translocation of Rap1 to the plasma membrane for GTP loading and may be a specific feature of anergy induced by DNA Ags.
23804711	Chronic Lymphocytic Leukemia	ARF1	Inhibit immunity	Transendothelial migration (TEM) of normal lymphocytes into lymph nodes requires the chemokine-induced activation of Rap1 and αLβ2 integrin. However, in most cases of CLL, Rap1 is refractory to chemokine stimulation, resulting in failed αLβ2 activation and TEM unless α4β1 is coexpressed. In this study, we show that the inability of CXCL12 to induce Rap1 GTP loading in CLL cells results from failure of Rap1-containing endosomes to translocate to the plasma membrane. Taken together, our findings indicate that chemokine unresponsiveness in CLL lymphocytes results from failure of Arf1/phospholipase D1-mediated translocation of Rap1 to the plasma membrane for GTP loading and may be a specific feature of anergy induced by DNA Ags.
23787049	Hepatocellular Carcinoma	TP53	Promote immunity	A new study reveals that p53 also acts through a novel non-cell-autonomous mechanism, by stimulating the innate immune system to maintain tissue homeostasis and suppress tumorigenesis.
23776241	Triple-Negative Breast Carcinoma	NT5E	Inhibit immunity; immunotherapy target	Using mouse models of breast cancer, we demonstrated that CD73 overexpression in tumor cells conferred chemoresistance to doxorubicin, a commonly used anthracycline, by suppressing adaptive antitumor immune responses via activation of A2A adenosine receptors. Targeted blockade of CD73 enhanced doxorubicin-mediated antitumor immune responses and significantly prolonged the survival of mice with established metastatic breast cancer. Taken together, our data suggest that CD73 constitutes a therapeutic target in TNBC.
23776241	Triple-Negative Breast Carcinoma	ADORA2A	Inhibit immunity	Using mouse models of breast cancer, we demonstrated that CD73 overexpression in tumor cells conferred chemoresistance to doxorubicin, a commonly used anthracycline, by suppressing adaptive antitumor immune responses via activation of A2A adenosine receptors. Targeted blockade of CD73 enhanced doxorubicin-mediated antitumor immune responses and significantly prolonged the survival of mice with established metastatic breast cancer. Taken together, our data suggest that CD73 constitutes a therapeutic target in TNBC.
23770850	Acute Promyelocytic Leukemia with PML-RARA	PML	Inhibit immunity (T cell function)	It has been established that impairment of the immunoproteasome subunits, that is, PSMB8, PSMB9 and PSMB10 (PSMBs), is critical for malignant cells to escape immune recognition. Collectively, our data demonstrate that PML/RARα suppresses PU.1-dependent activation of the immunosubunits, which may facilitate the escape of APL cells from immune surveillance in leukemia development, and ATRA treatment is able to reactivate their expression, which would promote more efficient T-cell-mediated recognition in the treatment.
23770850	Acute Promyelocytic Leukemia with PML-RARA	RARA	Inhibit immunity (T cell function)	It has been established that impairment of the immunoproteasome subunits, that is, PSMB8, PSMB9 and PSMB10 (PSMBs), is critical for malignant cells to escape immune recognition. Collectively, our data demonstrate that PML/RARα suppresses PU.1-dependent activation of the immunosubunits, which may facilitate the escape of APL cells from immune surveillance in leukemia development, and ATRA treatment is able to reactivate their expression, which would promote more efficient T-cell-mediated recognition in the treatment.
23770850	Acute Promyelocytic Leukemia with PML-RARA	SPI1	Inhibit immunity	It has been established that impairment of the immunoproteasome subunits, that is, PSMB8, PSMB9 and PSMB10 (PSMBs), is critical for malignant cells to escape immune recognition. We report here the regulatory mechanism of the repression of PU.1-dependent activation of PSMBs by PML/RARα in the pathogenesis of acute promyelocytic leukemia (APL) and the unidentified function of all-trans retinoic acid (ATRA) as an immunomodulator in the treatment of APL. Collectively, our data demonstrate that PML/RARα suppresses PU.1-dependent activation of the immunosubunits, which may facilitate the escape of APL cells from immune surveillance in leukemia development, and ATRA treatment is able to reactivate their expression, which would promote more efficient T-cell-mediated recognition in the treatment.
23770850	Acute Promyelocytic Leukemia with PML-RARA	PSMB8	Promote immunity; essential for immunotherapy	It has been established that impairment of the immunoproteasome subunits, that is, PSMB8, PSMB9 and PSMB10 (PSMBs), is critical for malignant cells to escape immune recognition. We report here the regulatory mechanism of the repression of PU.1-dependent activation of PSMBs by PML/RARα in the pathogenesis of acute promyelocytic leukemia (APL) and the unidentified function of all-trans retinoic acid (ATRA) as an immunomodulator in the treatment of APL. Collectively, our data demonstrate that PML/RARα suppresses PU.1-dependent activation of the immunosubunits, which may facilitate the escape of APL cells from immune surveillance in leukemia development, and ATRA treatment is able to reactivate their expression, which would promote more efficient T-cell-mediated recognition in the treatment.
23770850	Acute Promyelocytic Leukemia with PML-RARA	PSMB9	Promote immunity; essential for immunotherapy	It has been established that impairment of the immunoproteasome subunits, that is, PSMB8, PSMB9 and PSMB10 (PSMBs), is critical for malignant cells to escape immune recognition. We report here the regulatory mechanism of the repression of PU.1-dependent activation of PSMBs by PML/RARα in the pathogenesis of acute promyelocytic leukemia (APL) and the unidentified function of all-trans retinoic acid (ATRA) as an immunomodulator in the treatment of APL. Collectively, our data demonstrate that PML/RARα suppresses PU.1-dependent activation of the immunosubunits, which may facilitate the escape of APL cells from immune surveillance in leukemia development, and ATRA treatment is able to reactivate their expression, which would promote more efficient T-cell-mediated recognition in the treatment.
23770850	Acute Promyelocytic Leukemia with PML-RARA	PSMB10	Promote immunity	It has been established that impairment of the immunoproteasome subunits, that is, PSMB8, PSMB9 and PSMB10 (PSMBs), is critical for malignant cells to escape immune recognition. We report here the regulatory mechanism of the repression of PU.1-dependent activation of PSMBs by PML/RARα in the pathogenesis of acute promyelocytic leukemia (APL) and the unidentified function of all-trans retinoic acid (ATRA) as an immunomodulator in the treatment of APL. Collectively, our data demonstrate that PML/RARα suppresses PU.1-dependent activation of the immunosubunits, which may facilitate the escape of APL cells from immune surveillance in leukemia development, and ATRA treatment is able to reactivate their expression, which would promote more efficient T-cell-mediated recognition in the treatment.
23770212	HER2 Positive Breast Carcinoma	ERBB2	Inhibit immunity	An antibody-cytokine fusion protein consisting of the immunostimulatory cytokine interleukin-2 (IL-2) genetically fused to an antibody specific for human HER2/neu [anti-HER2/neu IgG3-(IL-2)] was covalently attached to the PMLA backbone to target HER2/neu expressing tumors and ensure the delivery of IL-2 to the tumor microenvironment. The nanobioconjugate exhibited marked anti-tumor activity manifested by significantly longer animal survival and significantly increased anti-HER2/neu immune response in immunocompetent mice bearing D2F2/E2 murine mammary tumors that express human HER2/neu.
23770212	HER2 Positive Breast Carcinoma	IL2	Promote immunity (T cell function); essential for immunotherapy	An antibody-cytokine fusion protein consisting of the immunostimulatory cytokine interleukin-2 (IL-2) genetically fused to an antibody specific for human HER2/neu [anti-HER2/neu IgG3-(IL-2)] was covalently attached to the PMLA backbone to target HER2/neu expressing tumors and ensure the delivery of IL-2 to the tumor microenvironment. The nanobioconjugate exhibited marked anti-tumor activity manifested by significantly longer animal survival and significantly increased anti-HER2/neu immune response in immunocompetent mice bearing D2F2/E2 murine mammary tumors that express human HER2/neu.
23754772	Melanoma	TNFRSF9	Promote immunity (T cell function); essential for immunotherapy	To that end, T cells purified from healthy donors and from vaccinated-melanoma patients were transduced to express high levels of constitutive 4-1BB. In addition, these cells expanded and proliferated at a higher rate, expressed heightened levels of the antiapoptotic molecule Bcl(XL) and were also relatively insensitive to immunosuppression mediated by transforming growth factor-β, compared to control cells. We also show that 4-1BBL expression on the target cell is essential to 4-1BB-mediated functional improvement. Overall, we conclude that the modification of human T cells with 4-1BB yields enhanced antitumor function which may have important applications in therapies based on the genetic modification of patient lymphocytes.
23754772	Melanoma	TGFB1	Inhibit immunity (T cell function)	To that end, T cells purified from healthy donors and from vaccinated-melanoma patients were transduced to express high levels of constitutive 4-1BB. In addition, these cells expanded and proliferated at a higher rate, expressed heightened levels of the antiapoptotic molecule Bcl(XL) and were also relatively insensitive to immunosuppression mediated by transforming growth factor-β, compared to control cells. We also show that 4-1BBL expression on the target cell is essential to 4-1BB-mediated functional improvement. Overall, we conclude that the modification of human T cells with 4-1BB yields enhanced antitumor function which may have important applications in therapies based on the genetic modification of patient lymphocytes.
23754388	Glioblastoma	IL12A	Promote immunity (T cell function); essential for immunotherapy	Using this model, we tested a genetically engineered oncolytic herpes simplex virus that is armed with an immunomodulatory cytokine, interleukin 12 (G47-mIL12). G47Δ-mIL12 infects and replicates similarly to its unarmed oncolytic herpes simplex virus counterpart in mouse 005 GSCs in vitro, whereas in vivo, it significantly enhances survival in syngeneic mice bearing intracerebral 005 tumors. Mechanistically, G47-mIL12 targets not only GSCs but also increases IFN-γ release, inhibits angiogenesis, and reduces the number of regulatory T cells in the tumor.
23752227	B16 Malignant Melanoma	IDO1	Inhibit immunity (infiltration); Inhibit immunity (T cell function); resistant to immunotherapy	Here, we examine the inhibitory role of indoleamine 2,3-dioxygenase (IDO) on the antitumor efficacy of CTLA-4 blockade. To highlight the therapeutic relevance of these findings, we show that CTLA-4 blockade strongly synergizes with IDO inhibitors to mediate rejection of both IDO-expressing and nonexpressing poorly immunogenic tumors, emphasizing the importance of the inhibitory role of both tumor- and host-derived IDO. This effect was T cell dependent, leading to enhanced infiltration of tumor-specific effector T cells and a marked increase in the effector-to-regulatory T cell ratios in the tumors. Overall, these data demonstrate the immunosuppressive role of IDO in the context of immunotherapies targeting immune checkpoints and provide a strong incentive to clinically explore combination therapies using IDO inhibitors irrespective of IDO expression by the tumor cells.
23752227	B16 Malignant Melanoma	CTLA4	Immunotherapy target	Here, we examine the inhibitory role of indoleamine 2,3-dioxygenase (IDO) on the antitumor efficacy of CTLA-4 blockade. To highlight the therapeutic relevance of these findings, we show that CTLA-4 blockade strongly synergizes with IDO inhibitors to mediate rejection of both IDO-expressing and nonexpressing poorly immunogenic tumors, emphasizing the importance of the inhibitory role of both tumor- and host-derived IDO. This effect was T cell dependent, leading to enhanced infiltration of tumor-specific effector T cells and a marked increase in the effector-to-regulatory T cell ratios in the tumors. Overall, these data demonstrate the immunosuppressive role of IDO in the context of immunotherapies targeting immune checkpoints and provide a strong incentive to clinically explore combination therapies using IDO inhibitors irrespective of IDO expression by the tumor cells.
23737488	Malignant Glioma	ENTPD1	Inhibit immunity (T cell function)	We demonstrated that increased suppression of responder CD4(+) T-cell proliferation suppression was induced by CD4(+)CD39(+) T cells in the presence of CD73(+) glioma cells, which could be alleviated by the CD39 inhibitor ARL67156, the CD73 inhibitor APCP, or the adenosine receptor A2aR antagonist SCH58261. Our data indicate that glioma-derived CD73 contributes to local adenosine-mediated immunosuppression in synergy with CD39 from infiltrating CD4(+)CD39(+) T lymphocytes, which could become a potential therapeutic target for treatment of malignant glioma and other immunosuppressive diseases.
23737488	Malignant Glioma	NT5E	Inhibit immunity (T cell function)	We demonstrated that increased suppression of responder CD4(+) T-cell proliferation suppression was induced by CD4(+)CD39(+) T cells in the presence of CD73(+) glioma cells, which could be alleviated by the CD39 inhibitor ARL67156, the CD73 inhibitor APCP, or the adenosine receptor A2aR antagonist SCH58261. Our data indicate that glioma-derived CD73 contributes to local adenosine-mediated immunosuppression in synergy with CD39 from infiltrating CD4(+)CD39(+) T lymphocytes, which could become a potential therapeutic target for treatment of malignant glioma and other immunosuppressive diseases.
23737434	Breast Carcinoma	KLF4	Inhibit immunity (T cell function)	Finally, we found that CXCL5/CXCR2 axis facilitated MDSC migration and that anti-GM-CSF antibodies neutralized CXCL5-induced accumulation of MDSCs. Taken together, our data suggest that KLF4 modulates maintenance of MDSCs in bone marrow by inducing GM-CSF production via CXCL5 and regulates recruitment of MDSCs into the primary tumors through the CXCL5/CXCR2 axis, both of which contribute to KLF4-mediated mammary tumor development.
23737434	Breast Carcinoma	CXCL5	Inhibit immunity (T cell function)	Finally, we found that CXCL5/CXCR2 axis facilitated MDSC migration and that anti-GM-CSF antibodies neutralized CXCL5-induced accumulation of MDSCs. Taken together, our data suggest that KLF4 modulates maintenance of MDSCs in bone marrow by inducing GM-CSF production via CXCL5 and regulates recruitment of MDSCs into the primary tumors through the CXCL5/CXCR2 axis, both of which contribute to KLF4-mediated mammary tumor development.
23737434	Breast Carcinoma	CXCR2	Inhibit immunity (T cell function)	Finally, we found that CXCL5/CXCR2 axis facilitated MDSC migration and that anti-GM-CSF antibodies neutralized CXCL5-induced accumulation of MDSCs. Taken together, our data suggest that KLF4 modulates maintenance of MDSCs in bone marrow by inducing GM-CSF production via CXCL5 and regulates recruitment of MDSCs into the primary tumors through the CXCL5/CXCR2 axis, both of which contribute to KLF4-mediated mammary tumor development.
23737434	Breast Carcinoma	CSF2	Inhibit immunity	Finally, we found that CXCL5/CXCR2 axis facilitated MDSC migration and that anti-GM-CSF antibodies neutralized CXCL5-induced accumulation of MDSCs. Taken together, our data suggest that KLF4 modulates maintenance of MDSCs in bone marrow by inducing GM-CSF production via CXCL5 and regulates recruitment of MDSCs into the primary tumors through the CXCL5/CXCR2 axis, both of which contribute to KLF4-mediated mammary tumor development.
23733874	Adult T-Cell Leukemia/Lymphoma	CNTN2	Promote immunity (infiltration); essential for immunotherapy	In these mice established with cells from a chronic-type patient, treatment by i.p. injection of autologous Tax-CTL resulted in greater infiltration of CD8-positive T cells into each ATL lesion. Thus, although the therapeutic effects were different for different ATL patients, to the best of our knowledge, this is the first report that adoptive therapy with Ag-specific CTL expanded from a cancer patient confers antitumor effects, leading to significant survival benefit for autologous primary cancer cell-bearing mice in vivo.
23732988	Lung Carcinoma	FAP	Promote immunity (T cell function); essential for immunotherapy	Fibroblast activation protein-α (FAP), a type 2 dipeptidyl peptidase, is expressed on CAFs in a majority of solid tumors making it an attractive immunotherapeutic target. In an established A549 lung cancer model, adoptive transfer of FAP-specific T cells significantly reduced FAP-positive stromal cells, with a concomitant decrease in tumor growth. Combining these FAP-specific T cells with T cells that targeted the EphA2 antigen on the A549 cancer cells themselves significantly enhanced overall antitumor activity and conferred a survival advantage compared to either alone. Our study underscores the value of co-targeting both CAFs and cancer cells to increase the benefits of T-cell immunotherapy for solid tumors.
23732988	Lung Carcinoma	EPHA2	Promote immunity (T cell function); essential for immunotherapy	Fibroblast activation protein-α (FAP), a type 2 dipeptidyl peptidase, is expressed on CAFs in a majority of solid tumors making it an attractive immunotherapeutic target. In an established A549 lung cancer model, adoptive transfer of FAP-specific T cells significantly reduced FAP-positive stromal cells, with a concomitant decrease in tumor growth. Combining these FAP-specific T cells with T cells that targeted the EphA2 antigen on the A549 cancer cells themselves significantly enhanced overall antitumor activity and conferred a survival advantage compared to either alone. Our study underscores the value of co-targeting both CAFs and cancer cells to increase the benefits of T-cell immunotherapy for solid tumors.
23728179	Central Nervous System Lymphoma	CTLA4	Inhibit immunity (T cell function); immunotherapy target	In tumor-bearing mice, we found that Tregs within the tumor preferentially express the cell surface markers CTLA-4 and OX40. We show that intratumoral coinjection of anti-CTLA-4 and anti-OX40 together with CpG depleted tumor-infiltrating Tregs. This in situ immunomodulation, which was performed with low doses of antibodies in a single tumor, generated a systemic antitumor immune response that eradicated disseminated disease in mice. Further, this treatment modality was effective against established CNS lymphoma with leptomeningeal metastases, sites that are usually considered to be tumor cell sanctuaries in the context of conventional systemic therapy.
23728179	Central Nervous System Lymphoma	TNFRSF4	Inhibit immunity (T cell function); immunotherapy target	In tumor-bearing mice, we found that Tregs within the tumor preferentially express the cell surface markers CTLA-4 and OX40. We show that intratumoral coinjection of anti-CTLA-4 and anti-OX40 together with CpG depleted tumor-infiltrating Tregs. This in situ immunomodulation, which was performed with low doses of antibodies in a single tumor, generated a systemic antitumor immune response that eradicated disseminated disease in mice. Further, this treatment modality was effective against established CNS lymphoma with leptomeningeal metastases, sites that are usually considered to be tumor cell sanctuaries in the context of conventional systemic therapy.
23722540	Ovarian Carcinoma	VTCN1	Inhibit immunity (T cell function); immunotherapy target	We identified anti-B7-H4 scFv that reversed in vitro inhibition of CD3-stimulated T cells by B7-H4 protein. Notably, these reagents rescued tumor antigen-specific T-cell activation, which was otherwise inhibited by coculture with antigen-loaded B7-H4+ APCs, B7-H4+ tumor cells, or B7-H4- tumor cells mixed with B7-H4+ TAMs; peritoneal administration of anti-B7-H4 scFv delayed the growth of established tumors.
23714729	Malignant Head and Neck Neoplasm	KIF20A	Promote immunity (T cell function); essential for immunotherapy	We identified promiscuous KIF20A-LPs bearing naturally processed epitopes recognized by CD4(+) T cells and CTLs. KIF20A-specific CTLs were induced by vaccination with a KIF20A-LP in vivo. KIF20A expression was detected in 55% of HNMT by immunohistochemistry, and significant frequencies of KIF20A-specific TH1 cell responses were detected after short-term in vitro stimulation of PBMCs with KIF20A-LPs in 50% of HNMT patients, but not in healthy donors. Furthermore, these responses were associated with KIF20A expression in HNMT tissues.
23692853	Lymphoma	TNFRSF14	Inhibit immunity (T cell function); immunotherapy target	BTLA was strongly expressed at the surface of resting Vγ9Vδ2 T cells and inversely correlated with T-cell differentiation. BTLA-HVEM blockade by monoclonal antibodies resulted in the enhancement of Vγ9Vδ2 T-cell receptor-mediated signaling, whereas BTLA-HVEM interaction led to a decrease in phosphoantigen-mediated proliferation by inducing a partial S-phase arrest. These data suggest that HVEM interaction with BTLA may play a role in lymphomagenesis by interfering with Vγ9Vδ2 T-cell proliferation.
23692853	Lymphoma	BTLA	Inhibit immunity (T cell function); immunotherapy target	BTLA was strongly expressed at the surface of resting Vγ9Vδ2 T cells and inversely correlated with T-cell differentiation. BTLA-HVEM blockade by monoclonal antibodies resulted in the enhancement of Vγ9Vδ2 T-cell receptor-mediated signaling, whereas BTLA-HVEM interaction led to a decrease in phosphoantigen-mediated proliferation by inducing a partial S-phase arrest. These data suggest that HVEM interaction with BTLA may play a role in lymphomagenesis by interfering with Vγ9Vδ2 T-cell proliferation.
23690482	Acute Myeloid Leukemia	FCGR3A	Promote immunity (NK cell function); essential for immunotherapy	We determined whether a novel bispecific killer cell engager (BiKE) signaling through CD16 and targeting CD33 could activate NK cells at high potency against acute myelogenous leukemia (AML) targets. Combination treatment with CD16 × 33 BiKE and ADAM17 inhibitor resulted in inhibition of CD16 shedding in NK cells, and enhanced NK cell activation.
23690482	Acute Myeloid Leukemia	CD33	Inhibit immunity (NK cell function); immunotherapy target	We determined whether a novel bispecific killer cell engager (BiKE) signaling through CD16 and targeting CD33 could activate NK cells at high potency against acute myelogenous leukemia (AML) targets. Combination treatment with CD16 × 33 BiKE and ADAM17 inhibitor resulted in inhibition of CD16 shedding in NK cells, and enhanced NK cell activation.
23690482	Acute Myeloid Leukemia	ADAM17	Inhibit immunity (NK cell function)	We determined whether a novel bispecific killer cell engager (BiKE) signaling through CD16 and targeting CD33 could activate NK cells at high potency against acute myelogenous leukemia (AML) targets. Combination treatment with CD16 × 33 BiKE and ADAM17 inhibitor resulted in inhibition of CD16 shedding in NK cells, and enhanced NK cell activation.
23690472	Pleural Malignant Mesothelioma	PDPN	Immunotherapy target	Podoplanin (Aggrus), which is a type I transmembrane sialomucin-like glycoprotein, is highly expressed in malignant pleural mesothelioma (MPM). In this study, we examined the antitumor effector functions of NZ-1 and NZ-8, a novel rat-human chimeric Ab generated from NZ-1 including Ab-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity against MPM in vitro and in vivo. These results strongly suggest that targeting therapy to podoplanin with therapeutic Abs (i.e., NZ-8) derived from NZ-1 might be useful as a novel immunotherapy against MPM.
23686489	Melanoma	CCL2	Promote immunity (T cell function)	We show that the inflammatory chemokine CCL2 and its receptor CCR2 are necessary for the accumulation of γδ TILs in B16 lesions, where they produce IFN-γ and display potent cytotoxic functions. Strikingly, the lack of γδ TILs in TCRδ-deficient but also in CCR2-deficient mice enhanced tumor growth in vivo, thus revealing an unanticipated protective role for CCR2/CCL2 through the recruitment of γδ T cells.
23686489	B16 Malignant Melanoma	CCR2	Promote immunity (T cell function)	We show that the inflammatory chemokine CCL2 and its receptor CCR2 are necessary for the accumulation of γδ TILs in B16 lesions, where they produce IFN-γ and display potent cytotoxic functions. Strikingly, the lack of γδ TILs in TCRδ-deficient but also in CCR2-deficient mice enhanced tumor growth in vivo, thus revealing an unanticipated protective role for CCR2/CCL2 through the recruitment of γδ T cells.
23686488	Follicular Lymphoma	CCR4	Inhibit immunity	Tumor supernatants induced preferential migration of Tregs and IL-4-producing T cells rather than IFN-γ-producing T cells, and Abs to CCR4 significantly abrogated the migration of Tregs.
23686488	Follicular Lymphoma	CD40LG	Inhibit immunity (T cell function)	We found that IL-4 and CD40L are expressed by intratumoral TFH and induce production of CCL17 and CCL22 by FL tumor cells. Tumor supernatants induced preferential migration of Tregs and IL-4-producing T cells rather than IFN-γ-producing T cells, and Abs to CCR4 significantly abrogated the migration of Tregs. Our results suggest that through two distinct mechanisms, intratumoral TFH induce production of CCL17 and CCL22 by FL tumor cells and facilitate active recruitment of Tregs and IL-4-producing T cells, which, in turn, may stimulate more chemokine production in a feed-forward cycle.
23686488	Follicular Lymphoma	IL4	Inhibit immunity (T cell function)	We found that IL-4 and CD40L are expressed by intratumoral TFH and induce production of CCL17 and CCL22 by FL tumor cells. Tumor supernatants induced preferential migration of Tregs and IL-4-producing T cells rather than IFN-γ-producing T cells, and Abs to CCR4 significantly abrogated the migration of Tregs. Our results suggest that through two distinct mechanisms, intratumoral TFH induce production of CCL17 and CCL22 by FL tumor cells and facilitate active recruitment of Tregs and IL-4-producing T cells, which, in turn, may stimulate more chemokine production in a feed-forward cycle.
23686488	Follicular Lymphoma	CCL17	Inhibit immunity (T cell function)	We found that IL-4 and CD40L are expressed by intratumoral TFH and induce production of CCL17 and CCL22 by FL tumor cells. Tumor supernatants induced preferential migration of Tregs and IL-4-producing T cells rather than IFN-γ-producing T cells, and Abs to CCR4 significantly abrogated the migration of Tregs. Our results suggest that through two distinct mechanisms, intratumoral TFH induce production of CCL17 and CCL22 by FL tumor cells and facilitate active recruitment of Tregs and IL-4-producing T cells, which, in turn, may stimulate more chemokine production in a feed-forward cycle.
23686488	Follicular Lymphoma	CCL22	Inhibit immunity (T cell function)	We found that IL-4 and CD40L are expressed by intratumoral TFH and induce production of CCL17 and CCL22 by FL tumor cells. Tumor supernatants induced preferential migration of Tregs and IL-4-producing T cells rather than IFN-γ-producing T cells, and Abs to CCR4 significantly abrogated the migration of Tregs. Our results suggest that through two distinct mechanisms, intratumoral TFH induce production of CCL17 and CCL22 by FL tumor cells and facilitate active recruitment of Tregs and IL-4-producing T cells, which, in turn, may stimulate more chemokine production in a feed-forward cycle.
23677467	Melanoma; Lung Carcinoma	IL2	Promote immunity (T cell function)	The IL-2 mutant induces in vitro proliferation of CD8(+)CD44(hi) and NK1.1 cells as efficiently as does wtIL-2, but it shows a reduced capacity to induce proliferation of CD4(+)Foxp3(+) regulatory T cells. The IL-2 mutant shows a higher antimetastatic effect than does wtIL-2 in several transplantable tumor models: the experimental metastasis model of MB16F0 melanoma and the experimental and spontaneous metastasis models for the mouse pulmonary carcinoma 3LL-D1222.
23674207	Prostate Carcinoma	TACSTD2	Inhibit immunity	TF12 is a trivalent bispecific antibody that consists of two anti-TROP-2 Fab fragments and one anti-histamine-succinyl-glycine (HSG) Fab fragment. TROP-2-expressing PC can be pretargeted efficiently with TF12, with very rapid uptake of the radiolabeled hapten-peptide, IMP288, sensitive immuno-PET, and effective therapy.
23665041	Hepatocellular Carcinoma	CD44	Inhibit immunity (T cell function)	Such CD14(+)HLA-DR(-/low) monocyte-derived MDSCs suppressed T-cell proliferation in an arginase-1 dependent fashion. HSC-induced development of CD14(+)HLA-DR(-/low) monocyte-derived MDSCs was not mediated by soluble factors, but required physical interaction and was abrogated by blocking CD44. Thus, our data suggest that local generation of MDSCs by liver-resident HSCs may contribute to immune suppression during inflammation and cancer in the liver.
23665041	Hepatocellular Carcinoma	ARG1	Inhibit immunity (T cell function)	Such CD14(+)HLA-DR(-/low) monocyte-derived MDSCs suppressed T-cell proliferation in an arginase-1 dependent fashion. HSC-induced development of CD14(+)HLA-DR(-/low) monocyte-derived MDSCs was not mediated by soluble factors, but required physical interaction and was abrogated by blocking CD44. Thus, our data suggest that local generation of MDSCs by liver-resident HSCs may contribute to immune suppression during inflammation and cancer in the liver.
23649004	Neuroblastoma	TNFRSF9	Inhibit immunity (T and NK cell function); immunotherapy target	In the Neuro2a model, treatment of established tumor with anti-4-1BB, anti-CD40, or anti-CTLA-4 mAb results in tumor regression and long-term survival in 40% to 60% of mice. This is dependent on natural killer (NK) and CD8(+) T cells and is associated with tumor CD8(+) lymphocyte infiltrate. These data suggest that the combination of antigen and costimulatory mAb may provide effective immunotherapy against neuroblastoma and may be of particular use in the minimal residual disease setting.
23649004	Neuroblastoma	CD40	Promote immunity	In the Neuro2a model, treatment of established tumor with anti-4-1BB, anti-CD40, or anti-CTLA-4 mAb results in tumor regression and long-term survival in 40% to 60% of mice. This is dependent on natural killer (NK) and CD8(+) T cells and is associated with tumor CD8(+) lymphocyte infiltrate. These data suggest that the combination of antigen and costimulatory mAb may provide effective immunotherapy against neuroblastoma and may be of particular use in the minimal residual disease setting.
23649004	Neuroblastoma	CTLA4	Inhibit immunity (T and NK cell function); immunotherapy target	In the Neuro2a model, treatment of established tumor with anti-4-1BB, anti-CD40, or anti-CTLA-4 mAb results in tumor regression and long-term survival in 40% to 60% of mice. This is dependent on natural killer (NK) and CD8(+) T cells and is associated with tumor CD8(+) lymphocyte infiltrate. These data suggest that the combination of antigen and costimulatory mAb may provide effective immunotherapy against neuroblastoma and may be of particular use in the minimal residual disease setting.
23649001	Breast Carcinoma	TEK	Inhibit immunity	TEMs from breast tumors are able to suppress tumor-specific immune responses. Importantly, proangiogenic and suppressive functions of TEMs are similarly driven by TIE-2 and VEGFR kinase activity.
23649001	Breast Carcinoma	KDR	Inhibit immunity	TEMs from breast tumors are able to suppress tumor-specific immune responses. Importantly, proangiogenic and suppressive functions of TEMs are similarly driven by TIE-2 and VEGFR kinase activity.
23641014	Adult T-Cell Leukemia/Lymphoma	TERT	Promote immunity (T cell function); essential for immunotherapy	Here we demonstrated for the first time that human telomerase reverse transcriptase (hTERT) is a promising therapeutic target for ATL, and we developed a novel redirected T-cell-based immunotherapy targeting hTERT. hTERT messenger RNA was produced abundantly in ATL tumor cells but not in steady-state normal cells.
23636788	Lung Carcinoma; Prostate Carcinoma	IFNB1	Promote immunity	We describe here a novel effect of dsRNA analogs on cancer cells: besides their potential to induce cancer cell apoptosis through an IFN-β autocrine loop, dsRNA-elicited IFN-β production improves dendritic cell (DC) functionality. Human A549 lung and DU145 prostate carcinoma cells significantly responded to poly I:C stimulation, producing IFN-β at levels that were capable of activating STAT1 and enhancing CXCL10, CD40, and CD86 expression on human monocyte-derived DCs.
23635779	Lung Carcinoma; Lung Adenocarcinoma	NFKB1	Promote immunity (infiltration)	Using a global RNA expression microarray, we demonstrated that NF-κB enhanced expression of several T cell chemokines, including Ccl2, and decreased CCL2 expression was associated with enhanced tumor growth in a mouse lung cancer model. In patient tumor samples, overall lung tumor NF-κB activity was strongly associated with T cell infiltration but not with cancer cell proliferation.
23635487	Breast Carcinoma	BECN1	Inhibit immunity (T cell function)	Silencing of BECN1 in target cells that have gone through the EMT restored CTL susceptibility to CTL-induced lysis.
23633494	Melanoma	KDR	Promote immunity (infiltration); Promote immunity (T cell function); essential for immunotherapy	Simultaneous transfer of genetically engineered syngeneic T cells expressing a chimeric antigen receptor targeting the VEGF receptor-2 (VEGFR2; KDR) that is overexpressed on tumor vasculature and T-cells specific for the tumor antigens gp100 (PMEL), TRP-1 (TYRP1), or TRP-2 (DCT) synergistically eradicated established B16 melanoma tumors in mice and dramatically increased the tumor-free survival of mice compared with treatment with either cell type alone or T cells coexpressing these two targeting molecules. The synergistic antitumor response was accompanied by a significant increase in the infiltration and expansion and/or persistence of the adoptively transferred tumor antigen-specific T cells in the tumor microenvironment and thus enhanced their antitumor potency.
23633494	B16 Malignant Melanoma	PMEL	Promote immunity (infiltration); Promote immunity (T cell function); essential for immunotherapy	Simultaneous transfer of genetically engineered syngeneic T cells expressing a chimeric antigen receptor targeting the VEGF receptor-2 (VEGFR2; KDR) that is overexpressed on tumor vasculature and T-cells specific for the tumor antigens gp100 (PMEL), TRP-1 (TYRP1), or TRP-2 (DCT) synergistically eradicated established B16 melanoma tumors in mice and dramatically increased the tumor-free survival of mice compared with treatment with either cell type alone or T cells coexpressing these two targeting molecules. The synergistic antitumor response was accompanied by a significant increase in the infiltration and expansion and/or persistence of the adoptively transferred tumor antigen-specific T cells in the tumor microenvironment and thus enhanced their antitumor potency.
23633494	B16 Malignant Melanoma	TYRP1	Promote immunity (infiltration); Promote immunity (T cell function); essential for immunotherapy	Simultaneous transfer of genetically engineered syngeneic T cells expressing a chimeric antigen receptor targeting the VEGF receptor-2 (VEGFR2; KDR) that is overexpressed on tumor vasculature and T-cells specific for the tumor antigens gp100 (PMEL), TRP-1 (TYRP1), or TRP-2 (DCT) synergistically eradicated established B16 melanoma tumors in mice and dramatically increased the tumor-free survival of mice compared with treatment with either cell type alone or T cells coexpressing these two targeting molecules. The synergistic antitumor response was accompanied by a significant increase in the infiltration and expansion and/or persistence of the adoptively transferred tumor antigen-specific T cells in the tumor microenvironment and thus enhanced their antitumor potency.
23633494	B16 Malignant Melanoma	DCT	Promote immunity	Simultaneous transfer of genetically engineered syngeneic T cells expressing a chimeric antigen receptor targeting the VEGF receptor-2 (VEGFR2; KDR) that is overexpressed on tumor vasculature and T-cells specific for the tumor antigens gp100 (PMEL), TRP-1 (TYRP1), or TRP-2 (DCT) synergistically eradicated established B16 melanoma tumors in mice and dramatically increased the tumor-free survival of mice compared with treatment with either cell type alone or T cells coexpressing these two targeting molecules. The synergistic antitumor response was accompanied by a significant increase in the infiltration and expansion and/or persistence of the adoptively transferred tumor antigen-specific T cells in the tumor microenvironment and thus enhanced their antitumor potency.
23633486	Melanoma	PTGS2	Inhibit immunity (T cell function)	Further, this induction is largely dependent on production of cyclooxygenase-2 (COX-2) because its inhibition in these MDSC-like cells limits their ability to suppress T-cell function. We confirmed our findings with CD14(+) cells isolated from patients with advanced stage melanoma, which inhibited autologous T cells in a manner relying up prostaglandin E2 (PGE2), STAT-3, and superoxide.
23633486	Melanoma	STAT3	Inhibit immunity (T cell function)	Further, this induction is largely dependent on production of cyclooxygenase-2 (COX-2) because its inhibition in these MDSC-like cells limits their ability to suppress T-cell function. We confirmed our findings with CD14(+) cells isolated from patients with advanced stage melanoma, which inhibited autologous T cells in a manner relying up prostaglandin E2 (PGE2), STAT-3, and superoxide.
23630276	Ovarian Carcinoma	RNASET2	Promote immunity (infiltration)	Indeed, hyperexpression of RNASET2 is able to control tumorigenesis by recruiting macrophages (mostly of the anticancer M1 subtype) at the tumor sites.
23628805	Ovarian Carcinoma; Lymphoma	KLRK1	Promote immunity (NK cell function)	Mice bearing the ID8 ovarian or RMA lymphoma tumors were treated with T cells transduced with a NKG2D-based CAR (chNKG2D). NKG2D CAR T-cell therapy protected mice from heterogeneous RMA tumors.
22466705	Leukemia	WT1	Promote immunity (T cell function); essential for immunotherapy	After lentiviral transfer of a TCR specific for the Wilms tumor 1 (WT1) antigen, these TCR-edited cells expressed the new TCR at high levels, were easily expanded to near purity and were superior at specific antigen recognition compared to donor-matched, unedited TCR-transferred cells.
22466343	Thyroid Gland Papillary Carcinoma	PDCD1	Inhibit immunity (T cell function)	PD-1(+) T cells were present at high frequency in TILN and markedly enriched in TILN that showed evidence of extranodal invasion. In TILN, Treg frequency correlated with PD-1(+) T cell frequencies. Although PD-1(+) T cells produced interferon-γ, they failed to fully down-regulate CD27 and were not actively proliferating.
22466331	Melanoma	CEACAM1	Inhibit immunity; immunotherapy target	We have previously identified CEACAM1 as a tumor escape mechanism from cytotoxic lymphocytes. Here, we present substantial evidence in vitro and in vivo that blocking of CEACAM1 function with a novel monoclonal antibody (MRG1) is a promising strategy for cancer immunotherapy.
22451919	Leiomyosarcoma	CD47	Inhibit immunity (T cell function); immunotherapy target	Antibodies against CD47, which block tumor cell CD47 interactions with macrophage signal regulatory protein-α, have been shown to decrease tumor size in hematological and epithelial tumor models by interfering with the protection from phagocytosis by macrophages that intact CD47 bestows upon tumor cells.
22451913	Breast Carcinoma	CD47	Inhibit immunity (T cell function); immunotherapy target	In vitro, blockade of CD47 signaling using targeted monoclonal antibodies enabled macrophage phagocytosis of tumor cells that were otherwise protected.? These data, taken together with similar findings with other human neoplasms, show that CD47 is a commonly expressed molecule on all cancers, its function to block phagocytosis is known, and blockade of its function leads to tumor cell phagocytosis and elimination. CD47 is therefore a validated target for cancer therapies.
22451343	Fibrosarcoma	FHIT	Promote immunity	In contrast, silencing of the Fhit gene produced the transcriptional down-regulation of APM components and MHC-I heavy chains and decreased MHC-I surface expression. These data indicate that defects in Fhit expression may promote MHC-I down-regulation in cancer cells and allow escape from immunosurveillance(#).
22420471	Basal-Like Breast Carcinoma	ESR1	Inhibit immunity (infiltration)	In the whole cohort, the presence of intratumoral tumor-infiltrating lymphocytes was significantly correlated with young age, high grade, estrogen receptor negativity, human epidermal growth factor receptor-2 positivity and core basal intrinsic subtype, and was associated with superior breast cancer specific survival.
22419581	Myeloma	PRF1	Promote immunity (NK cell function)	Expanded natural killer cells killed both allogeneic and autologous primary myeloma cells avidly via a perforin-mediated mechanism in which the activating receptor NKG2D, natural cytotoxicity receptors, and DNAX-accessory molecule-1 played a central role. The transferred, expanded natural killer cells proliferated in vivo in an interleukin-2 dose-dependent fashion, persisted up to 4 weeks, were readily detectable in the human bone, inhibited myeloma growth and protected bone from myeloma-induced osteolysis.
22419581	Myeloma	KLRK1	Promote immunity (NK cell function)	Expanded natural killer cells killed both allogeneic and autologous primary myeloma cells avidly via a perforin-mediated mechanism in which the activating receptor NKG2D, natural cytotoxicity receptors, and DNAX-accessory molecule-1 played a central role. The transferred, expanded natural killer cells proliferated in vivo in an interleukin-2 dose-dependent fashion, persisted up to 4 weeks, were readily detectable in the human bone, inhibited myeloma growth and protected bone from myeloma-induced osteolysis.
22419581	Myeloma	CD226	Promote immunity (NK cell function)	Expanded natural killer cells killed both allogeneic and autologous primary myeloma cells avidly via a perforin-mediated mechanism in which the activating receptor NKG2D, natural cytotoxicity receptors, and DNAX-accessory molecule-1 played a central role. The transferred, expanded natural killer cells proliferated in vivo in an interleukin-2 dose-dependent fashion, persisted up to 4 weeks, were readily detectable in the human bone, inhibited myeloma growth and protected bone from myeloma-induced osteolysis.
22419581	Myeloma	IL2	Promote immunity (NK cell function)	Expanded natural killer cells killed both allogeneic and autologous primary myeloma cells avidly via a perforin-mediated mechanism in which the activating receptor NKG2D, natural cytotoxicity receptors, and DNAX-accessory molecule-1 played a central role. The transferred, expanded natural killer cells proliferated in vivo in an interleukin-2 dose-dependent fashion, persisted up to 4 weeks, were readily detectable in the human bone, inhibited myeloma growth and protected bone from myeloma-induced osteolysis.
22419388	Triple-Negative Breast Carcinoma	TNFRSF10B	Immunotherapy target	Resulting immune serum or purified immune IgG induced apoptosis in triple-negative breast cancer (TNBC) cells, which were also TRAIL sensitive. Apoptotic cell death induced by anti-DR5 antibody was shown by the cleavage of PARP and caspase-3. In vivo, hDR5 reactive immune serum prevented growth of SUM159 TNBC cells in severe combined immune-deficient mice. These findings support DR5 as a promising vaccine target for controlling TNBC and other DR5-positive cancers.
22407828	Glioma	IL13RA2	Promote immunity (T cell function); essential for immunotherapy	We observed that although glioma IL13Rα2 expression varies between patients, for IL13Rα2(pos) cases this antigen was detected on both GSCs and more differentiated tumor cell populations. IL13-zetakine(+) CTL were capable of efficient recognition and killing of both IL13Rα2(pos) GSCs and IL13Rα2(pos) differentiated cells in vitro, as well as eliminating glioma-initiating activity in an orthotopic mouse tumor model.
22397502	Breast Carcinoma	LY75	Inhibit immunity (T cell function); immunotherapy target	We demonstrate that DEC-HER2 fusion mAb, but not Ctrl Ig-HER2, elicits strong, broad and multifunctional CD4+ T cell immunity, CD8+ T cell responses, and humoral immunity specific for HER2 antigen.
22397502	Breast Carcinoma	ERBB2	Inhibit immunity (T cell function); immunotherapy target	We demonstrate that DEC-HER2 fusion mAb, but not Ctrl Ig-HER2, elicits strong, broad and multifunctional CD4+ T cell immunity, CD8+ T cell responses, and humoral immunity specific for HER2 antigen.
22396543	Hepatocellular Carcinoma	HSPD1	Promote immunity (NK cell function)	ELISA results showed that the production of HSP60, HSP70, and HSP90 was up-regulated in both cell lines in a stress-specific manner. Acting as a decoy, the HSP-bearing exosomes efficiently stimulated NK cell cytotoxicity and granzyme B production, up-regulated the expression of inhibitory receptor CD94, and down-regulated the expression of activating receptors CD69, NKG2D, and NKp44.
22396543	Hepatocellular Carcinoma	HSPA4	Promote immunity (NK cell function)	ELISA results showed that the production of HSP60, HSP70, and HSP90 was up-regulated in both cell lines in a stress-specific manner. Acting as a decoy, the HSP-bearing exosomes efficiently stimulated NK cell cytotoxicity and granzyme B production, up-regulated the expression of inhibitory receptor CD94, and down-regulated the expression of activating receptors CD69, NKG2D, and NKp44.
22396543	Hepatocellular Carcinoma	HSP90AA1	Promote immunity (NK cell function)	ELISA results showed that the production of HSP60, HSP70, and HSP90 was up-regulated in both cell lines in a stress-specific manner. Acting as a decoy, the HSP-bearing exosomes efficiently stimulated NK cell cytotoxicity and granzyme B production, up-regulated the expression of inhibitory receptor CD94, and down-regulated the expression of activating receptors CD69, NKG2D, and NKp44.
22396496	Fibrosarcoma; Prostate Carcinoma; Metastatic Malignant Neoplasm in the Lung	NT5E	Inhibit immunity (T and NK cell function); immunotherapy target	CD73 deficiency suppressed the development of 3-methylcholanthrene (MCA)-induced fibrosarcomas through a mechanism relying upon IFN-γ, natural killer (NK) cells, and CD8(+) T cells. Importantly, treatment with an anti-CD73 monoclonal antibody effectively suppressed growth of established MCA-induced tumors or TRAMP-C1 prostate tumors and inhibited the development of TRAMP-C1 lung metastases.
22392913	Melanoma; Breast Carcinoma	CD80	Promote immunity (T cell function); essential for immunotherapy	Laser illumination also slightly but significantly enhanced the expression of costimulatory molecule CD80 and MHC I on inoculated DCs. As a result, more vigorous expansion of tumor-specific IFN-γ(+)CD8(+) T lymphocytes and enhanced CTL activity against 4T1 but not irrelevant tumor cells were obtained in the laser-treated group over the control group.
22392913	Melanoma; Breast Carcinoma	HLA-A	Promote immunity (T cell function); essential for immunotherapy	Laser illumination also slightly but significantly enhanced the expression of costimulatory molecule CD80 and MHC I on inoculated DCs. As a result, more vigorous expansion of tumor-specific IFN-γ(+)CD8(+) T lymphocytes and enhanced CTL activity against 4T1 but not irrelevant tumor cells were obtained in the laser-treated group over the control group.
22374984	Fibrosarcoma; Pancreatic carcinoma	HRG	Promote immunity (infiltration)	Compared with wild-type mice, fibrosarcomas in hrg(-/-) mice were more hypoxic, necrotic, and less perfused, indicating enhanced vessel abnormalization. HRG deficiency was associated with a suppressed antitumor immune response, with both increased infiltration of M2 marker-expressing macrophages and decreased infiltration of dendritic cells and cytotoxic T cells.
22374980	Prostate Carcinoma	IL2	Inhibit immunity (T cell function)	In addition, Treg expansion in Pten(-/-) mice was prevented by in vivo interleukin (IL)-2 blockade suggesting that increased IL-2 generated by castration and immunization promotes Treg expansion.
22364281	Acute Lymphoblastic Leukemia; Lymphoma	PIK3CD	Inhibit immunity (T cell function); immunotherapy target	Genetic and pharmacological experiments have shown that PI3K activation regulates many steps in the development, activation and differentiation of both B- and T-cells. An exciting discovery is that a selective inhibitor of the p110δ catalytic isoform of PI3K, CAL-101, achieves impressive clinical efficacy in certain B-cell malignancies. A model is emerging in which p110δ inhibition disrupts signals from the lymphoid microenvironment, leading to release of leukaemia and lymphoma cells from their protective niche.
22360982	B16 Malignant Melanoma	IL12A	Essential for immunotherapy	Adoptive transfer of tumor-specific CD8(+) T cells primed with IL-12 was significantly more effective in reducing tumor burden in mice preconditioned with cyclophosphamide compared with transfer of T cells primed without IL-12. This enhanced antitumor response was associated with increased frequencies of infused T cells in the periphery and tumor as well as elevated expression of effector molecules including granzyme B and interferon-γ (IFNγ).
22354003	B-cell Lymphoma; Chronic Lymphocytic Leukemia	MS4A1	Promote immunity	Here, we reveal that the induction of PCD by these mAbs, including the type II anti-CD20 mAb GA101 (obinutuzumab), directly correlates with their ability to produce reactive oxygen species (ROS) in human B-lymphoma cell lines and primary B-cell chronic lymphocytic leukemia cells. Instead, ROS generation was mediated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase.
22333315	Breast Carcinoma	PTGES2	Inhibit immunity (T and NK cell function); immunotherapy target	In murine breast cancer models, the two interferon-gamma (IFN-γ) inducible chemokines and CXC-chemokine receptor 3 (CXCR3) receptor ligands, monokine induced by γ-interferon (CXCL9) and interferon-γ-inducible protein-10 (CXCL10) impair tumor growth and metastasis formation through recruitment of natural killer (NK) cells and tumor-suppressive T lymphocytes. PGE2 impairs IFN-γ mediated CXCL9 and CXCL10 release from MCF-7 and MDA-MB 231 cells, and inhibition of endogenous cyclooxygenases by indomethacin or ASA correspondingly increases this secretion. Suppressing endogenous PGE2 synthesis by cyclooxygenase inhibition increases CXCL9 and CXCL10 release from breast cancer cells and is therefore a pharmacologic candidate to enhance intratumoral immune infiltration.
22333315	Breast Carcinoma	IFNG	Promote immunity (T and NK cell function)	In murine breast cancer models, the two interferon-gamma (IFN-γ) inducible chemokines and CXC-chemokine receptor 3 (CXCR3) receptor ligands, monokine induced by γ-interferon (CXCL9) and interferon-γ-inducible protein-10 (CXCL10) impair tumor growth and metastasis formation through recruitment of natural killer (NK) cells and tumor-suppressive T lymphocytes.
22333315	Breast Carcinoma	CXCL9	Promote immunity (infiltration)	In murine breast cancer models, the two interferon-gamma (IFN-γ) inducible chemokines and CXC-chemokine receptor 3 (CXCR3) receptor ligands, monokine induced by γ-interferon (CXCL9) and interferon-γ-inducible protein-10 (CXCL10) impair tumor growth and metastasis formation through recruitment of natural killer (NK) cells and tumor-suppressive T lymphocytes.
22333315	Breast Carcinoma	CXCL10	Promote immunity (infiltration)	In murine breast cancer models, the two interferon-gamma (IFN-γ) inducible chemokines and CXC-chemokine receptor 3 (CXCR3) receptor ligands, monokine induced by γ-interferon (CXCL9) and interferon-γ-inducible protein-10 (CXCL10) impair tumor growth and metastasis formation through recruitment of natural killer (NK) cells and tumor-suppressive T lymphocytes.
22315057	Colorectal Carcinoma	EGFR	Inhibit immunity	Pre-clinical data indicate enhanced anti-tumour activity when combining recombinant human interleukin-21 (rIL-21), a class 1 cytokine, with cetuximab, a monoclonal antibody, targeting the epidermal growth factor receptor.
22308288	Mantle Cell Lymphoma	MS4A1	Promote immunity	We conducted a pilot clinical trial testing a "third-generation" CD20-specific CAR with CD28 and 4-1BB costimulatory domains in patients with relapsed indolent B-cell and mantle cell lymphomas. In conclusion, adoptive immunotherapy with CD20-specific T cells was well tolerated and was associated with antitumor activity.
22289919	Chronic Lymphocytic Leukemia	ROR1	Inhibit immunity	A significantly higher frequency of ROR1 expression was found in patients with progressive versus non-progressive disease, and in those with unmutated versus mutated IgVH genes. Cross-linking of anti-ROR1 MAbs using the F(ab')(2) fragments of anti-Fc antibodies significantly augmented apoptosis. Two of the MAbs induced complement-dependent cytotoxicity (CDC) similar to that of rituximab and one anti-ROR1 MAb (KNG) (IgG1) showed killing activity by antibody-dependent cellular cytotoxicity.
22282655	Colorectal Carcinoma	CCL5	Promote immunity (infiltration); Inhibit immunity (T cell function)	We found that higher levels of CCL5 expression in human and murine colon tumor cells correlated with higher levels of apoptosis of CD8+ T cells and infiltration of T-regulatory cells (T(reg)). We also found tumor growth to be diminished in mice lacking CCR5, a CCL5 receptor, where a similar decrease in both T(reg) cell infiltration and CD8(+) T-cell apoptosis was noted. TGF-β signaling blockade diminished apoptosis of CD8(+) T cells, implicating TGF-β as an effector of CCL5 action. In support of this concept, CCL5 failed to enhance the production of TGF-β by CCR5-deficient T(reg) or to enhance their cytotoxic effects against CD8(+) T cells.
22282655	Colorectal Carcinoma	CCR5	Promote immunity (infiltration); Inhibit immunity (T cell function)	We found that higher levels of CCL5 expression in human and murine colon tumor cells correlated with higher levels of apoptosis of CD8+ T cells and infiltration of T-regulatory cells (T(reg)). We also found tumor growth to be diminished in mice lacking CCR5, a CCL5 receptor, where a similar decrease in both T(reg) cell infiltration and CD8(+) T-cell apoptosis was noted. TGF-β signaling blockade diminished apoptosis of CD8(+) T cells, implicating TGF-β as an effector of CCL5 action. In support of this concept, CCL5 failed to enhance the production of TGF-β by CCR5-deficient T(reg) or to enhance their cytotoxic effects against CD8(+) T cells.
22282655	Colorectal Carcinoma	TGFB1	Inhibit immunity (T cell function)	We found that higher levels of CCL5 expression in human and murine colon tumor cells correlated with higher levels of apoptosis of CD8+ T cells and infiltration of T-regulatory cells (T(reg)). We also found tumor growth to be diminished in mice lacking CCR5, a CCL5 receptor, where a similar decrease in both T(reg) cell infiltration and CD8(+) T-cell apoptosis was noted. TGF-β signaling blockade diminished apoptosis of CD8(+) T cells, implicating TGF-β as an effector of CCL5 action. In support of this concept, CCL5 failed to enhance the production of TGF-β by CCR5-deficient T(reg) or to enhance their cytotoxic effects against CD8(+) T cells.
22271878	Classic Hodgkin Lymphoma	JUN	Inhibit immunity (T cell function)	We identified an AP-1-responsive enhancer in the PD-L1 gene. In cHL Reed-Sternberg cells, which exhibit constitutive AP-1 activation, the PD-L1 enhancer binds AP-1 components and increases PD-L1 promoter activity. AP-1 signaling and EBV infection represent alternative mechanisms of PD-L1 induction and extend the spectrum of tumors in which to consider PD-1 blockade.
22258454	Melanoma	IDO1	Inhibit immunity (NK cell function)	We found that melanoma cells inhibited the expression of major NK receptors that trigger their immune function, including NKp30, NKp44, and NKG2D, with consequent impairment of NK cell-mediated cytolytic activity against various melanoma cell lines. This inhibitory effect was primarily mediated by indoleamine 2,3-dioxygenase (IDO) and prostaglandin E2 (PGE2).
22258454	Melanoma	NCR2	Promote immunity (NK cell function)	We found that melanoma cells inhibited the expression of major NK receptors that trigger their immune function, including NKp30, NKp44, and NKG2D, with consequent impairment of NK cell-mediated cytolytic activity against various melanoma cell lines. This inhibitory effect was primarily mediated by indoleamine 2,3-dioxygenase (IDO) and prostaglandin E2 (PGE2).
22258454	Melanoma	KLRK1	Promote immunity (NK cell function)	We found that melanoma cells inhibited the expression of major NK receptors that trigger their immune function, including NKp30, NKp44, and NKG2D, with consequent impairment of NK cell-mediated cytolytic activity against various melanoma cell lines. This inhibitory effect was primarily mediated by indoleamine 2,3-dioxygenase (IDO) and prostaglandin E2 (PGE2).
22258454	Melanoma	NCR3	Promote immunity (NK cell function)	We found that melanoma cells inhibited the expression of major NK receptors that trigger their immune function, including NKp30, NKp44, and NKG2D, with consequent impairment of NK cell-mediated cytolytic activity against various melanoma cell lines. This inhibitory effect was primarily mediated by indoleamine 2,3-dioxygenase (IDO) and prostaglandin E2 (PGE2).
22251483	Melanoma	KLRK1	Promote immunity	Blockade of NKG2D in mice also resulted in significantly diminished antitumor effects after immunotherapy. Human melanoma tissue biopsies obtained from patients after topically applied immunodulatory treatment resulted in increased numbers of these CD8(+) CD25(-) cells within the tumor site.
22245894	Hepatocellular Carcinoma	ASPH	Promote immunity (T cell function); essential for immunotherapy	We found that immunotherapy with ASPH-loaded DCs suppressed and delayed established HCC and tumor growth when administered prophylactically.
18250414	Glioma	STAT3	Inhibit immunity; immunotherapy target	These data suggest that systemic inhibition of STAT3 signaling can reverse the suppressive immunological environment of intracranial tumor bearing mice both systemically and locally, thereby promoting the efficacy of adoptive transfer therapy with Tc1.
18245551	Breast Carcinoma	ERBB2	Inhibit immunity	Effective treatment of established human breast tumor xenografts in immunodeficient mice with a single dose of the alpha-emitting radioisotope astatine-211 conjugated to anti-HER2/neu diabodies.
18245547	Non-Small Cell Lung Carcinoma	EGF	Inhibit immunity	There was a significantly better survival for vaccinated patients that showed the higher capacity to inhibit EGF/EGFR binding and for those who showed an immunodominance by the central region of EGF molecule.
18245488	Prostate Carcinoma	PSCA	Promote immunity (T cell function); essential for immunotherapy	Prostate stem cell antigen vaccination induces a long-term protective immune response against prostate cancer in the absence of autoimmunity. Our results show the induction of an immune response against a newly defined PSCA epitope that is mediated primarily by CD8 T cells.
18240144	Glioma	CTAG1B	Promote immunity (T cell function); essential for immunotherapy	In an orthotopic xenograft model, the systemic administration of 5-aza-CdR resulted in a significant volume reduction of the transplanted tumors and prolonged the survival of the animals after the adoptive transfer of NY-ESO-1-specific CTLs.
18230757	Lymphoma	TNFRSF8	Immunotherapy target	Human antibody RNase fusion protein targeting CD30+ lymphomas. Targeted RNases (TRs) are immunoenzymes with ribonucleases as cytotoxic effector domains, which are less immunogenic as plant or bacterial toxin components of classical immunotoxins. Proliferation of the CD30+ lymphoma cell line Karpas-299 was strongly inhibited by CD30-specific huTR protein (IC50=3.3 nM).
18227839	Lymphoma; Leukemia	CD19	Promote immunity (T cell function); essential for immunotherapy	In order to test whether this system can be used for genetically modifying both PB T cells and umbilical cord blood (UCB) T cells as graft-versus-leukemia effector cells, an SB transposon was constructed to coexpress a single-chain chimeric antigen receptor (CAR) for human CD19 and CD20. The engineered CD4(+) T cells and CD8(+) T cells both exhibited specific cytotoxicity against CD19(+) leukemia and lymphoma cell lines, as well as against CD19 transfectants, and produced high-levels of antigen-dependent Th1 (but not Th2) cytokines. The in vivo adoptive transfer of genetically engineered T cells significantly reduced tumor growth and prolonged the survival of the animal.
18224686	Colorectal Carcinoma	GAST	Inhibit immunity	This study was conducted to design antibodies able to block gastrin binding to the gastrin/cholecystokinin-2 (CCK-2) receptor in order to delay tumor growth. Moreover, the human antigastrin scFvs obtained in this study inhibited significantly the proliferation of Colo 320 tumoral cells.
18224680	Glioma	SOX6	Promote immunity (T cell function); essential for immunotherapy	Induction of protective and therapeutic antitumor immunity by a DNA vaccine with a glioma antigen, SOX6. Following SOX6-DNA vaccination, CTLs specific for SOX6-expressing glioma cells were induced, while normal autologous-cells that had restrictedly expressed SOX6 during embryogenesis were not destroyed.
18223233	Burkitt Lymphoma	CD52	Inhibit immunity	A novel Raji-Burkitt's lymphoma model for preclinical and mechanistic evaluation of CD52-targeted immunotherapeutic agents. The disseminated leukemia-lymphoma mouse model described herein using these stable cell lines can serve as an excellent system for in vivo therapeutic and mechanistic evaluation of existing and novel antibodies directed against CD52 molecule.
18203952	Hodgkin lymphoma	CD274	Inhibit immunity (T cell function)	Blockade of the PD-1 signaling pathway inhibited SHP-2 phosphorylation and restored the IFN-gamma-producing function of HL-infiltrating T cells. According to these results, deficient cellular immunity observed in HL patients can be explained by "T-cell exhaustion," which is led by the activation of PD-1-PD-L signaling pathway.
18199559	Skin Squamous Cell Carcinoma	TLR4	Promote immunity (T cell function)	TLR4-deficient C3H/HeJ mice developed more tumors relative to the TLR4-normal C3H/HeN mice. Interestingly, the cell-mediated immune response was mediated by IFN-gamma in C3H/HeN mice and by interleukin (IL)-17 in C3H/HeJ mice. Moreover, C3H/HeN mice had elevated circulating levels of IFN-gamma following topical application of DMBA, whereas IL-17 was elevated in C3H/HeJ mice. The results of this study indicate that TLR4 plays an important role in the prevention of DMBA skin tumorigenesis and that this is associated with differences in the T-cell subtype activated.
18094430	Melanoma	KLRK1	Promote immunity (T cell function)	Moreover, the engagement of NKG2D occurred in antitumor activity by both freshly isolated and in vitro cultured TILs. These findings indicate that NKG2D+ T cells have a role in the immunologic response against tumor.
18089828	Prostate Carcinoma	HSPA4	Promote immunity (T cell function); essential for immunotherapy	Induction of hsp70-mediated Th17 autoimmunity can be exploited as immunotherapy for metastatic prostate cancer. We show here that, in the prostate, hsp70 induces interleukin (IL)-6, which triggers a CD4- and CD8-dependent progressive autoimmune reactivity, associated with IL-17 expression.
18083706	Cervical Carcinoma; Globlastoma; Breast Carcinoma	CXCR4	Inhibit immunity (T cell function)	Here, we demonstrate that ligand (CXCL12) stimulation of CXCR4, a major chemokine receptor expressed in many malignant cancer cells, induced MHC-I heavy chain down-regulation from the cell surface of the human epithelioid carcinoma HeLa cells, the human U251 and U87 glioblastoma cells, the human MDA-MD 231 breast cancer cells, and the human SK-N-BE (2) neuroblastoma cells. Activation of CXCR4 induced ubiquitination of MHC-I heavy chain, and mutation of the C-terminal two lysine residues (Lys-332, Lys-337) on one of the MHC-I alleles, HLA.B7, blocked CXCR4-evoked ubiquitination and down-regulation of HLA.B7. All together, these findings shed new light on the role of CXCR4 in tumor evasion of immune surveillance via inducing MHC-I down-regulation from the cell surface.
18056198	Ovarian Carcinoma	IL2	Promote immunity (T cell function); essential for immunotherapy	CD8+ T cells induce complete regression of advanced ovarian cancers by an interleukin (IL)-2/IL-15 dependent mechanism.
18056169	Prostate Carcinoma	TLR8	Promote immunity (T cell function)	Importantly, the suppressive function of CD8(+) Treg cells could be reversed by human Toll-like receptor 8 (TLR8) signaling.
18025475	Actinic (Solar) Keratosis; Skin Basal Cell Carcinoma; Squamous Cell Carcinoma	EGFR	Inhibit immunity (T cell function)	Here we demonstrate that human keratinocyte-derived skin tumors may evade T cell-mediated antitumor immune responses by down-regulating the expression of CCL27 through the activation of epidermal growth factor receptor (EGFR)-Ras-MAPK-signaling pathways. Compared with healthy skin, CCL27 mRNA and protein expression was progressively lost in transformed keratinocytes of actinic keratoses and basal and squamous cell carcinomas.
18025475	Actinic (Solar) Keratosis; Skin Basal Cell Carcinoma; Squamous Cell Carcinoma	KRAS	Inhibit immunity (T cell function)	Here we demonstrate that human keratinocyte-derived skin tumors may evade T cell-mediated antitumor immune responses by down-regulating the expression of CCL27 through the activation of epidermal growth factor receptor (EGFR)-Ras-MAPK-signaling pathways. Compared with healthy skin, CCL27 mRNA and protein expression was progressively lost in transformed keratinocytes of actinic keratoses and basal and squamous cell carcinomas.
18025475	Actinic (Solar) Keratosis; Skin Basal Cell Carcinoma; Squamous Cell Carcinoma	MAPK1	Inhibit immunity (T cell function)	Here we demonstrate that human keratinocyte-derived skin tumors may evade T cell-mediated antitumor immune responses by down-regulating the expression of CCL27 through the activation of epidermal growth factor receptor (EGFR)-Ras-MAPK-signaling pathways. Compared with healthy skin, CCL27 mRNA and protein expression was progressively lost in transformed keratinocytes of actinic keratoses and basal and squamous cell carcinomas.
18025475	Actinic (Solar) Keratosis; Skin Basal Cell Carcinoma; Squamous Cell Carcinoma	CCL27	Promote immunity (T cell function)	Here we demonstrate that human keratinocyte-derived skin tumors may evade T cell-mediated antitumor immune responses by down-regulating the expression of CCL27 through the activation of epidermal growth factor receptor (EGFR)-Ras-MAPK-signaling pathways. Compared with healthy skin, CCL27 mRNA and protein expression was progressively lost in transformed keratinocytes of actinic keratoses and basal and squamous cell carcinomas.
18025180	Colon Carcinoma	TNFRSF18	Promote immunity (T cell function)	In this study, we demonstrate that the in vivo ligation of GITR on CD4(+) effector T cells renders them refractory to suppression by regulatory T (T(reg)) cells in the CT26 tumor-bearing mouse.
18025166	Prostate Carcinoma	TNFRSF4	Promote immunity (T cell function)	Currently, we demonstrate that provision of an OX40 agonist during the activation of naive CD8 T cells primed in vivo with either soluble or tumor-associated Ag significantly augments granzyme B expression and CD8 T cell cytolytic function through an IL-2-dependent mechanism. Furthermore, augmented CTL function required direct engagement of OX40 on the responding CD8 T cells and was associated with increased antitumor activity against established prostate tumors and enhanced the survival of tumor-bearing hosts.
18008004	Melanoma	CD200	Inhibit immunity (T cell function)	Employing 2 independent, genome-wide microarray analyses, we identified CD200 as a highly dynamic, downstream target of RAS/RAF/MEK/ERK activation in melanoma. CD200 protein was similarly overexpressed in human melanoma cell lines and primary tumors. Melanoma cell lines expressing endogenous CD200 repressed primary T cell activation by DCs, while knockdown of CD200 by shRNA abrogated this immunosuppressive effect.
18008004	Melanoma	NRAS	Inhibit immunity (T cell function)	Employing 2 independent, genome-wide microarray analyses, we identified CD200 as a highly dynamic, downstream target of RAS/RAF/MEK/ERK activation in melanoma. CD200 protein was similarly overexpressed in human melanoma cell lines and primary tumors. Melanoma cell lines expressing endogenous CD200 repressed primary T cell activation by DCs, while knockdown of CD200 by shRNA abrogated this immunosuppressive effect.
18008004	Melanoma	BRAF	Inhibit immunity (T cell function)	Employing 2 independent, genome-wide microarray analyses, we identified CD200 as a highly dynamic, downstream target of RAS/RAF/MEK/ERK activation in melanoma. CD200 protein was similarly overexpressed in human melanoma cell lines and primary tumors. Melanoma cell lines expressing endogenous CD200 repressed primary T cell activation by DCs, while knockdown of CD200 by shRNA abrogated this immunosuppressive effect.
18008004	Melanoma	MAP2K1	Inhibit immunity (T cell function)	Employing 2 independent, genome-wide microarray analyses, we identified CD200 as a highly dynamic, downstream target of RAS/RAF/MEK/ERK activation in melanoma. CD200 protein was similarly overexpressed in human melanoma cell lines and primary tumors. Melanoma cell lines expressing endogenous CD200 repressed primary T cell activation by DCs, while knockdown of CD200 by shRNA abrogated this immunosuppressive effect.
18008004	Melanoma	MAPK1	Inhibit immunity (T cell function)	Employing 2 independent, genome-wide microarray analyses, we identified CD200 as a highly dynamic, downstream target of RAS/RAF/MEK/ERK activation in melanoma. CD200 protein was similarly overexpressed in human melanoma cell lines and primary tumors. Melanoma cell lines expressing endogenous CD200 repressed primary T cell activation by DCs, while knockdown of CD200 by shRNA abrogated this immunosuppressive effect.
17450141	Lung Carcinoma; Esophageal Carcinoma; Gastric Carcinoma; Colorectal Carcinoma; Cervical Carcinoma; Breast Carcinoma	CASP8	Inhibit immunity (T cell function)	Using a haplotype-tagging SNP approach, we identified a six-nucleotide deletion (-652 6N del) variant in the CASP8 promoter associated with decreased risk of lung cancer. The deletion destroys a stimulatory protein 1 binding site and decreases CASP8 transcription. Biochemical analyses showed that T lymphocytes with the deletion variant had lower caspase-8 activity and activation-induced cell death upon stimulation with cancer cell antigens. Case-control analyses of 4,995 individuals with cancer and 4,972 controls in a Chinese population showed that this genetic variant is associated with reduced susceptibility to multiple cancers, including lung, esophageal, gastric, colorectal, cervical and breast cancers, acting in an allele dose-dependent manner.
17440061	Glioblastoma	CLEC2D	Inhibit immunity (NK cell function)	Lectin-like transcript-1 (LLT1) is a newly identified ligand for the inhibitory natural killer (NK) cell receptor CD161. Here, we report that glioma cells express LLT1 mRNA and protein in vitro and in vivo, whereas expression levels in normal brain are low. LLT1 expression in human gliomas increases with the WHO grade of malignancy. We further show that transforming growth factor-beta (TGF-beta) up-regulates the expression of LLT1 in glioma cells.
17440061	Glioblastoma	TGFB1	Inhibit immunity (NK cell function)	Lectin-like transcript-1 (LLT1) is a newly identified ligand for the inhibitory natural killer (NK) cell receptor CD161. Here, we report that glioma cells express LLT1 mRNA and protein in vitro and in vivo, whereas expression levels in normal brain are low. LLT1 expression in human gliomas increases with the WHO grade of malignancy. We further show that transforming growth factor-beta (TGF-beta) up-regulates the expression of LLT1 in glioma cells.
17419945	Burkitt Lymphoma	MYC	Inhibit immunity (T cell function)	Yet, it had remained open whether nonimmunogenicity is the default phenotype when EBNA2 and LMP1 are switched off, or whether c-MYC actively contributes to immunosuppression. We provide evidence also for the latter by showing that c-MYC down-regulates genes of the NF-kappaB and interferon pathway in a dose-dependent fashion.
17415709	Breast Carcinoma	CD274	Inhibit immunity	B7-H1, a co-inhibitory molecule, plays a role in immune escape of tumors. We have shown for the first time a direct association between proliferation and the expression of B7-H1 in breast cancer patients.
17375074	Melanoma	CSF2	Promote immunity (T cell function); essential for immunotherapy	We programmed mouse bone marrow (BM) cells with lentiviral vectors (LV-GI4) so that they produced granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4) in an autonomous manner. The immunostimulatory efficacy of DC/LV-GI4 cells was evaluated using MART1 and TRP2 as co-expressed melanoma antigens. Mice vaccinated with DC/LV-GI4 cells that self-differentiated in vitro or in vivo produced potent antigen-specific responses against melanoma, which correlated with protective and long-term therapeutic anti-tumor effects.
17375074	Melanoma	IL4	Promote immunity (T cell function); essential for immunotherapy	We programmed mouse bone marrow (BM) cells with lentiviral vectors (LV-GI4) so that they produced granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4) in an autonomous manner. The immunostimulatory efficacy of DC/LV-GI4 cells was evaluated using MART1 and TRP2 as co-expressed melanoma antigens. Mice vaccinated with DC/LV-GI4 cells that self-differentiated in vitro or in vivo produced potent antigen-specific responses against melanoma, which correlated with protective and long-term therapeutic anti-tumor effects.
17375044	Malignant Glioma	SOX2	Inhibit immunity	SOX2 was identified by screening an expression database for transcripts that are overexpressed in malignant glioma, but display minimal expression in normal tissues.? Human leucocyte antigen-A(*)0201-restricted SOX2-derived peptides were tested for the activation of glioma-reactive CD8+ cytotoxic T lymphocytes (CTLs). Specific CTLs were raised against the peptide TLMKKDKYTL and were capable of lysing glioma cells. The abundant and glioma-restricted overexpression of SOX2 and the generation of SOX2-specific and tumour-reactive CTLs may recommend this antigen as target for T-cell-based immunotherapy of glioma.
17374743	Myeloid Leukemia	USP18	Promote immunity	Ubp43 is an ISG15-specific isopeptidase, the expression of which is activated by IFN. Ubp43 deficiency increases the resistance to oncogenic transformation by BCR-ABL. This resistance to leukemic development is dependent on type 1 IFN (IFN-alpha/beta) signaling in Ubp43-deficient cells. These results suggest that inhibition of Ubp43-negative effect on IFN signaling can potentiate the response to increased endogenous IFN levels in innate immune responses against cancer development, indicating that pharmacological inhibition of Ubp43 may be of benefit in cancers and others diseases in which interferon is currently prescribed.
17374743	Myeloid Leukemia	IFNA1	Promote immunity (T cell function)	Ubp43 is an ISG15-specific isopeptidase, the expression of which is activated by IFN. Ubp43 deficiency increases the resistance to oncogenic transformation by BCR-ABL. This resistance to leukemic development is dependent on type 1 IFN (IFN-alpha/beta) signaling in Ubp43-deficient cells. These results suggest that inhibition of Ubp43-negative effect on IFN signaling can potentiate the response to increased endogenous IFN levels in innate immune responses against cancer development, indicating that pharmacological inhibition of Ubp43 may be of benefit in cancers and others diseases in which interferon is currently prescribed.
17374743	Myeloid Leukemia	IFNB1	Promote immunity (T cell function)	Ubp43 is an ISG15-specific isopeptidase, the expression of which is activated by IFN. Ubp43 deficiency increases the resistance to oncogenic transformation by BCR-ABL. This resistance to leukemic development is dependent on type 1 IFN (IFN-alpha/beta) signaling in Ubp43-deficient cells. These results suggest that inhibition of Ubp43-negative effect on IFN signaling can potentiate the response to increased endogenous IFN levels in innate immune responses against cancer development, indicating that pharmacological inhibition of Ubp43 may be of benefit in cancers and others diseases in which interferon is currently prescribed.
17372897	B16 Malignant Melanoma	CX3CL1	Promote immunity	We found that B16-treated CX3CR1-/- mice had increased lung tumor burden and cachexia. However, CX3CR1-deficient NK cells exhibited a tumorigenic cytokine production profile with defective IFN-gamma expression and enhanced IL-6 production in response to TLR3 activation with polyIC. Our studies indicate that CX3CR1 is an important contributor to innate immunity at multiple levels.
17372897	B16 Malignant Melanoma	CX3CR1	Promote immunity (T/NK cell function)	We found that B16-treated CX3CR1-/- mice had increased lung tumor burden and cachexia. However, CX3CR1-deficient NK cells exhibited a tumorigenic cytokine production profile with defective IFN-gamma expression and enhanced IL-6 production in response to TLR3 activation with polyIC. Our studies indicate that CX3CR1 is an important contributor to innate immunity at multiple levels.
17371978	Fibrosarcoma	IL5	Promote immunity (Eosinophil function)	It was found that MCA-induced tumor incidence and growth were significantly attenuated in IL-5 transgenic mice of both the BALB/c and C57BL/6 backgrounds. Histological examination revealed that the protective effect of IL-5 was associated with massively enhanced numbers of eosinophils within and surrounding tumors. Conversely, there was a higher tumor incidence in CCL11(-/-) BALB/c mice, which was associated with a reduced eosinophil influx into tumors.
17364027	Thymic Lymphoma	CBLB	Inhibit immunity	In vivo studies further demonstrated that Cblb(-/-) mice, but not WT controls, efficiently rejected inoculated E.G7 and EL4 lymphomas that did not express B7 ligands and that introduction of the Cblb(-/-) mutation into tumor-prone ataxia telangiectasia mutated-deficient mice markedly reduced the incidence of spontaneous thymic lymphomas. Immunohistological study showed that E.G7 tumors from Cblb(-/-) mice contained massively infiltrating CD8(+) T cells.
17363736	Multiple Myeloma-IgG	CD274	Inhibit immunity (T cell function); immunotherapy target	We observed that B7-H1 was expressed in most MM plasma cells, but not cells isolated from monoclonal gammopathy of undetermined significance or healthy donors. This expression was increased or induced by IFN-gamma and Toll-like receptor (TLR) ligands in isolated MM plasma cells. Blocking the MEK/ERK pathway inhibited IFN-gamma-mediated and TLR-mediated expression of B7-H1. Inhibition of the MyD88 and TRAF6 adaptor proteins of the TLR pathway blocked not only B7-H1 expression induced by TLR ligands but also that mediated by IFN-gamma. IFN-gamma-induced STAT1 activation, via MEK/ERK and MyD88/TRAF6, and inhibition of STAT1 reduced B7-H1 expression. MM plasma cells stimulated with IFN-gamma or TLR ligands inhibited cytotoxic T lymphocytes (CTLs) generation and this immunosuppressive effect was inhibited by preincubation with an anti-B7-H1 antibody, the UO126 MEK inhibitor, or by transfection of a dominant-negative mutant of MyD88.
17363736	Multiple Myeloma-IgG	IFNG	Inhibit immunity (T cell function)	We observed that B7-H1 was expressed in most MM plasma cells, but not cells isolated from monoclonal gammopathy of undetermined significance or healthy donors. This expression was increased or induced by IFN-gamma and Toll-like receptor (TLR) ligands in isolated MM plasma cells. Blocking the MEK/ERK pathway inhibited IFN-gamma-mediated and TLR-mediated expression of B7-H1. Inhibition of the MyD88 and TRAF6 adaptor proteins of the TLR pathway blocked not only B7-H1 expression induced by TLR ligands but also that mediated by IFN-gamma. IFN-gamma-induced STAT1 activation, via MEK/ERK and MyD88/TRAF6, and inhibition of STAT1 reduced B7-H1 expression. MM plasma cells stimulated with IFN-gamma or TLR ligands inhibited cytotoxic T lymphocytes (CTLs) generation and this immunosuppressive effect was inhibited by preincubation with an anti-B7-H1 antibody, the UO126 MEK inhibitor, or by transfection of a dominant-negative mutant of MyD88.
17363736	Multiple Myeloma-IgG	MAP2K1	Inhibit immunity (T cell function)	We observed that B7-H1 was expressed in most MM plasma cells, but not cells isolated from monoclonal gammopathy of undetermined significance or healthy donors. This expression was increased or induced by IFN-gamma and Toll-like receptor (TLR) ligands in isolated MM plasma cells. Blocking the MEK/ERK pathway inhibited IFN-gamma-mediated and TLR-mediated expression of B7-H1. Inhibition of the MyD88 and TRAF6 adaptor proteins of the TLR pathway blocked not only B7-H1 expression induced by TLR ligands but also that mediated by IFN-gamma. IFN-gamma-induced STAT1 activation, via MEK/ERK and MyD88/TRAF6, and inhibition of STAT1 reduced B7-H1 expression. MM plasma cells stimulated with IFN-gamma or TLR ligands inhibited cytotoxic T lymphocytes (CTLs) generation and this immunosuppressive effect was inhibited by preincubation with an anti-B7-H1 antibody, the UO126 MEK inhibitor, or by transfection of a dominant-negative mutant of MyD88.
17363736	Multiple Myeloma-IgG	MAPK1	Inhibit immunity (T cell function)	We observed that B7-H1 was expressed in most MM plasma cells, but not cells isolated from monoclonal gammopathy of undetermined significance or healthy donors. This expression was increased or induced by IFN-gamma and Toll-like receptor (TLR) ligands in isolated MM plasma cells. Blocking the MEK/ERK pathway inhibited IFN-gamma-mediated and TLR-mediated expression of B7-H1. Inhibition of the MyD88 and TRAF6 adaptor proteins of the TLR pathway blocked not only B7-H1 expression induced by TLR ligands but also that mediated by IFN-gamma. IFN-gamma-induced STAT1 activation, via MEK/ERK and MyD88/TRAF6, and inhibition of STAT1 reduced B7-H1 expression. MM plasma cells stimulated with IFN-gamma or TLR ligands inhibited cytotoxic T lymphocytes (CTLs) generation and this immunosuppressive effect was inhibited by preincubation with an anti-B7-H1 antibody, the UO126 MEK inhibitor, or by transfection of a dominant-negative mutant of MyD88.
17363736	Multiple Myeloma-IgG	STAT1	Inhibit immunity (T cell function)	We observed that B7-H1 was expressed in most MM plasma cells, but not cells isolated from monoclonal gammopathy of undetermined significance or healthy donors. This expression was increased or induced by IFN-gamma and Toll-like receptor (TLR) ligands in isolated MM plasma cells. Blocking the MEK/ERK pathway inhibited IFN-gamma-mediated and TLR-mediated expression of B7-H1. Inhibition of the MyD88 and TRAF6 adaptor proteins of the TLR pathway blocked not only B7-H1 expression induced by TLR ligands but also that mediated by IFN-gamma. IFN-gamma-induced STAT1 activation, via MEK/ERK and MyD88/TRAF6, and inhibition of STAT1 reduced B7-H1 expression. MM plasma cells stimulated with IFN-gamma or TLR ligands inhibited cytotoxic T lymphocytes (CTLs) generation and this immunosuppressive effect was inhibited by preincubation with an anti-B7-H1 antibody, the UO126 MEK inhibitor, or by transfection of a dominant-negative mutant of MyD88.
17363736	Multiple Myeloma-IgG	MYD88	Inhibit immunity (T cell function)	We observed that B7-H1 was expressed in most MM plasma cells, but not cells isolated from monoclonal gammopathy of undetermined significance or healthy donors. This expression was increased or induced by IFN-gamma and Toll-like receptor (TLR) ligands in isolated MM plasma cells. Blocking the MEK/ERK pathway inhibited IFN-gamma-mediated and TLR-mediated expression of B7-H1. Inhibition of the MyD88 and TRAF6 adaptor proteins of the TLR pathway blocked not only B7-H1 expression induced by TLR ligands but also that mediated by IFN-gamma. IFN-gamma-induced STAT1 activation, via MEK/ERK and MyD88/TRAF6, and inhibition of STAT1 reduced B7-H1 expression. MM plasma cells stimulated with IFN-gamma or TLR ligands inhibited cytotoxic T lymphocytes (CTLs) generation and this immunosuppressive effect was inhibited by preincubation with an anti-B7-H1 antibody, the UO126 MEK inhibitor, or by transfection of a dominant-negative mutant of MyD88.
17363736	Multiple Myeloma-IgG	TRAF6	Inhibit immunity (T cell function)	We observed that B7-H1 was expressed in most MM plasma cells, but not cells isolated from monoclonal gammopathy of undetermined significance or healthy donors. This expression was increased or induced by IFN-gamma and Toll-like receptor (TLR) ligands in isolated MM plasma cells. Blocking the MEK/ERK pathway inhibited IFN-gamma-mediated and TLR-mediated expression of B7-H1. Inhibition of the MyD88 and TRAF6 adaptor proteins of the TLR pathway blocked not only B7-H1 expression induced by TLR ligands but also that mediated by IFN-gamma. IFN-gamma-induced STAT1 activation, via MEK/ERK and MyD88/TRAF6, and inhibition of STAT1 reduced B7-H1 expression. MM plasma cells stimulated with IFN-gamma or TLR ligands inhibited cytotoxic T lymphocytes (CTLs) generation and this immunosuppressive effect was inhibited by preincubation with an anti-B7-H1 antibody, the UO126 MEK inhibitor, or by transfection of a dominant-negative mutant of MyD88.
17363548	Glioma	EGFR	Inhibit immunity	We examined the efficacy of two EGFR-specific mAbs (mAbs 806 and 528) against U87MG-derived glioma xenografts expressing EGFR variants. Whereas mAb 806 displayed antitumor activity against NR6 xenografts, mAb 528 therapy was ineffective, suggesting that mAb 528 mediates its antitumor activity by disrupting interactions between the de2-7 and wild-type EGFR. Finally, genetic disruption of Src in U87MG xenografts expressing the de2-7 EGFR dramatically enhanced mAb 806 efficacy.
17363539	Malignant Melanoma	HSP90AA1	Inhibit immunity	mAb 4C5 inhibits B16 F10 cell invasion by binding to surface HSP90 because it is not internalized. mAb 4C5 significantly inhibits melanoma metastasis in C57BL/6 mice inoculated with B16 F10 cells.
17332366	Melanoma	TNFRSF9	Inhibit immunity (NK cell function); immunotherapy target	We further show that the percentage of NK cells was higher in B16-1D8 melanomas expressing anti-CD137 scFv than in the WT tumors and that the percentage of FoxP3(+) cells was lower. Admixture of 10% K1735-1D8 cells prevented the progressive growth of transplanted K1735-WT cells in syngeneic mice and also of cells from the antigenically different sarcoma Ag104.
17332365	Neuroblastoma	CX3CL1	Promote immunity	Therefore, we tested the hypothesis that a combined increase of FKN and interleukin-2 (IL-2) in the neuroblastoma microenvironment induces an effective antitumor immune response. The depletion of T cells and NK cells in vivo abrogated the effect, and these effector cells showed the highest cytolytic activity in vitro. Finally, only the FKN- and IL-2-enriched neuroblastoma microenvironment resulted in T-cell activation and the release of proinflammatory cytokines.
17332365	Neuroblastoma	IL2	Promote immunity (T/NK cell function)	Therefore, we tested the hypothesis that a combined increase of FKN and interleukin-2 (IL-2) in the neuroblastoma microenvironment induces an effective antitumor immune response. The depletion of T cells and NK cells in vivo abrogated the effect, and these effector cells showed the highest cytolytic activity in vitro. Finally, only the FKN- and IL-2-enriched neuroblastoma microenvironment resulted in T-cell activation and the release of proinflammatory cytokines.
17332301	Lung Carcinoma	EGFR	Inhibit immunity	A logarithmic correlation was observed between the number of EGFRs and ADCC activity. In addition, ADCC activity was enhanced by interleukin-2 mainly through activation of NK cells and was less susceptible to immunosuppression by chemotherapy than NK activity in lung cancer patients.
17332301	Lung Carcinoma	IL2	Promote immunity (NK cell function)	A logarithmic correlation was observed between the number of EGFRs and ADCC activity. In addition, ADCC activity was enhanced by interleukin-2 mainly through activation of NK cells and was less susceptible to immunosuppression by chemotherapy than NK activity in lung cancer patients.
17326190	Liver Carcinoma	IL12A	Promote immunity (NK cell function); essential for immunotherapy	Our results demonstrated that IL-12, but not GM-CSF, monotherapy displayed significant therapeutic effects, whereas combination therapy with both cytokines displayed synergistic antitumor effects not only on transplanted tumor models with intermediate or large tumor loads, but also on carcinogen-induced multifocal liver tumors. Effector cell analyses, revealed by in vivo cell subset depletion, flow cytometry analysis, and immunohistochemical staining of tumor infiltrates, indicated that NK cells were the prominent antitumor effectors for the IL-12-mediated antitumor activity, whereas CD8+ T cells, NKT cells, and macrophages were more important than NK cells in the combination therapy-mediated antitumor effects
27572267	Basal-Like Carcinoma	PDCD1	Inhibit immunity (T cell function)	We also demonstrate that epidermal growth factor (EGF) stabilizes PD-L1 via GSK3β inactivation in basal-like breast cancer. Inhibition of EGF signalling by gefitinib destabilizes PD-L1, enhances antitumour T-cell immunity and therapeutic efficacy of PD-1 blockade in syngeneic mouse models
27553831	Lung Adenocarcinoma	HHLA2	Promote immunity (infiltration)	HHLA2 is widely expressed in NSCLC and is associated with EGFR mutation and high TILs in lung adenocarcinoma
27470968	Gastrointestinal Stromal Tumor	CD274	Inhibit immunity (T cell function); immunotherapy target	PD-1/PD-L1 Blockade Enhances T-cell Activity and Antitumor Efficacy of Imatinib in Gastrointestinal Stromal Tumors.
27470968	Gastrointestinal Stromal Tumor	KIT	Inhibit immunity (T cell function); immunotherapy target	PD-1 and PD-L1 blockade in vivo each had no efficacy alone but enhanced the antitumor effects of imatinib by increasing T-cell effector function in the presence of KIT and IDO inhibition.
27470968	Gastrointestinal Stromal Tumor	IDO1	Inhibit immunity (T cell function); immunotherapy target	PD-1 and PD-L1 blockade in vivo each had no efficacy alone but enhanced the antitumor effects of imatinib by increasing T-cell effector function in the presence of KIT and IDO inhibition.
27463676	Melanoma	CD274	Inhibit immunity (T cell function)	Interferon-γ (IFN-γ)-induced PD-L1 up-regulation on MB requires Cdk5, and disruption of Cdk5 expression in a mouse model of MB results in potent CD4(+) T cell-mediated tumor rejection.
28436963	Melanoma; Colon Carcinoma	TMEM173	Promote immunity	This effect is dependent on stimulator of interferon genes (STING), but not the Toll-like receptor or the mitochondrial antiviral-signalling protein (MAVS) pathway. Here, we report a minimalist nanovaccine, comprising a simple physical mixture of an antigen and a synthetic polymeric nanoparticle, PC7A NP, which generates a strong cytotoxic T-cell response with low systemic cytokine expression. Mechanistically, the PC7A NP achieves efficient cytosolic delivery of tumour antigens to antigen-presenting cells in draining lymph nodes, leading to increased surface presentation while simultaneously activating type I interferon-stimulated genes.
28424162	Chronic Lymphocytic Leukemia; Richter Syndrome	PDCD1	Inhibit immunity	Preclinical studies suggest that programmed death 1 (PD-1) pathway is critical to inhibit immune surveillance in CLL.
28419181	Head and Neck Squamous Cell Carcinoma	CD274	Inhibit immunity	In the clinic, some patients seem not only not to benefit from anti-PD-L1/PD-1 agents but rather to experience an acceleration of tumor growth kinetics (TGK).Hyperprogression was observed in 29% of patients with R/M HNSCC treated with anti-PD-L1/PD-1 agents and correlated with a shorter PFS.
28419181	Head and Neck Squamous Cell Carcinoma	PDCD1	Inhibit immunity	In the clinic, some patients seem not only not to benefit from anti-PD-L1/PD-1 agents but rather to experience an acceleration of tumor growth kinetics (TGK).Hyperprogression was observed in 29% of patients with R/M HNSCC treated with anti-PD-L1/PD-1 agents and correlated with a shorter PFS.
28416485	Triple-Negative Breast Carcinoma	CCL5	Inhibit immunity	We demonstrate here that an autocrine CCL5-CCR5 axis is a major regulator of immunosuppressive myeloid cells (IMC) of both monocytic and granulocytic lineages. The absence of the autocrine CCL5 abrogated the generation of granulocytic myeloid-derived suppressor cells and tumor-associated macrophagesThe changes in the?ccl5-null myeloid compartment subsequently resulted in increased tumor-infiltrating cytotoxic CD8+?T cells and decreased regulatory T cells in tumor-draining lymph nodes. Targeting the host CCL5 in bone marrow via nanoparticle-delivered expression silencing, in combination with the CCR5 inhibitor Maraviroc, resulted in strong reductions of IMC and robust antitumor immunities.
28416485	Triple-Negative Breast Carcinoma	CCR5	Inhibit immunity	We demonstrate here that an autocrine CCL5-CCR5 axis is a major regulator of immunosuppressive myeloid cells (IMC) of both monocytic and granulocytic lineages. An analysis of human triple-negative breast cancer specimens demonstrated an inverse correlation between "immune CCR5" levels and the maturation status of tumor-infiltrating neutrophils as well as 5-year-survival rates. Targeting the host CCL5 in bone marrow via nanoparticle-delivered expression silencing, in combination with the CCR5 inhibitor Maraviroc, resulted in strong reductions of IMC and robust antitumor immunities.
28410988	Melanoma; Non-small Cell Lung Carcinoma; Renal Cell Carcinoma	FCGR2B	Inhibit immunity	While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors.
28428785	Leukemia; Ewing Sarcoma; Lymphoma; Neuroblastoma	IFNG	Inhibit immunity (NK cell function)	We also observed a variable impact of IFNγ in NK cell-mediated lysis. For six of the cancer cell lines IFNγ resulted in increased resistance to NK cells, while for three of them it resulted in increased sensitivity. Modeling of the data suggests that the effect of IFNγ on NK cell-mediated tumor lysis is mostly dependent on changes in MHC-class I and ICAM-1 expression. For three of the cell lines with increased resistance, we observed higher upregulation of MHC-class I than ICAM-1.
28428785	Neuroblastoma; Glioblastoma	IFNG	Promote immunity (NK cell function)	Modeling of the data suggests that the effect of IFNγ on NK cell-mediated tumor lysis is mostly dependent on changes in MHC-class I and ICAM-1 expression. For the cell lines with increased sensitivity after IFNγ treatment, we observed upregulation of ICAM-1 exceeding MHC-class I upregulation. ICAM-1 upregulation resulted in increased conjugate formation between the NK cells and tumor cells, which can contribute to the increased sensitivity observed.
28408401	Non-small Cell Lung Carcinoma	HDAC6	Inhibit immunity (T cell function)	By evaluating human peripheral blood and NSCLC tumors, we show that the selective HDAC6 inhibitor ricolinostat promotes phenotypic changes that support enhanced T-cell activation and improved function of antigen-presenting cells.
28408386	Head and Neck Carcinoma	PDCD1	Inhibit immunity (T cell function)	The frequency of PD-1 and TIM-3 expression was significantly increased in CD8+ TILs compared with CD8+ PBLs (P = 0.008 and P = 0.02, respectively). Indeed, the increased frequency of PD-1+?and TIM-3+?CD8+?TILs was inversely correlated with clinical outcome of cetuximab therapy
28408386	Head and Neck Carcinoma	HAVCR2	Inhibit immunity (T cell function)	The frequency of PD-1 and TIM-3 expression was significantly increased in CD8+ TILs compared with CD8+ PBLs (P = 0.008 and P = 0.02, respectively). Indeed, the increased frequency of PD-1+?and TIM-3+?CD8+?TILs was inversely correlated with clinical outcome of cetuximab therapy
28407528	Non-small Cell Lung Carcinoma	CD274	Inhibit immunity (T cell function); immnotherapy target	Results from recent phase II and phase III randomised trials testing other ICIs have been presented. In Keynote-024, pembrolizumab, an anti-PD1 antibody, was reported to have great efficacy in the first-line treatment of PDL1?≥?50% tumours (30% of screened tumours), with a progression-free survival (PFS, median) of 10.4 months versus 6.0 months with chemotherapy (CT; hazard ratio [HR]?=?0.50; 95% confidence interval [95% CI] 0.37-0.68, P?<?0.001), overall response rate (ORR) of 45% versus 28% with CT (P?=?0.0011), and a 1-year overall survival (OS) of around 70%. An encouraging report of the efficacy of pembrolizumab in addition to CT in first-line treatment in unselected NSCLC was also presented (Keynote-021) with an ORR of 55% versus 29% with CT alone (P = 0.0016). Atezolizumab, an anti-PDL1 antibody, showed efficacy for second-line treatment compared with docetaxel (OAK phase III study) with an OS (median) of 13.8 months versus 9.6 months with docetaxel.
28394331	Pancreatic Ductal Adenocarcinoma	LGALS9	Inhibit immunity	We found that dectin 1 is highly expressed on macrophages in pancreatic ductal adenocarcinoma (PDA). Dectin 1 ligation accelerated the progression of PDA in mice, whereas deletion of Clec7a-the gene encoding dectin 1-or blockade of dectin 1 downstream signaling was protective. We found that dectin 1 can ligate the lectin galectin 9 in mouse and human PDA, which results in tolerogenic macrophage programming and adaptive immune suppression. Upon disruption of the dectin 1-galectin 9 axis, CD4+ and CD8+ T cells, which are dispensable for PDA progression in hosts with an intact signaling axis, become reprogrammed into indispensable mediators of anti-tumor immunity.
28394331	Pancreatic Ductal Adenocarcinoma	CLEC7A	Inhibit immunity	We found that dectin 1 is highly expressed on macrophages in pancreatic ductal adenocarcinoma (PDA). Dectin 1 ligation accelerated the progression of PDA in mice, whereas deletion of Clec7a-the gene encoding dectin 1-or blockade of dectin 1 downstream signaling was protective. We found that dectin 1 can ligate the lectin galectin 9 in mouse and human PDA, which results in tolerogenic macrophage programming and adaptive immune suppression. Upon disruption of the dectin 1-galectin 9 axis, CD4+ and CD8+ T cells, which are dispensable for PDA progression in hosts with an intact signaling axis, become reprogrammed into indispensable mediators of anti-tumor immunity.
28387924	Lung Carcinoma	EGFR	Promote immunity (infiltration)	We have investigated lung cancer specimens for somatic mutations in a targeted panel of 612 human genes, the majority being protein kinases. There was a significant inverse correlation between the number of infiltrating stromal CD8+ lymphocytes and the presence of EGFR mutations.
28381543	Breast Carcinoma	SETD1B	Inhibit immunity (T cell function)	Instead, tumor-induced MDSCs showed increased SETD1B expression as compared with their cellular equivalents in tumor-free mice. Chromatin immunoprecipitation revealed that H3K4me3, the target of SETD1B, was enriched at the nos2 promoter in tumor-induced MDSCs, and inhibition or silencing of SETD1B diminished iNOS expression in tumor-induced MDSCs. Our results show how tumor cells use the SETD1B-H3K4me3 epigenetic axis to bypass a normal role for IRF8 expression in activating iNOS expression in MDSCs when they are generated under pathologic conditions.
28378740	Breast Carcinoma	CD47	Inhibit immunity	We identify two distinct super-enhancers (SEs) associated with CD47 in certain cancer cell types. We show that a set of active constituent enhancers, located within the two CD47 SEs, regulate CD47 expression in different cancer cell types and that disruption of CD47 SEs reduces CD47 gene expression. Finally we report that the TNF-NFKB1 signalling pathway directly regulates CD47 by interacting with a constituent enhancer located within a CD47-associated SE specific to breast cancer. These results suggest that cancers can evolve SE to drive CD47 overexpression to escape immune surveillance.
28368722	Melanoma; Ovarian Carcinoma	CD274	Inhibit immunity (T cell function)	Our recent report shows that tumor cell-intrinsic CD274 promotes MTORC1 signaling in mouse melanoma and mouse and human ovarian cancer, inhibits autophagy and sensitizes some tumors to clinically available pharmacological autophagy inhibitors and confers resistance to MTOR inhibitors. Tumor CD274 could be a biomarker of autophagy or MTOR inhibitor response in selected tumors, and these inhibitors could improve anti-CD274 or anti-PDCD1 cancer immunotherapy.
28368410	Breast Carcinoma	CHI3L1	Promote immunity	Genetic ablation of Chi3L1 in fibroblasts in vivo attenuated tumor growth, macrophage recruitment and reprogramming to an M2-like phenotype, enhanced tumor infiltration by CD8+ and CD4+ T cells and promoted a Th1 phenotype. These results indicate that CAF-derived Chi3L1 promotes tumor growth and shifts the balance of the immune milieu towards type 2 immunity.
28356390	Melanoma	TBK1	Inhibit immunity	DC-specific deletion of Tbk1 causes T cell activation and autoimmune symptoms and also enhances antitumor immunity in animal models of cancer immunotherapy. The TBK1-deficient DCs have up-regulated expression of co-stimulatory molecules and increased T cell-priming activity.
28356386	Breast Carcinoma	IRF8	Promote immunity	We recently showed that IRF8 inversely controls MDSC burden in tumor models, particularly the PMN-MDSC subset. In this study, we showed that: 1) tumor growth was associated with a selective expansion of newly defined IRF8lo granulocyte progenitors (GPs); 2) tumor-derived GPs had an increased ability to form PMN-MDSCs; 3) tumor-derived GPs shared gene expression patterns with IRF8-/- GPs, suggesting that IRF8 loss underlies GP expansion; and 4) enforced IRF8 overexpression in vivo selectively constrained tumor-induced GP expansion. These findings support the hypothesis that PMN-MDSCs result from selective expansion of IRF8lo GPs, and that strategies targeting IRF8 expression may limit their load to improve immunotherapy efficacy.
28346412	Prostate Carcinoma	C10orf54	Inhibit immunity	To identify additional immune-inhibitory pathways in the prostate-tumor microenvironment, we evaluated untreated and ipilimumab-treated tumors from patients in a presurgical clinical trial. Levels of the PD-L1 and VISTA inhibitory molecules increased on independent subsets of macrophages in treated tumors. Our data suggest that VISTA represents another compensatory inhibitory pathway in prostate tumors after ipilimumab therapy.
28302645	Melanoma; Colorectal Adenocarcinoma	CD274	Inhibit immunity (T cell function)	We used three mouse tumor models sensitive to PD-1 blockade to evaluate the significance of PD-L1 on tumor versus nontumor cells. PD-L1 on nontumor cells is critical for inhibiting antitumor immunity in B16 melanoma and a genetically engineered melanoma. In contrast, PD-L1 on MC38 colorectal adenocarcinoma cells is sufficient to suppress antitumor immunity, as deletion of PD-L1 on highly immunogenic MC38 tumor cells allows effective antitumor immunity. MC38-derived PD-L1 potently inhibited CD8+ T cell cytotoxicity. Wild-type MC38 cells outcompeted PD-L1-deleted MC38 cells in vivo, demonstrating tumor PD-L1 confers a selective advantage. Thus, both tumor- and host-derived PD-L1 can play critical roles in immunosuppression. Our findings establish reduced cytotoxicity as a key mechanism by which tumor PD-L1 suppresses antitumor immunity and demonstrate that tumor PD-L1 is not just a marker of suppressed antitumor immunity.
28295457	Hepatocellular Carcinoma	IFIT3	Promote immunity (T cell function)	We found that higher expression of IFIT3, but not other IFITs, in HCC tissues predicts better response to IFN-α therapy, suggesting that IFIT3 may be a useful predictor of the response to IFN-α therapy in HCC patients. Mechanistically, IFIT3 enhanced the antitumor effects of IFN-α by promoting IFN-α effector responses both in vitro and in vivo. IFIT3 could bind signal transducer and activator of transcription 1 (STAT1) and STAT2 to enhance STAT1-STAT2 heterodimerization and nuclear translocation upon IFN-α treatment, thus promoting IFN-α effector signaling.
28295265	Melanoma	CARD9	Promote immunity (T cell function)	In vivo, Dectin-1-mediated Card9 activation after vaccination drives both expansion and activation of Ag-specific CTLs, resulting in long-lasting CTL responses that are sufficient to protect mice from tumor challenge. This Dectin-1-induced antitumor immune response was independent of NK cell function and completely abrogated in Card9-deficient mice.
28295265	Melanoma	CLEC7A	Promote immunity (T cell function)	In vivo, Dectin-1-mediated Card9 activation after vaccination drives both expansion and activation of Ag-specific CTLs, resulting in long-lasting CTL responses that are sufficient to protect mice from tumor challenge. This Dectin-1-induced antitumor immune response was independent of NK cell function and completely abrogated in Card9-deficient mice.
28292946	Chronic Myelomonocytic Leukemia	CYBB	Inhibit immunity (T cell function)	The dominant population of primary human CMML cells was found to express membrane-bound NOX2 and to release ROS, which, in turn, triggered extensive PARP-1-dependent cell death in cocultured NK cells, CD8+ T effector memory cells, and CD8+ T effector cells. Inhibitors of ROS formation and scavengers of extracellular ROS prevented CMML cell-induced lymphocyte death and facilitated NK cell degranulation toward Ab-coated, primary CMML cells. In patients with CMML, elevation of immature cell counts (CD34+) in blood was associated with reduced expression of several NK cell-activating receptors.
28290464	Breast Carcinoma	CCL18	Inhibit immunity (T cell function)	Here, we show that tumor-infiltrating naive CD4+ T cells and Tregs in human breast cancer have overlapping TCR repertoires, while hardly overlap with circulating Tregs, suggesting that intratumoral Tregs mainly develop from naive T cells in situ rather than from recruited Tregs. Furthermore, the abundance of naive CD4+ T cells and Tregs is closely correlated, both indicating poor prognosis for breast cancer patients. Naive CD4+ T cells adhere to tumor slices in proportion to the abundance of CCL18-producing macrophages. Moreover, adoptively transferred human naive CD4+ T cells infiltrate human breast cancer orthotopic xenografts in a CCL18-dependent manner. In human breast cancer xenografts in humanized mice, blocking the recruitment of naive CD4+ T cells into tumor by knocking down the expression of PITPNM3, a CCL18 receptor, significantly reduces intratumoral Tregs and inhibits tumor progression. These findings suggest that breast tumor-infiltrating Tregs arise from chemotaxis of circulating naive CD4+ T cells that differentiate into Tregs in situ.
28290464	Breast Carcinoma	PITPNM3	Promote immunity	Here, we show that tumor-infiltrating naive CD4+ T cells and Tregs in human breast cancer have overlapping TCR repertoires, while hardly overlap with circulating Tregs, suggesting that intratumoral Tregs mainly develop from naive T cells in situ rather than from recruited Tregs. Furthermore, the abundance of naive CD4+ T cells and Tregs is closely correlated, both indicating poor prognosis for breast cancer patients. Naive CD4+ T cells adhere to tumor slices in proportion to the abundance of CCL18-producing macrophages. Moreover, adoptively transferred human naive CD4+ T cells infiltrate human breast cancer orthotopic xenografts in a CCL18-dependent manner. In human breast cancer xenografts in humanized mice, blocking the recruitment of naive CD4+ T cells into tumor by knocking down the expression of PITPNM3, a CCL18 receptor, significantly reduces intratumoral Tregs and inhibits tumor progression. These findings suggest that breast tumor-infiltrating Tregs arise from chemotaxis of circulating naive CD4+ T cells that differentiate into Tregs in situ.
28288138	Non-Small Cell Lung Carcinoma	MUC1	Inhibit immunity	The present studies demonstrate that MUC1-C activates PD-L1 expression in NSCLC cells. We show that MUC1-C increases NF-κB p65 occupancy on the CD274/PD-L1 promoter and thereby drives CD274 transcription. In concert with these results, targeting MUC1-C in NSCLC tumors suppresses PD-L1 and induces these effectors of innate and adaptive immunity. These findings support a previously unrecognized central role for MUC1-C in integrating PD-L1 activation with suppression of immune effectors and poor clinical outcome.
28287407	Melanoma	MSN	Inhibit immunity	Here, we have discovered that moesin is translationally regulated by TGF-β and is also required for optimal TGF-β signaling that promotes efficient development of iTregs. Loss of moesin impaired the development and function of both peripherally derived iTregs and in vitro-induced Tregs. Mechanistically, we identified an interaction between moesin and TGF-β receptor II (TβRII) that allows moesin to control the surface abundance and stability of TβRI and TβRII. We also found that moesin is required for iTreg conversion in the tumor microenvironment, and the deletion of moesin from recipient mice supported the rapid expansion of adoptively transferred CD8+ T cells against melanoma.
24856586	Pancreatic Ductal Adenocarcinoma	CTLA4	Immunotherapy target	Although myofibroblast-depleted tumors did not respond to gemcitabine, anti-CTLA4 immunotherapy reversed disease acceleration and prolonged animal survival.
24848257	Rhabdomyosarcoma	CD274	Inhibit immunity (T cell function)	Murine RMS showed high surface expression of PD-L1, and anti-PD1 prevented tumor growth if initiated early after tumor inoculation; however, delayed anti-PD1 had limited benefit.
24848257	Rhabdomyosarcoma	CXCR2	Inhibit immunity (T cell fcuntion)	RMS induced robust expansion of CXCR2(+)CD11b(+)Ly6G(hi) MDSCs, and CXCR2 deficiency prevented CD11b(+)Ly6G(hi) MDSC trafficking to the tumor. When tumor trafficking of MDSCs was inhibited by CXCR2 deficiency, or after anti-CXCR2 monoclonal antibody therapy, delayed anti-PD1 treatment induced significant antitumor effects. Thus, CXCR2(+)CD11b(+)Ly6G(hi) MDSCs mediate local immunosuppression, which limits the efficacy of checkpoint blockade in murine RMS. Human pediatric sarcomas also produce CXCR2 ligands, including CXCL8. Patients with metastatic pediatric sarcomas display elevated serum CXCR2 ligands, and elevated CXCL8 is associated with diminished survival in this population. We conclude that accumulation of MDSCs in the tumor bed limits the efficacy of checkpoint blockade in cancer. We also identify CXCR2 as a novel target for modulating tumor immune escape and present evidence that CXCR2(+)CD11b(+)Ly6G(hi) MDSCs are an important suppressive myeloid subset in pediatric sarcomas
24837434	Head and Neck Carcinoma; Colorectal Carcinoma	TNFRSF9	Promote immunity (T cell function)	The costimulatory molecule CD137 (4-1BB) is expressed following NK and memory T cell activation. We found that isolated human NK cells substantially increased expression of CD137 when exposed to cetuximab-coated, EGFR-expressing HN and CRC cell lines. Furthermore, activation of CD137 with an agonistic mAb enhanced NK cell degranulation and cytotoxicity. In multiple murine xenograft models, including EGFR-expressing cancer cells, HN cells, and KRAS-WT and KRAS-mutant CRC, combined cetuximab and anti-CD137 mAb administration was synergistic and led to complete tumor resolution and prolonged survival, which was dependent on the presence of NK cells. In patients receiving cetuximab, the level of CD137 on circulating and intratumoral NK cells was dependent on postcetuximab time and host FcyRIIIa polymorphism. Interestingly, the increase in CD137-expressing NK cells directly correlated to an increase in EGFR-specific CD8+ T cells.
24824777	Hepatocellular Carcinoma	RB1	Promote immunity	We found that RB depletion in hepatoma cells resulted in a compromised immunological response to multiple stimuli and reduced the potential of these cells to recruit myeloid cells. Viral-mediated liver-specific RB deletion in vivo led to the induction of genes associated with proliferation and cell cycle entry as well as the significant attenuation of genes associated with immune function, as evidenced by decreases in cytokine and chemokine expression, leukocyte recruitment, and hepatic inflammation. To determine if these changes in gene expression were instructive in human disease, we compared our liver-specific RB-loss gene signature to existing profiles of HCC and found that this signature was associated with disease progression and confers a worse prognosis.
24819296	Melanoma	CD80	Promote immunity	Using T cells from CD28-deficient mice and antibodies to block CD28 on human T cells, we now report that a soluble form of CD80 mediates this effect by simultaneously neutralizing PD-1-PD-L1-mediated immunosuppression and by providing CD80-CD28 costimulation, and is more effective than antibodies to PD-L1 or PD-1 in maintaining IFNγ production by PD-1(+) activated T cells. Therefore, soluble CD80 may be a more effective therapeutic than these checkpoint antibodies for facilitating the development and maintenance of antitumor immunity because it has the dual functions of preventing PD-L1-mediated immunosuppression and simultaneously delivering the second signal for T-cell activation.
24812270	Pancreatic Ductal Adenocarcinoma	LGALS1	Inhibit immunity	Genetic ablation of Gal1 in a mouse model of PDAC (EIa-myc mice) dampened tumor progression by inhibiting proliferation, angiogenesis, desmoplasic reaction and by stimulating a tumor-associated immune response, yielding a 20% increase in relative lifesplan. Cellular analyses in vitro and in vivo suggested these effects were mediated through the tumor microenvironment. Mechanistic investigations revealed that Gal1 promoted Hedgehog pathway signaling in PDAC cells and stromal fibroblasts as well as in Ela-myc tumors.
24808361	Renal Cell Carcinoma	FAS	Promote immunity	We demonstrate in this study in two murine tumor models that Treg and MDSC loss within the tumor microenvironment after IL-2/αCD40 occurs through a Fas-dependent cell death pathway. Among tumor-infiltrating leukocytes, CD8(+) T cells, neutrophils, and immature myeloid cells expressed Fas ligand after treatment. Fas was expressed by tumor-associated Tregs and immature myeloid cells, including MDSCs. Tregs and MDSCs in the tumor microenvironment expressed active caspases after IL-2/αCD40 therapy and, in contrast with effector T cells, Tregs significantly downregulated Bcl-2 expression. Adoptive transfer of Fas-deficient Tregs or MDSCs into wild-type, Treg-, or MDSC-depleted hosts resulted in the persistence of Tregs or MDSCs and the loss of antitumor efficacy in response to IL-2/αCD40. These results demonstrate the importance of Fas-mediated Treg/MDSC removal for successful antitumor immunotherapy.
24806531	Melanoma; Breast Carcinoma	IFNB1	Promote immunity	Here, we provide evidence that endogenous IFN-β is regulating the apoptosis of pro-angiogenic tumor infiltrating neutrophils by influencing both, the extrinsic as well as the intrinsic apoptosis pathways. Accordingly, the life span of tumor associated neutrophils (TANs) is remarkably prolonged in tumor bearing Ifnb1(-/-) mice compared to wild type controls. Lower expression of Fas, reactive oxygen species, active Caspase 3 and 9, as well as a change in expression pattern of proapoptotic and antiapoptotic members of the Bcl-2 family and the major apoptosome constituent Apaf-1 is observed under such conditions. In line with inhibition of apoptosis and the prolonged neutrophil survival,
24799523	Lymphoma	TLR1	Promote immunity	We treated B-cell lymphoma cells with the TLR1/2 agonist Pam3CSK4 and the genotoxic anticancer agent 1-β-D-arabinofuranosylcytosine (Ara-C). The treatment of B-cell lymphoma cells with the TLR1/2 agonist Pam3CSK4 enhanced the anticancer effects of the genotoxic agent Ara-C. Mice injected with cotreated tumor cells survived longer than mice challenged with Pam3CSK4 or Ara-C-treated cells. Administration of Pam3CSK4 or Ara-C reduced the tumor load of mice injected with tumor cells.
24799523	Lymphoma	TLR2	Promote immunity	We treated B-cell lymphoma cells with the TLR1/2 agonist Pam3CSK4 and the genotoxic anticancer agent 1-β-D-arabinofuranosylcytosine (Ara-C). The treatment of B-cell lymphoma cells with the TLR1/2 agonist Pam3CSK4 enhanced the anticancer effects of the genotoxic agent Ara-C. Mice injected with cotreated tumor cells survived longer than mice challenged with Pam3CSK4 or Ara-C-treated cells. Administration of Pam3CSK4 or Ara-C reduced the tumor load of mice injected with tumor cells.
24796276	Breast Carcinoma	CSF1	Inhibit immunity	Here, we report that intense local proliferation of fully differentiated macrophages rather than low-pace recruitment of blood-borne precursors drives TAM accumulation in a mouse model of spontaneous mammary carcinogenesis, the MMTVneu strain. TAM differentiation and expansion is regulated by CSF1, whose expression is directly controlled by STAT1 at the gene promoter level. These findings appear to be also relevant for human breast cancer, in which an interrelationship between STAT1, CSF1, and macrophage marker expression was identified.
24796276	Breast Carcinoma	STAT1	Inhibit immunity	Here, we report that intense local proliferation of fully differentiated macrophages rather than low-pace recruitment of blood-borne precursors drives TAM accumulation in a mouse model of spontaneous mammary carcinogenesis, the MMTVneu strain. TAM differentiation and expansion is regulated by CSF1, whose expression is directly controlled by STAT1 at the gene promoter level. These findings appear to be also relevant for human breast cancer, in which an interrelationship between STAT1, CSF1, and macrophage marker expression was identified.
24793239	Ovarian Carcinoma	FASLG	Inhibit immunity (infiltration and cell function)	In these tumors, FasL expression was associated with scarce CD8(+) infiltration and a predominance of FoxP3(+) T regulatory (Treg) cells. Tumor-derived vascular endothelial growth factor A (VEGF-A), interleukin 10 (IL-10) and prostaglandin E2 (PGE2) cooperatively induced FasL expression in endothelial cells, which acquired the ability to kill effector CD8(+) T cells but not Treg cells because of higher levels of c-FLIP expression in Treg cells. In mice, genetic or pharmacologic suppression of FasL produced a substantial increase in the influx of tumor-rejecting CD8(+) over FoxP3(+) T cells. Pharmacologic inhibition of VEGF and PGE2 produced a marked increase in the influx of tumor-rejecting CD8(+) over FoxP3(+) T cells that was dependent on attenuation of FasL expression and led to CD8-dependent tumor growth suppression.
24793239	Ovarian Carcinoma	IL10	Inhibit immunity (infiltration and cell function)	In these tumors, FasL expression was associated with scarce CD8(+) infiltration and a predominance of FoxP3(+) T regulatory (Treg) cells. Tumor-derived vascular endothelial growth factor A (VEGF-A), interleukin 10 (IL-10) and prostaglandin E2 (PGE2) cooperatively induced FasL expression in endothelial cells, which acquired the ability to kill effector CD8(+) T cells but not Treg cells because of higher levels of c-FLIP expression in Treg cells. In mice, genetic or pharmacologic suppression of FasL produced a substantial increase in the influx of tumor-rejecting CD8(+) over FoxP3(+) T cells. Pharmacologic inhibition of VEGF and PGE2 produced a marked increase in the influx of tumor-rejecting CD8(+) over FoxP3(+) T cells that was dependent on attenuation of FasL expression and led to CD8-dependent tumor growth suppression.
24789737	Lung Carcinoma	IFNG	Promote immunity	Overexpression of miR-301a in DCs suppressed IL-12 secretion, decreased IFN-γ release from antigen-specific cytotoxic T cells, and shifted antigen-specific T helper cytokine profile away from IFN-γ towards IL-13 and IL-17A-secreting T cells.
24789737	Lung Carcinoma	IL12A	Promote immunity	Overexpression of miR-301a in DCs suppressed IL-12 secretion, decreased IFN-γ release from antigen-specific cytotoxic T cells, and shifted antigen-specific T helper cytokine profile away from IFN-γ towards IL-13 and IL-17A-secreting T cells.
24789574	Hepatocellular Carcinoma	TNFRSF9	Promote immunity (T cell function)	We assessed the therapeutic effects of stimulating CD137, a member of the TNF receptor family, with agonistic monoclonal antibodies (mAb). In an orthotopic HCC the treatment consistently leads to complete tumor regression in 40-60% of animals. The protection is long lasting in the animals responding to the treatment, which can reject a second tumor challenge more than 3 months after treatment and eradication of the first malignancy. The efficacy of anti-CD137 mAb treatment is associated with early, sustained recruitment of iNOS-positive macrophages within tumor nodules. Moreover, in the absence of treatment, tumor development is accompanied by infiltration by myeloid derived suppressor cells (MDSC) and regulatory T lymphocytes. In mice responding to the anti-CD137 mAb treatment, this infiltration is very limited, and a combination treatment with a depletion of MDSC leads to the recovery of 80% of the mice.
24786787	Breast Carcinoma	C5AR1	Inhibit immunity (T cell function)	In this report, we demonstrate in a preclinical mouse model of breast cancer that the complement anaphylatoxin C5a receptor (C5aR) facilitates metastasis by suppressing effector CD8(+) and CD4(+) T-cell responses in the lungs. Mechanisms of this suppression involve recruitment of immature myeloid cells to the lungs and regulation of TGFβ and IL10 production in these cells. TGFβ and IL10 favored generation of T regulatory cells (Treg) and Th2-oriented responses that rendered CD8(+) T cells dysfunctional. Importantly, pharmacologic blockade of C5aR or its genetic ablation in C5aR-deficient mice were sufficient to reduce lung metastases. In contrast to previous findings, we observed that C5aR signaling promoted Treg generation and suppressed T-cell responses in organs where metastases arose.
24780758	Pancreatic Adenocarcinoma	NCR3LG1	Promote immunity (T cell function)	Tumor cells from different cancer entities released B7-H6 by ectodomain shedding mediated by the cell surface proteases "a disintegrin and metalloproteases" (ADAM)-10 and ADAM-17, as demonstrated through the use of pharmacologic inhibitors or siRNA-mediated gene attenuation. Inhibiting this proteolytic shedding process increased the levels of B7-H6 expressed on the surface of tumor cells, enhancing NKp30-mediated activation of NK cells.
24780758	Pancreatic Adenocarcinoma	ADAM10	Inhibit immunity	Tumor cells from different cancer entities released B7-H6 by ectodomain shedding mediated by the cell surface proteases "a disintegrin and metalloproteases" (ADAM)-10 and ADAM-17, as demonstrated through the use of pharmacologic inhibitors or siRNA-mediated gene attenuation. Inhibiting this proteolytic shedding process increased the levels of B7-H6 expressed on the surface of tumor cells, enhancing NKp30-mediated activation of NK cells.
24780758	Pancreatic Adenocarcinoma	ADAM17	Inhibit immunity	Tumor cells from different cancer entities released B7-H6 by ectodomain shedding mediated by the cell surface proteases "a disintegrin and metalloproteases" (ADAM)-10 and ADAM-17, as demonstrated through the use of pharmacologic inhibitors or siRNA-mediated gene attenuation. Inhibiting this proteolytic shedding process increased the levels of B7-H6 expressed on the surface of tumor cells, enhancing NKp30-mediated activation of NK cells.
24778632	Breast Carcinoma	IL33	Inhibit immunity	Murine breast carcinoma models suggest disruption of ST2 signaling may enhance the anti-tumor immune response, suggesting IL-33 impedes anti-tumor immunity. However, the role of IL-33 in patients with breast cancers (BC) is not elucidated. Murine breast carcinoma models suggest disruption of ST2 signaling may enhance the anti-tumor immune response, suggesting IL-33 impedes anti-tumor immunity. However, the role of IL-33 in patients with breast cancers (BC) is not elucidated. We detected the expression of IL-33 in tumor tissue, and IL-33 and its related cytokines in serum from BC patients. Using Luminex and immunohistochemistry methods, we found that serum levels of IL-33 were nearly twofold higher in patients with BC, compared to patients with benign breast diseases. In cancer tissues, expression of IL-33 was higher than matched normal breast tissues from the same patients, and was also associated with a well-differentiated phenotype, HER2 overexpression, more lymph nodes involvement, and a family history of malignant carcinoma.
24778448	Melanoma	IKZF1	Inhibit immunity (T cell function)	Naive murine CD8 T cells haplo-insufficient for Ikzf1 failed to upregulate Ikaros, produced autocrine IL-2, and differentiated in an IL-2-dependent manner into IFN-γ-producing CTLs in response to TCR/CD28 stimulation alone. Furthermore, Ikzf1 haplo-insufficient CD8(+) T cells were more effective at controlling Listeria infection and B16 melanoma growth in vivo, and they could provide help to neighboring, non-IL-2-producing cells to differentiate into IFN-γ-producing effectors.
24778448	Melanoma	IL2	Promote immunity	Naive murine CD8 T cells haplo-insufficient for Ikzf1 failed to upregulate Ikaros, produced autocrine IL-2, and differentiated in an IL-2-dependent manner into IFN-γ-producing CTLs in response to TCR/CD28 stimulation alone. Furthermore, Ikzf1 haplo-insufficient CD8(+) T cells were more effective at controlling Listeria infection and B16 melanoma growth in vivo, and they could provide help to neighboring, non-IL-2-producing cells to differentiate into IFN-γ-producing effectors.
24778419	Melanoma; Lung Carcinoma; Colon Carcinoma; Breast Carcinoma	HIF1A	Inhibit immunity (T cell function)	Furthermore, PD-L1 up-regulation under hypoxia was dependent on hypoxia-inducible factor-1α (HIF-1α) but not HIF-2α. Chromatin immunoprecipitation and luciferase reporter assay revealed direct binding of HIF-1α to a transcriptionally active hypoxia-response element (HRE) in the PD-L1 proximal promoter. Blockade of PD-L1 under hypoxia enhanced MDSC-mediated T cell activation and was accompanied by the down-regulation of MDSCs IL-6 and IL-10. Finally, neutralizing antibodies against IL-10 under hypoxia significantly abrogated the suppressive activity of MDSCs.
24778419	Melanoma; Lung Carcinoma; Colon Carcinoma; Breast Carcinoma	CD274	Inhibit immunity (T cell function)	We demonstrate that MDSCs at the tumor site show a differential expression of PD-L1 as compared with MDSCs from peripheral lymphoid organ (spleen). Hypoxia caused a rapid, dramatic, and selective up-regulation of PD-L1 on splenic MDSCs in tumor-bearing mice. This was not limited to MDSCs, as hypoxia also significantly increased the expression of PD-L1 on macrophages, dendritic cells, and tumor cells. Blockade of PD-L1 under hypoxia enhanced MDSC-mediated T cell activation and was accompanied by the down-regulation of MDSCs IL-6 and IL-10.
24778419	Melanoma; Lung Carcinoma; Colon Carcinoma; Breast Carcinoma	IL10	Inhibit immunity (T cell function)	Finally, neutralizing antibodies against IL-10 under hypoxia significantly abrogated the suppressive activity of MDSCs.
24778323	Lymphoma; Melanoma; Colon Carcinoma; Breast Carcinoma	ODC1	Inhibit immunity (infiltration)	A polyamine-blocking therapy (PBT) that combines the well-characterized ornithine decarboxylase (ODC) inhibitor difluoromethylornithine (DFMO) with AMXT 1501, a novel inhibitor of the polyamine transport system, blocked tumor growth in immunocompetent mice but not in athymic nude mice lacking T cells\j Analysis of CD45(+) tumor immune infiltrates revealed that PBT decreased levels of Gr-1(+)CD11b(+) myeloid suppressor cells and increased CD3(+) T cells.
24778318	Lung Carcinoma; Fibrosacroma	LRP1	Promote immunity	Using targeted genetic disruption of the interaction between HSPs and CD91, we demonstrated that specific ablation of CD91 in APCs prevented the establishment of antitumor immunity. The antitumor immunity was also inhibited when the transfer of tumor-derived HSPs to APCs was prevented using an endogenous inhibitor of CD91.
24778275	Lung Carcinoma; Pancreatic Ductal Adenocarcinoma	HMOX1	Inhibit immunity	A basis for the function of the FAP(+)/CD45(+) subset is shown to be the immune inhibitory enzyme, heme oxygenase-1 (HO-1). The FAP(+)/CD45(+) cells are the major tumoral source of HO-1, and an inhibitor of HO-1, Sn mesoporphyrin, causes the same extent of immune-dependent arrest of LL2/OVA tumor growth as does the depletion of these cells. Because this observation of immune suppression by HO-1 expressed by the FAP(+)/CD45(+) stromal cell is replicated in a transplanted model of pancreatic ductal adenocarcinoma, we conclude that pharmacologically targeting this enzyme may improve cancer immunotherapy.
24778163	Bladder Carcinoma	CD40	Promote immunity	Despite the lack of a slow-release system, local anti-CD40 therapy was dependent on tumor antigen at the injection site for clearance of distant tumors. To summarize, local low-dose administration of anti-CD40 antibody mediates antitumor effects in murine models with reduced toxicity and may represent an attractive treatment alternative in the clinic.
24778130	Clear Cell Renal Cell Carcinoma	VEGFA	Inhibit immunity (infiltration)	In addition, there was a significant and positive relationship between the presence of TIL as assessed by IHC for CD3 and PDL-1 by IHC (r = 0.25; P = 0.015), and there was a trend toward an inverse relationship between TIL and VEGFA gene expression (r = -0.18; P = 0.089).
24777531	Melanoma; Colon Carcinoma	USP15	Inhibit immunity (T cell function)	Here we identified the DUB USP15 as a crucial negative regulator of T cell activation. USP15 stabilized the E3 ubiquitin ligase MDM2, which in turn negatively regulated T cell activation by targeting the degradation of the transcription factor NFATc2. USP15 deficiency promoted T cell activation in vitro and enhanced T cell responses to bacterial infection and tumor challenge in vivo. USP15 also stabilized MDM2 in cancer cells and regulated p53 function and cancer-cell survival.
24777531	Melanoma; Colon Carcinoma	MDM2	Inhibit immunity (T cell function)	Here we identified the DUB USP15 as a crucial negative regulator of T cell activation. USP15 stabilized the E3 ubiquitin ligase MDM2, which in turn negatively regulated T cell activation by targeting the degradation of the transcription factor NFATc2. USP15 deficiency promoted T cell activation in vitro and enhanced T cell responses to bacterial infection and tumor challenge in vivo. USP15 also stabilized MDM2 in cancer cells and regulated p53 function and cancer-cell survival.
24777531	Melanoma; Colon Carcinoma	NFATC2	Inhibit immunity	Here we identified the DUB USP15 as a crucial negative regulator of T cell activation. USP15 stabilized the E3 ubiquitin ligase MDM2, which in turn negatively regulated T cell activation by targeting the degradation of the transcription factor NFATc2. USP15 deficiency promoted T cell activation in vitro and enhanced T cell responses to bacterial infection and tumor challenge in vivo. USP15 also stabilized MDM2 in cancer cells and regulated p53 function and cancer-cell survival.
24777249	Sacroma	IL6	Inhibit immunity (T cell function)	Here, we showed that in tumor-bearing mice, generation of tumor antigen-specific effector T-helper cells (TH1) was significantly attenuated, and impaired TH1 differentiation was restored by the temporal blockade of interleukin (IL)-6 activity at the T-cell priming phase. Despite comparable suppressive activity of IL-6(+/+) and IL-6(-/-) MDSC on primary T-cell activation, transfer of IL-6(+/+) MDSC, but not IL-6(-/-) MDSC, dampened the efficient induction of effector TH1 cells and counteracted CD4(+) T cell-mediated antitumor immunity including cognate help for CD8(+) T cells in vivo.
24769443	Melanoma	CLEC4G	Inhibit immunity (T cell function)	Here we report the finding that LSECtin is expressed commonly in melanomas where it blunts tumor-specific T-cell responses. When expressed in B16 melanoma cells, LSECtin promoted tumor growth, whereas its blockade slowed tumor growth in either wild-type or LSECtin-deficient mice. Mechanistic investigations determined that LSECtin inhibited the proliferation of tumor-specific effector T cells by downregulating the cell cycle kinases CDK2, CDK4, and CDK6. Accordingly, as expressed in B16, tumor cells LSECtin inhibited tumor-specific T-cell responses relying upon proliferation in vitro and in vivo.
24769442	Breast Carcinoma	API5	Inhibit immunity (T cell function)	In this study, we show that the antiapoptotic gene API5 acts as an immune escape gene in tumors by rendering them resistant to apoptosis triggered by tumor antigen-specific T cells. Its RNAi-mediated silencing in tumor cells expressing high levels of API5 restored antigen-specific immune sensitivity. Conversely, introducing API5 into API5(low) cells conferred immune resistance. Mechanistic investigations revealed that API5 mediated resistance by upregulating FGF2 signaling through a FGFR1/PKCδ/ERK effector pathway that triggered degradation of the proapoptotic molecule BIM.
24752296	Melanoma	TNFSF11	Inhibit immunity	We show that in vivo RANKL blockade selectively and transiently depletes Aire and TSA expression in the thymus to create a window of defective negative selection. Furthermore, we demonstrate that RANKL blockade can rescue melanoma-specific T cells from thymic deletion and that persistence of these tumor-specific effector T cells promoted increased host survival in response to tumor challenge.
24746181	Pancreatic Ductal Adenocarcinoma	L1CAM	Inhibit immunity (T cell function)	Predominantly T-regs but not T-effs showed an increased migration on L1CAM expressing H6c7 and Panc1 cells. Whereas proliferation of T-regs did not change in the presence of L1CAM, T-effs proliferated less, exhibited a decreased CD25 expression and an increased expression of CD69. Moreover, these T-effs exhibited a regulatory phenotype as they inhibited proliferation of autologous T cells. Accordingly, CD4(+)CD25(-)CD69(+) T cells were highly abundant in PDAC tissues compared to blood being associated with nodal invasion and higher grading in PDAC patients.
24732076	Colorectal Carcinoma	TNFRSF4	Promote immunity (T cell function)	Here, we explored the mechanism of antitumor activity mediated by an agonistic antibody (clone OX86) to the co-stimulatory TNFR OX40 (CD134). OX40 was highly expressed by intratumoral T cells, particularly those of the FoxP3(+) regulatory T-cell (Treg) lineage. OX86 administration resulted in the depletion of intratumoral regulatory T cells in an activating FcγR-dependent manner, which correlated with tumor regression.
24729415	B-cell non-Hodgkin Lymphoma; Nodular Lymphocyte Predominant Hodgkin Lymphoma	CXCR5	Inhibit immunity	In vivo imaging revealed that CXCR5::CD3 and its parental CXCR5 antibody efficiently prevent tumor growth in a xenograft model of B-cell lymphoma in mice and prolong their survival
24726056	Primary Effusion Lymphoma	CD47	Inhibit immunity	Knocking down CD47 and anti-CD47 Ab promoted phagocytic activities of macrophages in a CD47 expression-dependent manner in vitro. Treatment with anti-CD47 Ab inhibited ascite formation and organ invasion completely in vivo compared with control IgG-treated mice.
24698324	Melanoma	PRF1	Promote immunity	When immunodeficient mice were injected with miR-150(-/-) NK cells, there was a significant reduction in tumor growth and metastasis of B16F10 melanoma. We report that miR-150 binds to 3' untranslated regions of mouse and human Prf1, posttranscriptionally downregulating its expression. Mouse wild-type NK cells displayed downregulated miR-150 expression in response to IL-15, which led to corresponding repression and induction of Prf1 during rest and after IL-15 activation, respectively.
24696473	Nasopharyngeal Carcinoma	IDO1	Inhibit immunity (T cell function)	Here, we showed that some macrophages in the tumor stroma of nasopharyngeal carcinoma (NPC) tissue expressed the immunosuppressive protein indoleamine 2,3-dioxygenase (IDO) more strongly than did tumor cells. Moreover, the activation of IDO in response to EBV infection of MDMs suppressed the proliferation of T cells and impaired the cytotoxic activity of CD8(+) T cells, whereas the inhibition of IDO activity with 1-methyl-l-tryptophan (1-MT) did not affect T cell proliferation and function.
24691994	Melanoma	C10orf54	Inhibit immunity (T cell function)	VISTA monoclonal antibody (mAb) treatment increased the number of tumor-specific T cells in the periphery and enhanced the infiltration, proliferation, and effector function of tumor-reactive T cells within the TME. VISTA blockade altered the suppressive feature of the TME by decreasing the presence of monocytic myeloid-derived suppressor cells and increasing the presence of activated dendritic cells within the tumor microenvironment. In addition, VISTA blockade impaired the suppressive function and reduced the emergence of tumor-specific Foxp3(+)CD4(+) regulatory T cells. Consequently, VISTA mAb administration as a monotherapy significantly suppressed the growth of both transplantable and inducible melanoma.
24691438	Melanoma	NOS1	Inhibit immunity (T cell function)	Here, we demonstrated in a coculture system that melanoma cells differentially impairs the IFN-α response in PBMCs and that the inhibitory potential of a particular melanoma cell correlates with NOS1 expression. Evaluation of NOS1 levels in melanomas and IFN responsiveness of purified PBMCs from patients indicated a negative correlation between NOS1 expression in melanomas and the responsiveness of PBMCs to IFN-α.
21061445	Neuroblastoma	MICA	Inhibit immunity (NK cell function)	Most importantly, elevated sMICA levels in patients plasma correlated significantly with impaired dNK-cell-mediated cytotoxicity. This effect could be reversed by high-dose infusion of activated dNK cells, which display high levels of surface NKG2D. Our data suggest that the provided excess of NKG2D leads to clearance of sMICA and preserves cytotoxicity of dNK cells via non-occupied NKG2D.
21057494	Castration-Resistant Prostate Carcinoma	CDH2	Inhibit immunity	In vivo, these antibodies slowed the growth of multiple established CRPC xenografts, blocked local invasion and metastasis and, at higher doses, led to complete regression. N-cadherin-specific antibodies markedly delayed the time to emergence of castration resistance, markedly affected tumor histology and angiogenesis, and reduced both AKT serine-threonine kinase activity and serum interleukin-8 (IL-8) secretion.
21041732	Melanoma; Lung Carcinoma	TLR2	Promote immunity	Tumor growth inhibition after peritumoral administration of Pam(3)CSK(4) was restored in Kit(W-sh/W-sh) mice by local reconstitution with wild-type, but not TLR2-deficient, mast cells. Mast cells secrete multiple mediators after Pam(3)CSK(4) activation, and in vivo mast cell reconstitution studies also revealed that tumor growth inhibition required mast cell-derived IL-6, but not TNF. TLR2-activated mast cells also inhibited the growth of lung cancer cells in vivo.
21037100	Cervical Intraepithelial Neoplasia	MADCAM1	Promote immunity (infiltration)	Vascular endothelial expression of mucosal addressin cell adhesion molecule-1, the ligand that supports entry of α(4)β(7)(+) T cells into tissues, colocalized tightly with the distribution of CD8 T cells and was not expressed in persistent dysplastic epithelium.
20980695	Pleural Malignant Mesothelioma	ICOS	Promote immunity (T cell function)	COS stimulation induced c-MAF, RORC2, and T-bet expression in these cells, leading to increased secretion of interleukin-21 (IL-21), IL-17, and interferon-γ (IFN-γ) compared with cells stimulated with CD28. Conversely, CD28 ligation abrogated ICOS costimulation, dampening RORC2 expression while promoting the expression of the aryl hydrocarbon receptor, which led to reduced secretion of IL-17 and enhanced production of IL-22 compared with cells stimulated with ICOS. Moreover, ICOS promoted the robust expansion of IL-17(+)IFN-γ(+) human T cells, and the antitumor activity of these cells after adoptive transfer into mice bearing large human tumors was superior to that of cells expanded with CD28.
20978210	Bladder Carcinoma	PECAM1	Inhibit immunity (T cell function)	Here we report that tumor and allograft rejection are significantly enhanced in CD31-deficient mice, which are also resistant to tolerance induction. We show that loss of CD31 interactions leads to enhanced primary clonal expansion, increased killing capacity, and diminished regulatory functions by T cells.
20955708	Pancreatic Intraductal Papillary Mucinous Neoplasm, Pancreatobiliary-Type	CXCL17	Promote immunity (infiltration)	CXCL17 and ICAM2 induced infiltration and accumulation of the tumor epithelial layer by immature myeloid dendritic cells. This was followed by a cellular immune reaction and ICAM2 simultaneously promoted the susceptibility of the tumor cells to cytotoxic T-cell-mediated cytolysis. These processes had a synergistic effect to increase the anti-tumor immune response.
20955708	Pancreatic Intraductal Papillary Mucinous Neoplasm, Pancreatobiliary-Type	ICAM2	Promote immunity (infiltration; T cell function)	CXCL17 and ICAM2 induced infiltration and accumulation of the tumor epithelial layer by immature myeloid dendritic cells. This was followed by a cellular immune reaction and ICAM2 simultaneously promoted the susceptibility of the tumor cells to cytotoxic T-cell-mediated cytolysis. These processes had a synergistic effect to increase the anti-tumor immune response.
20940398	Pancreatic Carcinoma	IL2	Promote immunity	Production of interleukin-2 by tumor resident CD4(+) T cells enhanced CD8(+) T-cell proliferation and upregulated expression of granzyme B.
20935648	Melanoma	IL12A	Promote immunity (T cell function)	IL-12 initiated local antitumor immunity by stimulating a subset of NKp46(+) lymphoid tissue-inducer (LTi) cells dependent on the transcription factor RORγt. The presence of these NKp46(+) LTi cells induced upregulation of adhesion molecules in the tumor vasculature and resulted in more leukocyte invasion.
20924104	Breast Carcinoma	SHC1	Inhibit immunity (infiltration)	Inactivation of ShcA signaling within tumor cells results in extensive CD4(+) T-cell infiltration and induction of a humoral immune response in mammary tumors. This is associated with a robust CTL response in preneoplastic lesions that are deficient in ShcA signaling. Moreover, mammary tumor progression of ShcA-deficient hyperplasias is accelerated in a T cell-deficient background. We also uncover a clinically relevant correlation between high ShcA expression and low CTL infiltration in human breast cancers.
20889921	Melanoma	IFNG	Inhibit immunity (T cell function)	Surprisingly, CTL tumor recognition and antitumor effects decreased in the presence of interferon γ (IFNγ), a cytokine that can provide therapeutic benefit. Tumors exposed to IFNγ evade CTLs by inducing large amounts of noncognate major histocompatibility complex class I molecules, which limit T-cell activation and effector function.
20878981	Prostate Carcinoma	IL18BP	Inhibit immunity	IL-18BP was expressed and secreted by the prostate cancer cell lines DU145 and PC3 but not by LNCaP and CWR22, upon interferon-γ (IFN-γ) stimulation. IFN-γ-induced secretion of IL-18BP was enhanced by added TNF-α, IFN-α and IFN-β. The IL-18BP secreted from DU145 and PC3 functionally inhibited IL-18. Immunohistochemical analyses showed positive IL-18BP staining in prostate cancer cells as well as in macrophages in radical prostatectomy specimens. Significant differences in urinary IL-18BP levels (normalized by total protein) collected post-DRE were found between cases with and without cancer on biopsy (p = 0.02) and serum IL-18BP levels correlated with Gleason score (p = 0.03).
20871598	Skin Basal Cell Carcinoma	KRT17	Inhibit immunity (T cell function)	We here show that genetic ablation of keratin 17 (Krt17) protein, which is induced in basaloid skin tumors and co-polymerizes with Krt5 in vivo, delays basaloid follicular hamartoma tumor initiation and growth in mice with constitutive Hh signaling in epidermis. This delay is preceded by a reduced inflammation and a polarization of inflammatory cytokines from a Th1- and Th17-dominated profile to a Th2-dominated profile. Re-expression of Krt17 in Gli2(tg); Krt17(-/-) keratinocytes induces select Th1 chemokines that have established roles in BCC.
20858897	Skin Basal Cell Carcinoma	TGFB1	Inhibit immunity (T cell function)	Furthermore, inhibition of TGFβ signaling by TGFβ receptor I inhibitor SD208 significantly reduced tumor area in K14cre/R26SmoM2 mice. Tumor shrinkage in mice was associated with an increased number of lymphocytes, suggesting an immune suppression role of TGFβ signaling.
20852124	Triple-Negative Breast Carcinoma	CSPG4	Inhibit immunity	CSPG4-specific mAb 225.28 statistically significantly inhibited growth, adhesion, and migration of TNBC cells in vitro. mAb 225.28 induced 73.1% regression of tumor metastasis in a TNBC cell-derived experimental lung metastasis model (mAb 225.28 vs control, mean area of metastatic nodules = 44590.8 vs 165950.8 μm(2); difference of mean = 121360.0 μm(2), 95% confidence interval = 91010.7 to 151709.4 μm(2); P < .001). Additionally, mAb 225.28 statistically significantly reduced spontaneous lung metastases and tumor recurrences in an orthotopic xenograft mouse model. The mechanisms responsible for antitumor effect included increased apoptosis and reduced mitotic activity in tumor cells, decreased blood vessel density in the tumor microenvironment, and reduced activation of signaling pathways involved in cell survival, proliferation and metastasis.
20849618	Breast Carcinoma	CXCL12	Promote immunity (T cell function)	While expression of CXCL12(P2G) significantly inhibited metastasis, expression of wild-type CXCL12 potently inhibited both metastasis and primary tumor growth. The effects of wild-type CXCL12 were attributed to an immune response characterized by the induction of CD8+ T cell activity, enhanced cell-mediated cytotoxicity, increased numbers of CD11c+ cells in the tumor-draining lymph nodes and reduced accumulation of myeloid-derived suppressor cells in the spleen
20826579	Adrenal Cortex Carcinoma; Adenoma	TLR4	Promote immunity (T cell function)	Real-time PCR analysis of human ACC (n=8), adenoma (n=8), and ACC cell lines (SW13, NCI-H295R, and HAC15) revealed a significant down-regulation of TLR4, MD2 (myeloid differentiation protein-2), and cluster of differentiation 14 (CD14) mRNA compared with normal human adrenal cortex and adrenocortical cells in primary culture. Western blot analysis of MAPK, AKT, activator protein-1, and nuclear factor-κB signaling revealed that the ACC cell lines are unresponsive to lipopolysaccharide action. Restoration of TLR4 signaling by stable transfection of TLR4-CD14 plasmid into NCI-H295R cells sensitized them to lipopolysaccharide incubation as shown by nuclear factor-κB activation and decreased cell viability and induced apoptosis in these cells
20826039	Lymphoma	SOCS1	Inhibit immunity (T cell function)	Gene knockdown of the suppressor of cytokine signaling 1 (SOCS1), a negative-feedback regulator of the immune response in BMDCs resulted in an enhanced phosphorylation of STAT1, and the production of proinflammatory cytokines. Moreover, SOCS1-silenced BMDCs were more potent in suppressing tumor growth.
20823157	Adenocarcinoma	IFNA1	Promote immunity (T cell function)	In vitro experiments indicated that IFNγ significantly enhanced the expression of immune stimulatory molecules and interleukin-12 by DCs derived from canine monocytes. IFNγ also significantly strengthened DC-mediated growth suppression against tumor cell lines. DC inoculation with concomitant delivery of IFNγ into primary or recurrent tumors elicited significant clinical responses, including four complete responses and two partial responses against malignant tumors, also eliciting partial responses against benign but actively growing tumors.
20823152	Colon Carcinoma; Colorectal Carcinoma; Melanoma; Breast Carcinoma	MYD88	Promote immunity (T cell function)	Importantly, in vivo intratumoral injection of Ad-MyD88 into established tumor masses enhanced adaptive immune responses and inhibited local tumor immunosuppression, resulting in significantly inhibited local and systemic growth of multiple tumor types. Finally, Ad-MyD88 infection of primary human dendritic cells, tumor-associated fibroblasts, and colorectal carcinoma cells elicited significant Th1-type cytokine responses, resulting in enhanced tumor cell lysis and expansion of human tumor antigen-specific T cells.
20822802	Ovarian Carcinoma	VEGFA	Inhibit immunity	These antibodies were shown to inhibit ovarian cancer xenograft growth in a nude mouse model following intraperitoneal passive immunization. Active immunization with the VEGF peptide vaccine inhibited VEGF-dependent pancreatic islet cell tumor growth in RIP1-Tag2 transgenic mice and was associated with decreased vasculogenesis in these tumors compared with animals vaccinated with an irrelevant peptide. Active immunization also inhibited growth of tumors from a VEGF overexpressing ovarian cancer cell line, resulting in decreased tumor size and tumor vessel density compared with control mice
20819927	Colon Carcinoma	HAVCR2	Inhibit immunity	We have found that T cell immunoglobulin mucin (Tim) 3 is expressed on CD8(+) tumor-infiltrating lymphocytes (TILs) in mice bearing solid tumors.Tim-3(+)PD-1(+) TILs exhibit the most severe exhausted phenotype as defined by failure to proliferate and produce IL-2, TNF, and IFN-γ. We further find that combined targeting of the Tim-3 and PD-1 pathways is more effective in controlling tumor growth than targeting either pathway alone.
20807806	Melanoma	TLR2	Promote immunity	TLR2-stimulated pmel CD8 T cells, but not TLR2(-/-)pmel or MyD88(-/-)pmel T cells, responded to significantly lower TAg levels and resulted in increased production of effector molecules and cytotoxicity. Wild-type or MyD88(-/-) mice treated with TLR2 ligand and pmel T cells, but not TLR2(-/-)pmel or MyD88(-/-)pmel T cells, showed tumor regression of an established melanoma tumor. Overexpressing TLR2 in TAg-specific T cells eradicated tumors; four times fewer cells were needed to generate antitumor responses. The enhanced antitumor activity of TLR2-MyD88-stimulated T cells was associated with increased effector function but perhaps more importantly with improved survival of T cells.
20805420	Pancreatic Ductal Adenocarcinoma	IL6	Promote immunity (T cell function)	Mice bearing IL-6 Pan02 tumors demonstrated significant delay in tumor growth and better overall median survival compared with mice bearing WT or EV Pan02 tumors. Immunohistochemical analysis demonstrated an increase in Th17 cells (CD4(+)IL-23R(+) cells and CD4(+)IL-17(+) cells) in tumors of the IL-6 Pan02 group compared with WT or EV Pan02 tumors. Thus, the addition of IL-6 to the tumor microenvironment skews the balance toward Th17 cells in a murine model of pancreatic cancer.
20801903	Acute Myeloid Leukemia	IDO1	Inhibit immunity (T cell function)	Indoleamine 2,3-dioxygenase-positive acute myeloid leukemia dendritic cells catabolize tryptophan into kynurenine metabolite and inhibit T-cell proliferation through an indoleamine 2,3-dioxygenase-dependent mechanism. Moreover, indoleamine 2,3-dioxygenase-positive leukemic dendritic cells increase the number of allogeneic and autologous CD4(+)CD25(+) Foxp3(+) T cells and this effect is completely abrogated by the indoleamine 2,3-dioxygenase-inhibitor, 1-methyl tryptophan
20715101	Melanoma	ERBB2	Inhibit immunity (T cell function)	A significant reduction of HLA-A2 levels was found when melanoma and carcinoma cell lines were transfected with a human HER2 gene. A signaling-competent HER2 molecule was crucial for the observed HLA-A2 down-regulation, as transfectants expressing high levels of HER2 mutated in the tyrosine signaling domain did not show altered HLA-A2 expression. Importantly, the human melanoma cell line EST049 demonstrated reduced HER2 and melanoma antigen-specific recognition by CTLs upon HER2 transfection. In addition, high expression of HER2 prevented both IFN-γ mediated HLA-A2 up-regulation and improved recognition by HLA-A2-restricted CTLs in treated cells.
20714339	Erythroleukemia	IL10	Inhibit immunity (T cell function)	MICA mRNA levels decreased in IL-10-treated FMS and IL-10-transduced BL cell lines. Interestingly, we observed that MICB surface expression and its mRNA levels increased upon IL-10 treatment in a melanoma cell line. These changes in NKG2D ligands surface expression patterns owing to IL-10 treatment resulted in an effect on lysis susceptibility mediated by lymphocyte-activated killer cells, as tumour cell lines that displayed a higher decrease of MICA on their surface had lower levels of lysis.
20713880	Melanoma	TBX21	Promote immunity (infiltration)	In this paper, we show that the combined germline deletion of T-bet and T cell-specific deletion of Eomes resulted in profound defects in adaptive antitumor immune responses. T-bet and Eomes drive Tc1 differentiation by preventing alternative CD8(+) T cell differentiation to Tc17 or Tc2 cells. Surprisingly, T-bet and Eomes are not critical for the generation of systemic CTL activities against cancer cells. Instead, T-bet and Eomes are crucial for tumor infiltration by CD8(+) T cells.
20713880	Melanoma	EOMES	Promote immunity (infiltration)	In this paper, we show that the combined germline deletion of T-bet and T cell-specific deletion of Eomes resulted in profound defects in adaptive antitumor immune responses. T-bet and Eomes drive Tc1 differentiation by preventing alternative CD8(+) T cell differentiation to Tc17 or Tc2 cells. Surprisingly, T-bet and Eomes are not critical for the generation of systemic CTL activities against cancer cells. Instead, T-bet and Eomes are crucial for tumor infiltration by CD8(+) T cells.
19915059	Lymphoma	IL21	Inhibit immunity (T cell function)	Surprisingly, host IL-21 significantly restricted the expansion of Ag-specific CD8(+) T cells and inhibited primary CD8(+) T cell immunity against OVA-expressing EG7 lymphomas, as well as the secondary expansion of memory CD8(+) T cells.
19911426	Ovarian Carcinoma	CCL19	Promote immunity (infiltration)	The mouse ovarian cancer cell line OV2944-HM-1 (HM-1) was inoculated subcutaneously into B6C3F1 mice, along with CCL19-tranduced eEPCs (eEPC-CCL19), resulting in immunologic activity and tumor-inhibitory effects. In this model, eEPC-CCL19 showed tumor repression accompanied by increased tumor-infiltrating CD8+ lymphocytes compared with the control group.
19903784	Melanoma	CD4	Inhibit immunity ( cell function)	Partial CD4 depletion reduces regulatory T cells induced by multiple vaccinations and restores therapeutic efficacy. Anti-CD4 administration reduced the absolute number of T(reg) cells 9-fold. Effector T-cells generated from anti-CD4-treated mice were significantly (P < 0.0001) more therapeutic in adoptive transfer studies than T cells from multiply vaccinated animals with a full complement of CD4+ cells.
19890064	Lymphoma	TLR7	Promote immunity (NK cell function)	Use of gene-deficient mice showed that NK activation is entirely TLR7-dependent. Reconstitution of TLR7-deficient mice with wild-type dendritic cells restores NK activation upon treatment with immunostimulatory RNA oligonucleotides.
19887600	Pancreatic Carcinoma	TLR3	Promote immunity (T cell function)	Toll-like receptors 3 and 7 agonists enhance tumor cell lysis by human gammadelta T cells. Poly(I:C) treatment of pancreatic adenocarcinomas followed by coculture with gammadelta T cells resulted in an upregulation of CD54 on the tumor cells. The interaction of CD54 and the corresponding ligand CD11a/CD18 expressed on gammadelta T cells is responsible for triggering effector function in gammadelta T cells.
19887600	Pancreatic Carcinoma	TLR7	Promote immunity (T cell function)	Toll-like receptors 3 and 7 agonists enhance tumor cell lysis by human gammadelta T cells. Poly(I:C) treatment of pancreatic adenocarcinomas followed by coculture with gammadelta T cells resulted in an upregulation of CD54 on the tumor cells. The interaction of CD54 and the corresponding ligand CD11a/CD18 expressed on gammadelta T cells is responsible for triggering effector function in gammadelta T cells.
19887544	Breast Carcinoma; Colon Carcinoma	HPGD	Promote immunity	Preclinical and clinical evidence shows that cyclooxygenase-2 (Cox-2)-mediated prostaglandin E(2) (PGE(2)) overexpression plays an important role in tumor growth, metastasis, and immunosuppression. It has been shown that expression of NAD(+)-linked 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a key enzyme responsible for PGE(2) inactivation, is suppressed in the majority of cancers, including breast and colon carcinoma. The in vitro study showed that Ad-mediated 15-PGDH expression significantly decreased proliferation and migration of cancer cells. Animal breast and colon tumor therapy studies showed that 15-PGDH gene therapy produced a significant delay in 2LMP and LS174T tumor growth. Combined therapy using 15-PGDH and anti-VEGF antibody (bevacizumab) significantly increased inhibition of growth of LS174T tumor xenografts in comparison with agents alone.
19881547	Colorectal Carcinoma	TLR4	Promote immunity	The knockout of toll-like receptor 4 (TLR4), the receptor for HMGB1, also resulted in a deficient immune response against OXP-treated CT26 cells. However, patients carrying the TLR4 loss-of-function allele exhibited reduced progression-free and overall survival, as compared with patients carrying the normal TLR4 allele.
19880164	Ovarian Carcinoma	IL2	Promote immunity (NK cell function)	Therapy consisted of low-dose subcutaneous IL-2 and oral RA, administered on intermittent schedules for up to 5 years. A statistically significant improvement in lymphocyte and NK counts and a decrease in VEGF levels were observed with respect to baseline values among the 65 evaluable patients.
19864600	Follicular Lymphoma	ENTPD1	Inhibit immunity	As the rate limiting step for adenosine generation from pericellular ATP is the ecto-ATPase CD39, we next show that inhibition of CD39 activity using the inhibitor ARL 67156 partially overcomes T cell hyporesponsiveness in a subset of patient samples.
19861464	Glioma	TGFB1	Inhibit immunity (T cell function)	Flow cytometric analyses of brain-infiltrating lymphocytes revealed that 1D11 treatment suppressed phosphorylation of Smad2, increased GAA-reactive/IFN-gamma-producing CD8(+) T cells, and reduced CD4(+)/FoxP3(+) T(reg) cells in the glioma microenvironment. Neutralization of TGF-beta also upregulated plasma levels of interleukin-12, macrophage inflammatory protein-1 alpha, and IFN-inducible protein-10, suggesting a systemic promotion of type-1 cytokine/chemokine production. Furthermore, 1D11 treatment upregulated plasma interleukin-15 levels and promoted the persistence of GAA-reactive CD8(+) T cells in glioma-bearing mice.
19856307	Breast Carcinoma	ERBB2	Inhibit immunity	Our in vitro studies demonstrated that HER2 vaccine-induced antibodies effectively caused a decrease in HER2 expression, but when combined with lapatinib caused significant inhibition of HER2 signaling, decreased pERK and pAKT levels and reduced breast tumor cell proliferation. In addition, a known mechanism of resistance to lapatinib, induction of survivin, was inhibited. The combination of Ad-HER2-ki plus lapatinib also showed superior antitumor efficacy in vivo.
19844235	Pancreatic Carcinoma	CD276	Inhibit immunity (infiltration)	B7-H3 blockade promoted CD8(+) T-cell infiltration into the tumour and induced a substantial anti-tumour effect on murine pancreatic cancer.
19841169	Melanoma	IL2RA	Inhibit immunity	Although anti-CD25 mAb injections resulted in the efficient Treg depletion from lymphoid organs of transgenic mice, melanoma development was not significantly delayed.
19830696	Colon Carcinoma	TGFB1	Inhibit immunity (T cell function)	However, tumor growth was inhibited significantly more in vaccinated mice treated with anti-TGF-beta antibodies compared to vaccinated mice without anti-TGF-beta, suggesting that anti-TGF-beta synergistically enhanced irradiated tumor vaccine efficacy.
19826413	Ovarian Carcinoma	TLR4	Inhibit immunity (T cell function)	In MyD88(+) SCOV3 cells, LPS or PTX binding to TLR4 induced IRAK4 activation and cJun phosphorylation, activated the NF-kappaB pathway and promoted interleukin (IL)-8, IL-6, vascular endothelial growth factor and monocyte chemotactic protein-1 production and resistance to drug-induced apoptosis. Silencing of TLR4 in SCOV3 cells with small interference RNA resulted in phosphorylated-cJun (p-cJun) downregulation and a loss of PTX resistance. In PTX-sensitive, MyD88(neg) A2780 cells, TLR4 stimulation upregulated TRIF, and TLR4 silencing eliminated this effect.
19826049	Hepatocellular Carcinoma	CD274	Inhibit immunity (T cell function)	PD-1(+)CD8(+) T cells had decreased proliferative ability and effector function as shown by reduced granule and cytokine expression compared with PD-1(-) T cells. Importantly, blocking KC B7-H1 interaction with PD-1(+)CD8(+) cells using neutralizing antibodies recovered effector T-cell function.
19825957	Head and Neck Carcinoma	ENTPD1	Inhibit immunity (T cell function)	The percentages and expression levels of CD39 and CD73 in CD4(+) T cells and Treg were greater in HNSCC than in normal controls and highest in patients with no evident disease. Patients' Treg hydrolyzed ATP at higher rates and produced higher levels of adenosine than normal controls' Treg. The increased frequency and enzymatic activity of CD4(+)CD39(+) cells corresponded to increased adenosine-mediated suppression of effector T cells, which was partly inhibited by ARL67156, an ectonucleotidase inhibitor, and by ZM241385, a selective A(2a)/A(2b) receptor antagonist.
19820019	Thyroid Gland Carcinoma	SPAG9	Inhibit immunity (T cell function)	It is interesting to note that majority of early-stage (T1) thyroid cancer patients exhibited higher antibody response against SPAG9. Small interfering RNA-mediated knockdown of SPAG9 expression in thyroid cancer cell significantly reduced cellular growth and colony formation.
19815501	Melanoma	CBLB	Inhibit immunity (T cell function)	We show here that the decreased IFN-gamma production and failed tumor rejection observed in anergized NKT cells are rescued by Cbl-b deficiency. Cbl-b binds and promotes monoubiquitination to CARMA1, a critical signaling molecule in NFkappaB activation.
19815501	Melanoma	CARD11	Promote immunity (T cell function)	CARMA1(-/-) NKT cells are defective in IFN-gamma production.
19805226	Leukemia	CEBPA	Inhibit immunity (T cell function)	These T cells also reveal a unique molecular signature, including a strong expression of C/EBPalpha normally expressed in myeloid-lineage cells, with diminished c-Myc and cyclin D1. Transduction of Cebpa in regular CD4(+) T cells inhibited the TCR-mediated proliferation with c-Myc and cyclin D1 repression and caused a striking activation of Spp1 encoding osteopontin along with concomitant repression of T cell lymphokine genes. The results suggest that global T cell immunodepression in senescence and leukemia is attributable to the increase in PD-1(+) MP CD4(+) T cells expressing C/EBPalpha
19801517	Ovarian Carcinoma	PVR	Promote immunity	Coincubation of NK cells with ovarian carcinoma cells expressing the DNAM-1 ligand CD155 led to reduction of DNAM-1 expression. Therefore, NK cell-mediated rejection of ovarian carcinoma may be limited by perturbed DNAM-1 expression on tumor-associated NK cells induced by chronic ligand exposure.
19789345	Melanoma; Lymphoma	AOC3	Inhibit immunity	We found an unexpected defect in tumor angiogenesis in the absence of VAP-1. VAP-1 also selectively enhanced the recruitment of Gr-1+CD11b+ myeloid cells into the tumors. Generation of mice expressing enzymatically inactive VAP-1 showed that the oxidase activity of VAP-1 was necessary to support neoangiogenesis, myeloid cell recruitment, and tumor growth in vivo.
19789316	Primary Cutaneous Anaplastic Large Cell Lymphoma; Lymphomatoid Papulosis	TNFRSF8	Essential for immunotherapy	The overall objective response rate [complete response (CR) + partial response (PR)] was 70% (16 of 23 patients): 10 patients achieved a CR and another 6 patients achieved a PR. Overall, clinical benefit of SGN-30, as assessed by achieving a response to therapy or stable disease (CR + PR + stable disease), was shown by 87% of patients during the study, including all patients with pc-ALCL or LyP and two thirds of patients with T-MF or with multiple clinical diagnoses. Nine of the 10 patients who achieved a CR and 5 of the 6 patients who achieved a PR were in remission at their follow-up evaluation (median duration, 84 days).
19789309	Melanoma	CTLA4	Inhibit immunity	Autologous DC were pulsed with MART-1(26-35) peptide and administered with a dose escalation of the CTLA4-blocking antibody tremelimumab. Four patients had an objective tumor response, two partial responses and two complete responses, all melanoma free between 2 and 4 years after study initiation. There was no difference in immune monitoring results between patients with an objective tumor response and those without a response.
19755991	Ovarian Carcinoma	MICA	Promote immunity	Tumours expressing high levels of HLA class I had significantly improved survival (P=0.044). HLA class I antigen was shown to be expressed at higher levels in patients with good overall survival in platinum-resistant patients (P=0.042). HLA class I significantly correlated with overall survival on multivariate analyses (P=0.034).
19755673	Chronic Lymphocytic Leukemia	TNFSF13B	Inhibit immunity	TCL1 x BAFF-Tg mice developed CLL-like disease at a significantly younger age and had more rapid disease progression and shorter survival than TCL1-Tg mice. Leukemia cells of TCL1 x BAFF-Tg mice had similar proportions of proliferating cells, but fewer proportions of dying cells, than did the CLL cells of TCL1-Tg mice. Moreover, leukemia cells from either TCL1 x BAFF-Tg or TCL1-Tg mice produced more aggressive disease when transferred into BAFF-Tg mice than into wild-type (WT) mice. Neutralization of CD257 resulted in rapid reduction in circulating leukemia cells.
19739080	Ovarian Carcinoma	NOS2	Inhibit immunity (T cell function)	The immunosuppression of CD4(+) T cells is independent of direct contact with the Hospicells and is mainly due to nitric oxide produced by the inducible nitric oxide synthase and to products of the tryptophan degradation by indoleamine 2,3-dioxygenase.
19739080	Ovarian Carcinoma	IDO1	Inhibit immunity (T cell function)	The immunosuppression of CD4(+) T cells is independent of direct contact with the Hospicells and is mainly due to nitric oxide produced by the inducible nitric oxide synthase and to products of the tryptophan degradation by indoleamine 2,3-dioxygenase.
19739077	Erythroleukemia; Colorectal Carcinoma	HSPA9	Inhibit immunity (T cell function)	As shown here, knock down of mortalin with specific siRNA reduces MAC elimination and enhances cell sensitivity to MAC-induced cell death. Similar results were obtained with MKT-077, a cationic rhodacyanine dye that inhibits mortalin. Treatment of human erythroleukemia K562 and colorectal carcinoma HCT116 cells with MKT-077 sensitizes them to cell death mediated by MAC but not by streptolysin O.
19737940	Colon Carcinoma	XIAP	Inhibit immunity (T cell function)	Infection of HT29 and HCT116 cells with Adv-XIAP-shRNA led to enhanced caspase-3 activity, which was associated with increased apoptosis and reduced cell proliferation. The therapeutic effect of Adv-XIAP-shRNA was then tested in xenograft tumors in nude mice. We showed that treatment of the xenograft tumors derived from HCT116 cells with Adv-XIAP-shRNA resulted in a retardation of tumor growth, which was associated with enhanced apoptosis, increased caspase-3 activity, and reduced expression of proliferating cell nuclear antigen in the tumor tissues. Thus, Adv-XIAP-shRNA-mediated down-regulation of XIAP exerts a therapeutic effect in colon cancer by promoting apoptosis and inhibiting proliferation of colon cancer cells, and the antitumor effect of Adv-XIAP-shRNA was unlikely to be related to virus-induced immune response.
19723650	Melanoma; Colon Carcinoma; Pancreatic Carcinoma; Renal Cell Carcinoma; Lung Carcinomal; Glioma	LILRA4	Inhibit immunity (T cell function)	High ILT7L-expressing cancer cells inhibited production of IFN-alpha and tumor necrosis factor-alpha by pDC stimulated with CpG.
19710501	Non-Hodgkin Lymphoma; Burkitt Lymphoma	IFNA1	Promote immunity	Interferon-alpha (IFN-alpha) has direct inhibitory effects on some tumors and is a potent stimulator of both the innate and adaptive immune systems. The 20-2b shows enhanced antibody-dependent cellular cytotoxicity compared with veltuzumab but lacks complement-dependent cytotoxicity. The 20-2b inhibits in vitro proliferation of lymphoma cells and depletes them from whole human blood more potently than the combination of veltuzumab and a nontargeting, irrelevant, mAb-IFN-alpha. The 20-2b demonstrated superior therapeutic efficacy compared with veltuzumab or nontargeting mAb-IFN-alpha in 3 human lymphoma xenograft models, even though mouse immune cells respond poorly to human IFN-alpha2b.
19710456	Melanoma	CD274	Inhibit immunity (T cell function)	Depletion or blockade of B7-H1 on activated DCs increased the magnitude of effector CD8 T cell expansion. DC-based or protein-based tumor vaccines, in combination with B7-H1 blockade, induced strong effector CD8 T cell responses, resulting in protective immunity against newly established tumors.
19208793	Melanoma; Colon Carcinoma	PDCD1	Inhibit immunity (T cell function)	The studies reported here show that combining PD-1 blockade with GM-CSF-secreting tumor cell immunotherapy prolonged the survival of tumor-bearing animals compared with animals treated with either therapy alone. Prolonged survival correlated with strong antigen-specific T-cell responses detected by tetramer staining and an in vivo CTL assay, higher secretion levels of proinflammatory cytokines by splenocytes, and the persistence of functional CD8+ T cells in the tumor microenvironment.
19202127	Renal Cell Carcinoma; Lung Carcinoma	PRF1	Promote immunity (NK cell function)	Bioluminescence imaging of mice with established tumors showed treatment with bortezomib and syngeneic NK cells reduced tumor growth and prolonged survival compared with controls receiving bortezomib or NK cells alone. In contrast, tumor progression was not delayed when animals received bortezomib and perforin-deficient NK cells, showing drug-induced augmentation in NK-cell cytotoxicity was mediated through perforin/granzyme.
19201856	Melanoma	TLR3	Promote immunity (T cell function)	In vivo, administration of the TLR3 agonist poly(I:C) at the peak of DC expansion (day 12 postlymphopenia) induced inflammatory cytokine production and increases in the number of activated DCs in lymph nodes.
19201850	Lymphoma	PRKCQ	Promote immunity (infiltration; NK cell function)	In the present work, we show that in vivo development of a MHC-I-deficient tumor (RMA-S) is much favored in PKCtheta(-/-) mice compared with wild-type mice. This is associated with a reduced recruitment of NK cells to the site of tumor development and a reduced activation status of recruited NK cells. This correlates with a reduced ex vivo and in vivo cytotoxic potential of NK cells isolated from PKCtheta(-/-) mice treated with polyinosinic:polycytidylic acid. Consistently, polinosinic:cytidilic acid treatment induces PKCtheta expression and activation of its enzymatic activity in NK cells in an indirect manner.
19201847	Lymphoma	CD40	Promote immunity	Several receptor-ligand pairs are reciprocally expressed on Mphi and L5178Y cell membranes and can be potentially involved in Mphi priming. Of these, the CD40-CD154 pair played the most important role, as blocking the interaction of these molecules substantially reduced in vitro Mphi priming. These results suggest that contact with certain tumor cells via CD40, NKG2D, and CD18 molecules on the Mphi may facilitate Mphi-mediated antitumor immune surveillance.
19201847	Lymphoma	CD40LG	Promote immunity	Several receptor-ligand pairs are reciprocally expressed on Mphi and L5178Y cell membranes and can be potentially involved in Mphi priming. Of these, the CD40-CD154 pair played the most important role, as blocking the interaction of these molecules substantially reduced in vitro Mphi priming. These results suggest that contact with certain tumor cells via CD40, NKG2D, and CD18 molecules on the Mphi may facilitate Mphi-mediated antitumor immune surveillance.
19201693	Renal Cell Carcinoma	VEGFA	Inhibit immunity (T cell function)	Treatment of RCC patients with anti-VEGF antibody bevacizumab, however, did not reduce the accumulation of MDSC in peripheral blood. In contrast, the addition of interleukin-2 to the treatment increased the number of MDSC in peripheral blood and the plasma levels of arginase I.
19201693	Renal Cell Carcinoma	IL2	Inhibit immunity (T cell function)	High levels of VEGF have been shown to increase suppressor immature myeloid dendritic cells in cancer patients. Treatment of RCC patients with anti-VEGF antibody bevacizumab, however, did not reduce the accumulation of MDSC in peripheral blood. In contrast, the addition of interleukin-2 to the treatment increased the number of MDSC in peripheral blood and the plasma levels of arginase I
19197941	Lymphoma	PTGS2	Inhibit immunity (T cell function)	By analyzing freshly isolated TCRVgamma9Vdelta2(+) lymphocytes and primary cell lines stimulated with synthetic phosphoantigen or B-cell lymphoma cell lines in the presence of MSC, we demonstrated that MSC were potent suppressors of gammadelta-cell proliferation, cytokine production and cytolytic responses in vitro. This inhibition was mediated by the COX-2-dependent production of prostaglandin E2 (PGE(2)) and by MSC through EP2 and EP4 inhibitory receptors expressed by Vgamma9Vdelta2 T lymphocytes.
19197941	Lymphoma	PTGER4	Inhibit immunity (T cell function)	By analyzing freshly isolated TCRVgamma9Vdelta2(+) lymphocytes and primary cell lines stimulated with synthetic phosphoantigen or B-cell lymphoma cell lines in the presence of MSC, we demonstrated that MSC were potent suppressors of gammadelta-cell proliferation, cytokine production and cytolytic responses in vitro. This inhibition was mediated by the COX-2-dependent production of prostaglandin E2 (PGE(2)) and by MSC through EP2 and EP4 inhibitory receptors expressed by Vgamma9Vdelta2 T lymphocytes.
19197941	Lymphoma	PTGER2	Inhibit immunity (T cell function)	By analyzing freshly isolated TCRVgamma9Vdelta2(+) lymphocytes and primary cell lines stimulated with synthetic phosphoantigen or B-cell lymphoma cell lines in the presence of MSC, we demonstrated that MSC were potent suppressors of gammadelta-cell proliferation, cytokine production and cytolytic responses in vitro. This inhibition was mediated by the COX-2-dependent production of prostaglandin E2 (PGE(2)) and by MSC through EP2 and EP4 inhibitory receptors expressed by Vgamma9Vdelta2 T lymphocytes.
19196663	Lymphoma	PLAU	Inhibit immunity	Because MUC1/sec was previously shown to down-regulate tumor expression of urokinase plasminogen activator (uPA), a protease linked to tumor aggressiveness and metastasis, the potential role of uPA in MDSC recruitment was investigated. Tumor-derived uPA is capable of recruiting MDSCs, and correlates with tumor development.
19196663	Lymphoma	MUC1	Inhibit immunity	In addition to diminishing recruitment of MDSCs, the effect of MUC1/sec on MDSC-suppressive mechanisms was investigated. MUC1/sec, or its unique immunoenhancing peptide, is capable of blocking expression of arginase 1 and production of reactive oxygen species in MDSCs, implicated in the suppression of T cells.
19190335	Glioma	CXCL10	Promote immunity	Interestingly, the antitumor functions were abrogated with CXCL10(-/-) mouse-derived DC1s.
19190149	Breast Carcinoma	SPAG9	Inhibit immunity	Our reverse transcription-PCR and immunohistochemical analyses revealed SPAG9 expression in 88% breast cancer specimens independent of tumor stages and grades. Further, the humoral immune response against SPAG9 was detected in 80% breast cancer patients with SPAG9-expressing tumors. The linear regression modeling predicted a direct relationship between presence of lymphovascular invasion and high SPAG9 IRS, whereas the univariate and multivariate logistic regression models predicted a strong association of SPAG9 IRS with tumor grade.
19190115	Melanoma	TNFRSF9	Inhibit immunity (T cell function)	Anti-4-1BB protected na?ve T cells from CTX and promoted proliferation of memory/effector and memory T cells. The combination treatment produced approximately 60- and 2.2-fold more CTLs per tumor-associated antigen compared with CTX or anti-4-1BB alone, respectively. This indicates that anti-4-1BB promoted a preferential expansion of tumor-specific CD8(+) T cells among the repopulated lymphocytes following CTX-mediated lymphopenia. CTX treatment enhanced 4-1BB expression on CD4 and CD8 T cells, and CTX alone or in combination with anti-4-1BB effectively suppressed peripheral regulatory T cells.
19188665	Colon Carcinoma	EPCAM	Inhibit immunity (T cell function)	Here, we analyzed T-cell immune responses to the epithelial cell adhesion molecule (EpCAM), one of the most common tumor-associated antigens (TAA) serving as immune target in colon cancer patients. Th-cell priming against EpCAM inevitably resulted in interleukin-4 (IL-4)-dominated Th2 responses, even under most stringent Th1-inducing conditions. These EpCAM-reactive Th2 cells rather promoted growth of EpCAM-expressing tumors.
19188665	Colon Carcinoma	IL4	Inhibit immunity (T cell function)	To analyze the role of IL-4 in tumor immune evasion, we generated EpCAM-reactive Th1 cells from IL-4.ko mice. These Th1 cells provided tumor-specific protection and established highly protective Th1 memory responses, even in naive BALB/c mice. Inhibition of tumor growth by Th1 cells resulted in intra-tumoral expression of cytokines of the IL-12 family and of IFN-gamma.
19188179	Renal Cell Carcinoma	IL2	Inhibit immunity	Increased intratumoral FOXP3-positive regulatory immune cells during interleukin-2 treatment in metastatic renal cell carcinoma. A significant increase in absolute intratumoral FOXP3-positive immune cells was observed comparing baseline (median 23 cells/mm2; range, 0-183) and on-treatment biopsies (median, 89 cells/mm2; range, 11-388; P < 0.001). FOXP3-positive cells were positively correlated with CD3-positive, CD4-positive, and CD8-positive tumor-infiltrating immune cells at baseline and during treatment (P < 0.05 in all comparisons). All patients achieving high numbers (>180 cells/mm2) of on-treatment FOXP3-positive intratumoral immune cells were dead within 22 months (n = 11), whereas patients with low numbers (<180 cells/mm2) of on-treatment FOXP3-positive cells (n = 31) had a 5-year survival rate of 19% (hazard ratio, 2.2; confidence interval, 1.03-4.5; P = 0.043).
19188178	Breast Carcinoma	CYP19A1	Inhibit immunity (T cell function)	This study suggests that aromatase inhibitors may have an indirect antitumor mechanism of action through reducing Tregs in breast tumors and may be of use in estrogen receptor-alpha-negative tumors in combination with immunotherapy approaches.
19188168	Hepatocellular Carcinoma	CD274	Inhibit immunity	Patients with higher expression of PD-L1 had a significantly poorer prognosis than patients with lower expression. Although patients with higher expression of PD-L2 also had a poorer survival, the difference in recurrence was not statistically significant. Multivariate analysis identified tumor expression of PD-L1 as an independent predictor for postoperative recurrence.
19188167	Colon Adenocarcinoma	CD80	Inhibit immunity	Here, we showed that short-term administration of anti-B7-1/B7-2 monoclonal antibodies in TRAMP mice leads to significant inhibited primary tumor growth and the size of metastatic lesions. The treatment is effective to inhibit MC38 colon cancer growth. Correspondingly, this treatment results in a transient reduction of Treg in both thymus and the periphery. In vivo cytotoxicity assay revealed T antigen-specific CTL effectors in anti-B7-treated but not control IgG-treated TRAMP mice.
19188167	Colon Adenocarcinoma	CD86	Inhibit immunity	Here, we showed that short-term administration of anti-B7-1/B7-2 monoclonal antibodies in TRAMP mice leads to significant inhibited primary tumor growth and the size of metastatic lesions. The treatment is effective to inhibit MC38 colon cancer growth. Correspondingly, this treatment results in a transient reduction of Treg in both thymus and the periphery. In vivo cytotoxicity assay revealed T antigen-specific CTL effectors in anti-B7-treated but not control IgG-treated TRAMP mice.
19171873	Leukemia	IRF8	Promote immunity	Here we show that the type I IFNs (alpha and beta) regulate expression of the IFN consensus sequence-binding protein (ICSBP) in BCR-ABL-transformed cells and as shown previously for ICSBP, induce a vaccine-like immunoprotective effect in a murine model of BCR-ABL-induced leukemia. We identify the chemokines CCL6 and CCL9 as genes prominently induced by the type I IFNs and ICSBP, and demonstrate that these immunomodulators are required for the immunoprotective effect of ICSBP expression.
19155524	Pancreatic Carcinoma	CCR5	Inhibit immunity (infiltration)	When CCR5/CCL5 signaling is disrupted, either by reducing CCL5 production by tumor cells or by systemic administration of a CCR5 inhibitor (N,N-dimethyl-N-{{4-{[2-(4-methylphenyl)-6,7-dihydro-5H-benzocyclohepten-8-yl]carbonyl}amino}}benzyl]-N,N-dimethyl-N- {{{4-{{{[2-(4-methylphenyl)-6,7-dihydro-5H-benzocycloheptan-8-yl]carbonyl}amino}}benzyl}}}tetrahydro-2H-pyran-4-aminiumchloride; TAK-779), Treg migration to tumors is reduced and tumors are smaller than in control mice. Thus, this study demonstrates the importance of Tregs in immune evasion by tumors, how blockade of Treg migration might inhibit tumor growth, and, specifically in pancreatic adenocarcinoma, the role of CCR5 in the homing of tumor-associated Tregs.
19155524	Pancreatic Carcinoma	CCL5	Inhibit immunity (infiltration)	When CCR5/CCL5 signaling is disrupted, either by reducing CCL5 production by tumor cells or by systemic administration of a CCR5 inhibitor (N,N-dimethyl-N-{{4-{[2-(4-methylphenyl)-6,7-dihydro-5H-benzocyclohepten-8-yl]carbonyl}amino}}benzyl]-N,N-dimethyl-N- {{{4-{{{[2-(4-methylphenyl)-6,7-dihydro-5H-benzocycloheptan-8-yl]carbonyl}amino}}benzyl}}}tetrahydro-2H-pyran-4-aminiumchloride; TAK-779), Treg migration to tumors is reduced and tumors are smaller than in control mice. Thus, this study demonstrates the importance of Tregs in immune evasion by tumors, how blockade of Treg migration might inhibit tumor growth, and, specifically in pancreatic adenocarcinoma, the role of CCR5 in the homing of tumor-associated Tregs.
19147983	Prostate Carcinoma	PIM1	Inhibit immunity	Treatment of human and mouse prostate cancer cell lines with the PIM-1-specific mAb resulted in disruption of PIM-1/Hsp90 complexes, decreased PIM-1 and Hsp90 levels, reduced Akt phosphorylation at Ser473, reduced phosphorylation of Bad at Ser112 and Ser136, and increased cleavage of caspase-9, an indicator of activation of the mitochondrial cell death pathway. The mAb induced cancer cell apoptosis and synergistically enhanced antitumor activity when used in combination with cisplatin and epirubicin. In tumor models, the PIM-1-specific mAb substantially inhibited growth of the human prostate cancer cell line DU145 in SCID mice and the mouse prostate cancer cell TRAMP-C1 in C57BL/6 mice.
19147771	Renal Cell Carcinoma	TNFSF10	Inhibit immunity	The death ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptors (TRAIL-R) are involved in immune surveillance and tumor development. High TRAIL-R2 expression levels were associated with high-grade RCCs (P < 0.001) and correlated negatively with disease-specific survival (P = 0.01). Similarly, high TRAIL expression was associated with a shorter disease-specific survival (P = 0.01).
19147771	Renal Cell Carcinoma	TNFRSF10B	Inhibit immunity	The death ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptors (TRAIL-R) are involved in immune surveillance and tumor development. High TRAIL-R2 expression levels were associated with high-grade RCCs (P < 0.001) and correlated negatively with disease-specific survival (P = 0.01). Similarly, high TRAIL expression was associated with a shorter disease-specific survival (P = 0.01).
19147765	Breast Carcinoma	CTLA4	Inhibit immunity	The response to radiotherapy plus 9H10 was markedly enhanced in the absence of iNKT cells, with 50% of iNKT-/- versus 0% of wild-type mice showing complete tumor regression, long-term survival, and resistance to a challenge with 4T1 cells. Administration of the iNKT cell activator alpha-galactosylceramide did not enhance the response of wild-type mice to radiotherapy plus 9H10. Tumor-infiltrating iNKT cells were markedly reduced in wild-type mice treated with radiotherapy plus 9H10.
19147575	Prostate Carcinoma	CTLA4	Inhibit immunity	Of the six patients treated at the highest dose level, three had confirmed PSA declines of >50%, including one patient that had a partial response in visceral metastases. Expansion of activated, circulating CD25(+) CD69(+) CD8(+) T cells occurred more frequently at higher doses of treatment and was greater in magnitude than was seen in patients who received the same doses of either ipilimumab or GM-CSF alone.
19143470	Glioblastoma	HMGB1	Promote immunity (T cell function)	Specific activation of TLR2 signaling was induced by supernatants from Ad-TK (+GCV)-treated GBM cells; this activation was blocked by glycyrrhizin (a specific HMGB1 inhibitor) or with antibodies to HMGB1. HMGB1 was also released from melanoma, small cell lung carcinoma, and glioma cells treated with radiation or temozolomide. Administration of either glycyrrhizin or anti-HMGB1 immunoglobulins to tumor-bearing Ad-Flt3L and Ad-TK treated mice, abolished therapeutic efficacy, highlighting the critical role played by HMGB1-mediated TLR2 signaling to elicit tumor regression.
19111878	Lymphoma	PDGFC	Inhibit immunity	Unlike normal skin fibroblasts or TAFs from TIB6 tumors that are sensitive to anti-VEGF treatment (TAF-TIB6), TAFs from resistant EL4 tumors (TAF-EL4) can stimulate TIB6 tumor growth even when VEGF is inhibited.We show that platelet-derived growth factor C (PDGF-C) is upregulated in TAFs from resistant tumors. PDGF-C-neutralizing antibodies blocked the angiogenesis induced by such TAFs in vivo, slowed the growth of EL4 and admixture (TAF-EL4 + TIB6) tumors, and exhibited additive effects with anti-VEGF-A antibodies.
19109206	Leukemia	CD70	Promote immunity (T cell function)	Both CD70 and CD80/CD86 up-regulated on CD40-stimulated blasts contribute to primary stimulation of T cell proliferation and cytokine production in an additive manner. These two signals also cooperate in the prevention of T cell anergy. In contrast to blockade of CD70 during the effector phase, inhibition of CD70-mediated costimulation during generation of antileukemic T cells prevents effector cell proliferation and reduces their cytotoxic capacity.
19109206	Leukemia	CD80	Promote immunity (T cell function)	Both CD70 and CD80/CD86 up-regulated on CD40-stimulated blasts contribute to primary stimulation of T cell proliferation and cytokine production in an additive manner. These two signals also cooperate in the prevention of T cell anergy. In contrast to blockade of CD70 during the effector phase, inhibition of CD70-mediated costimulation during generation of antileukemic T cells prevents effector cell proliferation and reduces their cytotoxic capacity.
19109155	Hepatocellular Carcinoma	TGFB1	Inhibit immunity (T cell function)	Furthermore, membrane-bound TGF-beta1 on MDSC is responsible for MDSC-mediated suppression of NK cells. The impaired function of hepatic NK cells in orthotopic liver cancer-bearing mice could be restored by depletion of MDSC, but not regulatory T cells. Therefore, cancer-expanded MDSC can induce anergy of NK cells via membrane-bound TGF-beta1. MDSC, but not regulatory T cells, are main negative regulator of hepatic NK cell function in tumor-bearing host.
19109152	Pancreatic Ductal Adenocarcinoma	PTGS2	Inhibit immunity	Progression of pancreatic adenocarcinoma is significantly impeded with a combination of vaccine and COX-2 inhibition. The mechanism for the increased immune response was attributed to the down-regulation of circulating prostaglandin E(2) and indoleamine 2, 3,-dioxygenase enzymatic activity, as well as decreased levels of T regulatory and myeloid suppressor cells within the tumor microenvironment.
19109141	Hepatocellular Carcinoma; Lung Carcinoma; Melanoma	TGFB1	Inhibit immunity (T cell function)	Interestingly, the fixed CD69(+)CD4(+)CD25(-) T cells still have suppressive activity, and neutralizing Abs against TGF-beta1 can block their suppressive activity. We found that CD69(+)CD4(+)CD25(-) T cells express membrane-bound TGF-beta1, which mediates suppression of T cell proliferation. Furthermore, engagement of CD69 maintains high expression of membrane-bound TGF-beta1 on CD69(+)CD4(+)CD25(-) T cells via ERK activation.
19107122	Myeloma	AKT1	Inhibit immunity (T cell function)	Retroviral transfer of a constitutively active form of Akt into the parental tumor significantly increased its resistance against E7-specific CD8(+) T-cell mediated apoptosis. The observed resistance against apoptosis was found to be associated with the upregulation of antiapoptotic molecules.
19092852	Chronic Lymphocytic Leukemia	HMMR	Inhibit immunity	CLL cases with a higher RHAMM expression showed a significantly shorter median treatment-free survival. Among patients with mutated immunoglobulin heavy chain genes, an analysis of RHAMM expression enabled to distinguish subgroup of patients with favorable prognosis. In lymph nodes, RHAMM staining correlated with a higher Ki-67 index and CD40L expression. Functionally, stimulation with CD40L enhanced RHAMM expression in CLL.
19089914	Melanoma	IFNG	Inhibit immunity (NK cell function)	Upon IFN-gamma treatment, expression of MICA, in some cases, also of ULBP2 decreased. Besides melanoma, this observation was made also for glioma cells. Down-regulation of NKG2DL surface expression was dependent on the cytokine dose and the duration of treatment, but was neither due to an intracellular retention of the molecules nor to an increased shedding of ligands from the tumor cell surface. Instead, quantitative RT-PCR revealed a decrease of MICA-specific mRNA levels upon IFN-gamma treatment and siRNA experiments pointed to an involvement of STAT-1 in this process. Importantly, IFN-gamma-treated MHC class I-negative melanoma cells were less susceptible to NKG2D-mediated NK cell cytotoxicity.
19088040	Glioma	STAT3	Inhibit immunity (T cell function)	p-STAT3 expression was associated with the population of tumor-infiltrating immune cells but not with that of T regulatory cells.
19074888	Melanoma	WNT5A	Inhibit immunity (T cell function)	Melanosomal antigen expression is governed by MITF, PAX3, and SOX10 and is inhibited upon signal transducers and activators of transcription 3 (STAT3) activation, via decreases in PAX3 and subsequently MITF expression. Increasing Wnt5A in Wnt5A-low cells activated STAT3, and STAT3 was decreased upon Wnt5A knockdown. CTL activation studies showed that increases in Wnt5A correspond to decreased CTL activation and vice versa, suggesting that targeting Wnt5A before immunotherapy may lead to the enhancement of current targeted immunotherapy for patients with metastatic melanoma.
19074859	Melanoma	CA9	Promote immunity (T cell function)	In a murine melanoma model, a complex of CA9 and gp100 generated a gp100-specific antitumor response. A soluble form of CA9 shed from tumor cells had the same chaperone-like functions, providing renal tumors and hypoxic cells with a mechanism for stimulating an immune response against extracellular antigens. Interleukin-2 treatment of patient renal tumors in short-term culture increased CA9 shedding, suggesting a strategy for augmenting the immunogenicity of renal tumors.
19074859	Melanoma	PMEL	Promote immunity (T cell function)	In a murine melanoma model, a complex of CA9 and gp100 generated a gp100-specific antitumor response. A soluble form of CA9 shed from tumor cells had the same chaperone-like functions, providing renal tumors and hypoxic cells with a mechanism for stimulating an immune response against extracellular antigens. Interleukin-2 treatment of patient renal tumors in short-term culture increased CA9 shedding, suggesting a strategy for augmenting the immunogenicity of renal tumors.
19074732	Melanoma	MAGEA3	Promote immunity (T cell function)	Three of 10 patients treated with MAGE-A3-GML showed an increase of circulating anti-MAGE-A3 T cells, and developed skin delayed-type hypersensitivity to MAGE-A3. Interestingly, in 2 of these patients, with progressive and measurable tumors at study entry, anti-MAGE-A3 T cells were detected not only in the blood but also within tumors resected after vaccination.
19074257	Melanoma	CTLA4	Inhibit immunity	Fifteen patients were selected on the basis of availability of suitable specimens for immunologic monitoring, and eight of these showed evidence of clinical benefit. Five of the eight patients with evidence of clinical benefit had NY-ESO-1 antibody, whereas none of seven clinical non-responders was seropositive for NY-ESO-1. All five NY-ESO-1 seropositive patients had clearly detectable CD4(+) and CD8(+) T cells against NY-ESO-1 following treatment with ipilimumab. Overall, NY-ESO-1-specific T cell responses increased in frequency and functionality during anti-CTLA-4 treatment, revealing a polyfunctional response pattern of IFN-gamma, MIP-1beta and TNF-alpha.
19050262	Pancreatic Carcinoma	TNFRSF6B	Inhibit immunity (T cell function)	Flow cytometry assays indicated that apoptosis was not seen in AsPC-1 cells incubated with soluble FasL or membrane-bound FasL, but was seen when DcR3 small interfering RNA-transfected AsPC-1 cells underwent the same treatment.
19050070	Acute Myeloid Leukemia	IDO1	Inhibit immunity	High INDO expression was correlated to significantly shortened overall and relapse-free survival. Correlation of INDO expression to relevant known prognostic factors and survival identified high INDO expression as a strong negative independent predicting variable for overall and relapse-free survival.
19029379	Fibrosarcoma	CD226	Promote immunity (T cell function)	DNAM-1-deficient cytotoxic T lymphocyte (CTL) and NK cells showed significantly less cytotoxic activity against DNAM-1 ligand-expressing tumors in vitro than wild-type (WT) cells. The methylcholanthrene (MCA)-induced fibrosarcoma cell line Meth A expressed the DNAM-1 ligand CD155, and DNAM-1-deficient mice showed increased tumor development and mortality after transplantation of Meth A cells. Moreover, the DNAM-1-deficient mice developed significantly more DNAM-1 ligand-expressing fibrosarcoma and papilloma cells in response to the chemical carcinogens MCA and 7,12-dimethylbenz[a]anthracene (DMBA), respectively, than did WT mice.
19022917	Colorectal Carcinoma	IL6	Inhibit immunity (T cell function)	Moreover, T8reg were able to suppress CD4(+)CD25(-) T cell proliferation and Th1 cytokine production ex vivo, demonstrating that tumour-infiltrating T8reg have strong suppressive capacities. T8reg numbers correlated with the tumour stage and with micro-invasive status. Finally, interleukin 6 and TGF beta 1 synergistically induced the generation of CD8(+)CD25(+)Foxp3(+) T cells ex vivo.
19022917	Colorectal Carcinoma	TGFB1	Inhibit immunity (T cell function)	Moreover, T8reg were able to suppress CD4(+)CD25(-) T cell proliferation and Th1 cytokine production ex vivo, demonstrating that tumour-infiltrating T8reg have strong suppressive capacities. T8reg numbers correlated with the tumour stage and with micro-invasive status. Finally, interleukin 6 and TGF beta 1 synergistically induced the generation of CD8(+)CD25(+)Foxp3(+) T cells ex vivo.
19010917	Colorectal Carcinoma	LEP	Promote immunity (T cell function)	Systemic leptin enhanced the proinflammatory cytokines in normal colonocytes and in HT29 xenografted tumor colonocytes. Colonocyte-derived products after leptin treatment stimulated perforin and granzyme B expressions in normal CD8(+) T cells in vitro.
19010907	Colorectal Carcinoma	HDAC2	Inhibit immunity	Enzymatic degradation of PGE(2) involves the NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH). We report here that treatment of CRC cells with histone deacetylase (HDAC) inhibitors, including sodium butyrate and valproic acid, induces 15-PGDH expression. Additionally, we show that pretreatment of CRC cells with HDAC inhibitors can block epidermal growth factor-mediated or Snail-mediated transcriptional repression of 15-PGDH.
19010841	Endometrial Carcinoma	IDO1	Inhibit immunity	However, in vivo tumor growth was markedly enhanced in AMEC-IDO-xenografted nude mice when compared with AMEC-pcDNA-xenografted mice. Finally, oral administration of the IDO inhibitor 1-methyl-D-tryptophan in combination with paclitaxel in AMEC-IDO-xenografted mice strongly potentiated the antitumor effect of paclitaxel, resulting in significantly prolonged survival.
29515790	Hepatocellular Carcinoma	GPX4	Promote immunity (T cell function)	GPx4-overexpressing cells displayed impaired tumor growth, reduced proliferation, altered angiogenesis and decreased expression of clinically relevant cytokine interleukin-8 and C-reactive protein. Moreover, GPx4 overexpression impaired migration of endothelial cells in vitro, and enhanced expression of thrombospondin 1, an endogenous inhibitor of angiogenesis. In patients, GPx4 expression in tumors positively correlated with survival and was linked to pathways which regulate cell proliferation, motility, tissue remodelling, immune response and M1 macrophage polarization.
29510614	Breast Carcinoma	PSMB8	Promote immunity (infiltration)	In 668 consecutive breast cancer cohort, 40% of tumors showed high level of LMP7 expression, and tumors with high expression of LMP7 had more tumor-infiltrating lymphocytes (TILs) in each subtype of breast cancer. In another cohort of 681 triple-negative breast cancer patients cohort, the expression of LMP7 in tumor cells was significantly correlated with the amount of TILs and the expression of interferon-associated molecules (MxA [p < 0.001] and PKR [p < 0.001]), endoplasmic reticulum stress-associated molecules (PERK [p=0.012], p-eIF2a [p=0.001], and XBP1 [p < 0.001]), and damage-associated molecular patterns (HMGN1 [p < 0.001] and HMGB1 [p < 0.001]).
29508025	Hepatocellular Carcinoma	TNFSF9	Promote immunity (T cell function)	Expression of exhaustion markers is reduced on T cells activated by CD137L-DCs. Furthermore, these T cells are metabolically more active and have a higher capacity to utilize glucose. CD137L-induced monocyte to DC differentiation leads to the formation of AIM2 inflammasome, with IL-1beta contributing to CD137L-DCs possessing a stronger T cell activation ability.
29506555	Head and Neck Carcinoma	HAVCR2	Inhibit immunity	In the transgenic HNSCC mouse model, blockade of TIM3 by the anti-TIM3 monoclonal antibody induced a reduction of CD4+CD25+Foxp3+ Tregs. Meanwhile, the population of TIM3+ Tregs was also decreased. The increased IFN-γ production on CD8+ T cells in anti-TIM3 treatment mice showed that the antitumor immune response was enhanced through suppression of these negative immune factors.
29486738	Breast Carcinoma; Melanoma	IL6	Inhibit immunity (T cell function)	IL-6, IL-8 and XIAP showed increased expressions in PTX-treated cells and this over-production effect was inhibited in TLR4-transient knockdown cells. Apoptotic cells were detected higher when PTX and CpdA were combined than PTX treatment alone. Isobologram exhibited the synergistic effect of CpdA and PTX. CpdA could significantly decrease expressions of IL-6, XIAP and IL-8, as well as excreted IL-8 levels together with reduced cancer viability after PTX treatment. The acquired TLR4-mediated PTX resistance in BCA and melanoma is explained partly by the paracrine effect of IL-6 and IL-8 released into the tumor microenvironment and over-production of anti-apoptotic protein, XIAP, in BCA cells and importantly CpdA could reduce this effect and sensitize PTX-induced apoptosis in a synergistic manner.
29486738	Breast Carcinoma; Melanoma	CXCL8	Inhibit immunity (T cell function)	IL-6, IL-8 and XIAP showed increased expressions in PTX-treated cells and this over-production effect was inhibited in TLR4-transient knockdown cells. Apoptotic cells were detected higher when PTX and CpdA were combined than PTX treatment alone. Isobologram exhibited the synergistic effect of CpdA and PTX. CpdA could significantly decrease expressions of IL-6, XIAP and IL-8, as well as excreted IL-8 levels together with reduced cancer viability after PTX treatment. The acquired TLR4-mediated PTX resistance in BCA and melanoma is explained partly by the paracrine effect of IL-6 and IL-8 released into the tumor microenvironment and over-production of anti-apoptotic protein, XIAP, in BCA cells and importantly CpdA could reduce this effect and sensitize PTX-induced apoptosis in a synergistic manner.
29486738	Breast Carcinoma; Melanoma	XIAP	Inhibit immunity (T cell function)	IL-6, IL-8 and XIAP showed increased expressions in PTX-treated cells and this over-production effect was inhibited in TLR4-transient knockdown cells. Apoptotic cells were detected higher when PTX and CpdA were combined than PTX treatment alone. Isobologram exhibited the synergistic effect of CpdA and PTX. CpdA could significantly decrease expressions of IL-6, XIAP and IL-8, as well as excreted IL-8 levels together with reduced cancer viability after PTX treatment. The acquired TLR4-mediated PTX resistance in BCA and melanoma is explained partly by the paracrine effect of IL-6 and IL-8 released into the tumor microenvironment and over-production of anti-apoptotic protein, XIAP, in BCA cells and importantly CpdA could reduce this effect and sensitize PTX-induced apoptosis in a synergistic manner.
29486141	Head and Neck Carcinoma	BST2	Inhibit immunity	We found that CD317 expression was up-regulated in HNSCC tumor cells, and the CD317 expression level was independent of the histological grade, tumor size, and lymph node metastasis. Moreover, Kaplan-Meier survival curve analysis showed that patients with high expression of CD317 had a poor prognosis compared with patients with low expression. Furthermore, CD317 overexpression in HNSCC was correlated with immune checkpoint molecules PD-L1, B7-H3, and B7-H4 and tumor-associated macrophage markers (CD68 and CD163)
29478948	Melanoma	HSP90AA1	Inhibit immunity (T cell function)	Targeting HSP70/90 in melanoma cells resulted in reduced induction of immune suppressive cells on a phenotypic and functional basis, for which a more potent effect was observed when HSP90 was inhibited under hypoxic conditions.
29478948	Melanoma	HSPA4	Inhibit immunity (T cell function)	Targeting HSP70/90 in melanoma cells resulted in reduced induction of immune suppressive cells on a phenotypic and functional basis, for which a more potent effect was observed when HSP90 was inhibited under hypoxic conditions.
29473266	Burkitt Lymphoma	SIRPA	Inhibit immunity	With the use of Rag2-/- γc-/- mice harboring a transgene for human SIRPα under the control of human regulatory elements (hSIRPα-DKO mice), we here show that a blocking Ab to human SIRPα significantly enhanced the ADCP activity of macrophages derived from these mice for human cancer cells. The anti-human SIRPα Ab also markedly enhanced the inhibitory effect of rituximab on the growth of tumors formed by Raji cells in hSIRPα-DKO mice.
29464090	Ewing Sarcoma	HLA-G	Inhibit immunity (T cell function)	We hypothesized that the non-classical, immune-inhibitory HLA-molecule HLA-G contributes to immune escape of EwS. HLA-G expression was not associated with risk-related patient variables or response to standard chemotherapy, but with significantly increased numbers of tumor-infiltrating CD3+ T cells compared to HLA-Gneg EwS biopsies. In a mouse model, EwS xenografts after adoptive therapy with tumor antigen-specific CAR T cells strongly expressed HLA-G whereas untreated control tumors were HLA-Gneg.
29453519	Tongue Squamous Cell Carcinoma; Lung Carcinoma	IL12A	Promote immunity (infiltration)	Neutralizing IL12 signaling with an IL12 antibody abrogated TriCurin-induced intra-tumor entry of activated natural killer (NK) cells and Cytotoxic T lymphocytes (CTL), thereby confirming that IL12 triggers recruitment of NK cells and CTL. These activated NK cells and CTL join the M1 TAM to elicit apoptosis of the E6+?tumor cells. Corroboratively, neutralizing IL12 signaling partially reversed this TriCurin-mediated apoptosis
29450641	Chronic Lymphocytic Leukemia	TLR9	Inhibit immunity	TLR9-activated CLL cells were found to increase the frequency of CD4+CD25hiFOXp3+ regulatory T-cells (Tregs) and to inhibit autologous CD4+ T-cell proliferation. This signaling cascade proved to control IL-10 generation in CLL cells, which in turn promoted the inhibition of T-cell proliferation by CLL cells.
29440650	Hepatocellular Carcinoma	IL33	Promote immunity (infiltration)	Our data support the model that IL-33 dependent tumour-infiltrating ILC2s are mobilized from the lungs and other tissues through chemoattraction to enter tumours, and subsequently mediate tumour immune-surveillance by cooperating with dendritic cells to promote adaptive cytolytic T cell responses.
29437708	Breast Carcinoma	FABP4	Inhibit immunity (T cell function)	Although upregulation of A-FABP was inversely associated with breast cancer survival, deficiency of A-FABP significantly reduced mammary tumor growth and metastasis. Furthermore, the protumor effect of A-FABP was mediated by TAM, in particular, in a subset of TAM with a CD11b+F4/80+MHCII-Ly6C- phenotype. A-FABP expression in TAM facilitated protumor IL6/STAT3 signaling through regulation of the NFκB/miR-29b pathway.
29435131	Non-Small Cell Lung Carcinoma	CD274	Inhibit immunity (T cell function)	Mechanistic studies indicated that upregulation of YAP1 by PD-L1 might be responsible for EGFR mutation-independent TKI resistance via the ROS/HIF-1α axis. An unfavorable TKI response was more common in patient tumors with high PD-L1 or YAP1 mRNA expression than in patient tumors with low mRNA expression of these genes.
29423109	Lung Carcinoma	HLA-A	Promote immunity (T cell function)	All HLA-I+/PD-L1+ tumors had a high degree of intratumoral infiltration with CD8+T-lymphocytes, whereas HLA-I loss was associated with a significantly reduced number of tumor infiltrating T-lymphocytes mostly restrained in the stroma surrounding the tumor nest. HLA-I-negative/PD-L1-positive tumors had bigger size (T) and lower grade of infiltration with CD8+T-cells.
29411237	Triple-Negative Breast Carcinoma	FZD7	Essential for immunity	The scFvs inhibited cell growth of MDA-MB-231 cells significantly as compared to untreated cells. Growth inhibition of 58.6 and 53.1% were detected for scFv-I and scFv-II, respectively. No significant growth inhibition was detected for SKBR-3 negative control cells. The scFvs induced apoptotic effects in the MDA-MB-231 treated cells after 48?h, which were 81.6 and 74.9% for scFv-I and scFv-II, respectively. Downregulation of Surivin, c-Myc and Dvl genes were also shown after 48h treatment of cells with either of scFvs (59.3-93.8%).
17982058	Pancreatic Carcinoma	CD40	Promote immunity	In this report, we show that the conditioning of tumor-bearing RIP1-Tag4 mice with agonistic anti-CD40 Ab induces extensive expansion of naive epitope I-specific TCR transgenic (TCR-I) T cells in this tolerogenic environment and delays their loss from the host. In addition, functional TCR-I T cells intensively infiltrate pancreatic tumors, resulting in increased survival of RIP1-Tag4 mice.
17974996	Prostate Carcinoma; Melanoma	TLR4	Promote immunity	We show that (a) activating TLR4 signaling in two different tumor cell lines in vitro modifies the tumor outgrowth in vivo; (b) this effect is not due to a direct consequence of TLR4 signaling on the proliferation/apoptosis balance of the tumor cells; (c) the T-cell compartment is somehow involved in the described phenomenon because the inhibitory effect observed is not seen in athymic nude mice; and (d) tumor-infiltrating lymphocytes purified from tumors induced by TLR4-activated cells show strong induction of IFN gamma transcript in detriment of interleukin-10 transcript, suggesting a change in their functionality.
17971488	Colorectal Carcinoma	CDC42	Inhibit immunity (T cell function)	We have identified Cdc42, a GTPase regulating actin dynamics and growth factor signaling that is highly expressed in invasive cancers, as determinator of cancer cell susceptibility to antigen-specific CTLs in vitro and adoptively transferred immune effectors in vivo. Cdc42 prevents CTL-induced apoptosis via mitogen-activated protein kinase (MAPK) signaling and posttranscriptional stabilization of Bcl-2. Pharmacologic inhibition of MAPK/extracellular signal-regulated kinase (ERK) kinase (MEK) overcomes Cdc42-mediated immunoresistance and activation of Bcl-2 in vivo.
17947638	Hepatocellular Carcinoma	IL10	Inhibit immunity (T cell function)	We demonstrate here that DCs devoid of IL-10, a potent immunosuppressive cytokine, are superior over conventional DCs in triggering antitumor immunity. The IL-10(-/-)DCs were highly immunogenic, expressed enhanced levels of surface MHC class II molecules, and secreted increased amounts of Th1-related cytokines.
17942936	Breast Carcinoma	IL1R1	Inhibit immunity (T cell function)	We have tested this hypothesis using the 4T1 mammary carcinoma and IL-1 receptor (IL-1R)-deficient mice which have a reduced potential for inflammation, and IL-1R antagonist-deficient mice, which have an increased potential for inflammation. Consistent with our hypothesis, IL-1R-deficient mice have a delayed accumulation of MDSC and reduced primary and metastatic tumor progression.
17942936	Breast Carcinoma	IL1RN	Promote immunity (T cell function)	In contrast, excessive inflammation in IL-1R antagonist-deficient mice promotes the accumulation of MDSC and produces MDSC with enhanced suppressive activity.
17942936	Breast Carcinoma	IL6	Inhibit immunity (T cell function)	We have tested this hypothesis using the 4T1 mammary carcinoma and IL-1 receptor (IL-1R)-deficient mice which have a reduced potential for inflammation, and IL-1R antagonist-deficient mice, which have an increased potential for inflammation. Consistent with our hypothesis, IL-1R-deficient mice have a delayed accumulation of MDSC and reduced primary and metastatic tumor progression.Accumulation of MDSC and tumor progression are partially restored by IL-6, indicating that IL-6 is a downstream mediator of the IL-1beta-induced expansion of MDSC.
17942891	Glioblastoma	STAT3	Inhibit immunity (T cell function)	Signal transducers and activators of transcription 3 (STAT3) has recently emerged as a potential target for effective immunotherapy, and in this study, we describe a novel small molecule inhibitor of STAT3 that can penetrate the central nervous system (CNS) in mice and in physiologically relevant doses in vitro and reverse tolerance in immune cells isolated from glioblastoma multiforme (GBM) patients. Specifically, it induces the expression of costimulatory molecules on peripheral macrophages and tumor-infiltrating microglia, stimulates the production of the immune-stimulatory cytokines interleukin 2 (IL-2), IL-4, IL-12, and IL-15, and induces proliferation of effector T cells from GBM patients that are refractory to CD3 stimulation.
17938258	Hepatocellular Carcinoma	FPR2	Promote immunity (T cell function)	In the present study, we showed that stimulation of FPRL1 agonist ligands (W peptide from a synthetic peptide library, N36 peptide from HIV-1 gp41, and F peptide from HIV-1 envelope protein gp120) elevated endogenous tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression in human THP-1 monocytes, primary neutrophils, and mouse leukocytes. Activation of nuclear factor kappaB was required by the FPRL1-mediated TRAIL expression in the human THP-1 cells and primary neutrophils. The increased TRAIL expression in the mice significantly suppressed the growth of transplanted mouse liver tumor cells by inducing apoptotic cell death.
17932562	Prostate Adenocarcinoma	LAG3	Inhibit immunity	In vivo antibody blockade of LAG-3 or genetic ablation of the Lag-3 gene resulted in increased accumulation and effector function of antigen-specific CD8+ T cells within organs and tumors that express their cognate antigen. Most notably, combining LAG-3 blockade with specific antitumor vaccination resulted in a significant increase in activated CD8+ T cells in the tumor and disruption of the tumor parenchyma.
17925549	Renal Cell Carcinoma	TNF	Inhibit immunity	Tumor necrosis factor alpha (TNF-alpha) may play a role in renal cell carcinoma (RCC). We performed two sequential phase II studies of infliximab, an anti-TNF-alpha monoclonal antibody, in patients with immunotherapy-resistant or refractory RCC. In study 1, three patients (16%) achieved partial response (PR) and three patients (16%) achieved stable disease (SD). Median duration of response (PR + SD) was 7.7 months (range, 5.0 to 40.5+ months). In study 2, 11 patients (61%) achieved SD. Median duration of response was 6.2 months (range, 3.5 to 24+ months).
17923873	Breast Carcinoma	CD40LG	Promote immunity (T cell function)	Finally, by comparing a range of clinically available maturation stimuli, we demonstrate that conditioning with soluble CD40L induces the highest level of maturation and improved T-cell priming.
17919943	Lymphoma; Melanoma; Acute Myeloid Leukemia	GZMB	Inhibit immunity (T cell; NK function)	Adoptive transfer of WT Treg cells, but not granzyme B- or perforin-deficient Treg cells, into granzyme B-deficient mice partially restored susceptibility to tumor growth; Treg cells derived from the tumor environment could induce NK and CD8(+) T cell death in a granzyme B- and perforin-dependent fashion.
17918178	Metastatic Malignant Neoplasm in the Lung; Breast Carcinoma	IFNGR1	Inhibit immunity (infiltration)	Interestingly, disruption of IFN-gammaR function did not alter tumor cell susceptibility to CTL-mediated cytotoxicity, but is linked to enhanced infiltration of endogenous T cells in the tumor microenvironment in vivo.
17911631	Prostate Carcinoma; Melanoma	PEBP1	Promote immunity (T cell function)	Treatment with RKIP small interfering RNA (siRNA) inhibited TRAIL-induced apoptosis. RKIP overexpression was paralleled with up-regulation of DR5 transcription and expression; no change in DR4, decoy receptor 1, and decoy receptor 2 expression; and inhibition of YY1 transcription and expression. Inhibition of YY1 by YY1 siRNA sensitized the cells to TRAIL apoptosis concomitantly with DR5 up-regulation. RKIP overexpression inhibited several antiapoptotic gene products such as X-linked inhibitor of apoptosis (XIAP), c-FLIP long, and Bcl-x(L) that were accompanied with mitochondrial membrane depolarization. RKIP overexpression in combination with TRAIL resulted in the potentiation of these above effects and activation of caspases 8, 9, and 3, resulting in apoptosis.
17909051	Prostate Carcinoma	CCL2	Inhibit immunity	Using neutralizing antibodies to human CCL2 (CNTO888) and the mouse homologue CCL2/JE (C1142), we show that treatment with anti-CCL2/JE antibody (2 mg/kg, twice weekly i.p.) attenuated PC-3Luc-mediated overall tumor burden in our in vivo model of prostate cancer metastasis by 96% at 5 weeks postintracardiac injection. Anti-CCL2 inhibition was not as effective as docetaxel (40 mg/kg, every week for 3 weeks) as a single agent, but inhibition of CCL2 in combination with docetaxel significantly reduced overall tumor burden compared with docetaxel alone, and induced tumor regression relative to initial tumor burden.
17898788	Adult T-Cell Leukemia/Lymphoma	TFRC	Inhibit immunity	A24 binds TfR-1 (K(d) 2.7 nM) and competes with transferrin for receptor binding. It blocks the proliferation of malignant cells (TfR-1(high)), such as HTLV-I-infected T cells but not of resting cells. A24 induces TfR-1 endocytosis in lysosomal compartments where the receptor is degraded leading to intracellular iron deprivation. In HTLV-I-infected cells, A24 targets and induces apoptosis of both chronic and acute ATLL forms, independent of antibody aggregation, antibody-dependent cellular cytotoxicity and/or complement addition.
17885078	Colon Carcinoma	KITLG	Inhibit immunity (T cell function)	Mice bearing tumor cells with SCF siRNA knockdown exhibited significantly reduced MDSC expansion and restored proliferative responses of tumor-infiltrating T cells. Furthermore, the prevention of MDSC accumulation in conjunction with immune activation therapy showed synergistic therapeutic effect when treating mice bearing large tumors.
17885078	Colon Carcinoma	KIT	Inhibit immunity (T cell function)	More importantly, blockade of SCF receptor (ckit)-SCF interaction by anti-ckit prevented tumor-specific T-cell anergy, Treg development, and tumor angiogenesis. Furthermore, the prevention of MDSC accumulation in conjunction with immune activation therapy showed synergistic therapeutic effect when treating mice bearing large tumors.
17849467	Malignant Uterine Neoplasm	EBAG9	Inhibit immunity	Knockdown of RCAS1 expression by siRNA significantly suppressed the in vivo growth of SiSo and HOUA tumor cells (P < .005); however, in vitro cell growth was not affected significantly. Enhanced RCAS1 expression significantly promoted in vivo growth, but not in vitro growth, of tumors derived from COS-7 cells (P = .0039).
17848619	Ovarian Carcinoma	LIF	Inhibit immunity (T cell function)	Ovarian cancer ascites contained high concentrations of LIF and IL-6. Recombinant LIF and IL-6 skew monocyte differentiation into TAM-like cells by enabling monocytes to consume monocyte-colony-stimulating factor (M-CSF). Depletion of LIF, IL-6, and M-CSF in ovarian cancer ascites suppressed TAM-like cell induction.
17848619	Ovarian Carcinoma	IL6	Inhibit immunity (T cell function)	Ovarian cancer ascites contained high concentrations of LIF and IL-6. Recombinant LIF and IL-6 skew monocyte differentiation into TAM-like cells by enabling monocytes to consume monocyte-colony-stimulating factor (M-CSF). Depletion of LIF, IL-6, and M-CSF in ovarian cancer ascites suppressed TAM-like cell induction.
17804750	Pancreatic Ductal Adenocarcinoma	FOXP3	Inhibit immunity (T cell function)	Coculture of Foxp3-expressing tumor cells with naive T cells completely inhibited T-cell proliferation, but not activation, and this antiproliferative effect was partially abrogated following specific inhibition of Foxp3 expression.
17785868	Primary Cutaneous T-Cell Non-Hodgkin Lymphoma	CXCR3	Promote immunity (infilration)	In this study, we show that advanced cutaneous T cell lymphoma (CTCL) is associated with selective and efficient inactivation of CXCR3-dependent T cell migration. Our studies demonstrate that this alteration is at least in part due to CXCR3 down-regulation in vivo by elevated serum levels of CXCR3 ligands. The T cell population most affected by this down-regulatory mechanism are CD8+ cytotoxic effector T cells. In CTCL patients, cytotoxic effector T cells have strongly reduced surface CXCR3 expression, accumulate in peripheral blood, but are virtually absent from CTCL tumor lesions, indicating an inability to extravasate into lymphoma tissue.
17785863	Glioma	NOS2	Inhibit immunity	In this study, we show that the inducible NO synthase (iNOS)-specific inhibitor mercaptoethylguanidine (MEG) superiorly enhanced lymphocyte reactivity after polyclonal stimulation compared with the iNOS-specific inhibitor L-NIL and the unspecific NO synthase inhibitor L-NAME. Both iNOS inhibitors increased the number and proliferation of T cells but not of B cells.
17785813	Melanoma	HCST	Inhibit immunity (NK cell function)	Mice lacking DAP10 (DAP10KO), showed enhanced immunity against melanoma malignancies due to hyperactive functioning of NK1.1+CD3+ NKT cells. DAP10 deficiency resulted in substantially increased NKT cell functions, including cytokine production and cytotoxicity, leading to efficient killing of melanoma tumors. Moreover, the antitumor phenotype of DAP10KO mice correlated with impaired activation status of CD4+CD25+ T regulatory cells (Tregs).
17785576	Sacroma; Breast Carcinoma	LTBR	Promote immunity (T cell function)	Blocking LTbetaR with LTbetaR-specific neutralizing monoclonal antibody decreased CTL cytotoxicity in vitro. Silencing LTbetaR using LTbetaR-specific short hairpin RNA reduced the ability of pfp CTLs to induce tumor rejection in vivo.
17768418	Skin Carcinoma	TGFB1	Inhibit immunity (infitration)	Flow cytometry was used to show that TGFbeta-mediated tumour progression was accompanied by an increase in tumour-associated macrophages (TAM) and a decrease in tumour-infiltrating dendritic cells (DCs). TAM in TGFbeta-secreting tumours expressed lower levels of major histocompatibility complex II and CD86 compared to DC in control tumours and had a high phagocytic capacity as measured by uptake of latex beads in vivo. Indeed, TGFbeta was directly responsible not only for the enhanced macrophage phagocytosis but also altering the ratio of antigen-presenting cells to favour macrophages over DC.
17710228	Neuroblastoma	MYCN	Inhibit immunity (infiltration)	Here, we report that the v-myc myelocytomatosis viral related oncogene, neuroblastoma derived (MYCN), the hallmark of aggressive neuroblastoma, repressed expression of monocyte chemoattractant protein-1/CC chemokine ligand 2 (MCP-1/CCL2), a chemokine required for NKT cell chemoattraction. MYCN knockdown in MYCN-amplified neuroblastoma cell lines restored CCL2 production and NKT cell chemoattraction. MYCN overexpression in neuroblastoma xenografts in NOD/SCID mice severely inhibited their ability to attract human NKT cells, T cells, and monocytes. Patients with MYCN-amplified neuroblastoma metastatic to bone marrow had 4-fold fewer NKT cells in their bone marrow than did their nonamplified counterparts, indicating that the MYCN-mediated immune escape mechanism, which we believe to be novel, is operative in metastatic cancer and should be considered in tumor immunobiology and for the development of new therapeutic strategies.
17709550	Burkitt Lymphoma; Neuroblastoma; Amelanotic Melanoma	CCL2	Inhibit immunity (infilration)	We compared the chemokines secreted by tumor cell lines with high chemotactic activity with those that failed to elicit T cell chemotaxis (Daudi lymphoma, 10HTB neuroblastoma, and A2058 melanoma cells) and found a correlation between tumor-derived production of MCP-1/CCL2 (> or =10 ng/ml) and T cell chemotaxis. Chemokine immunodepletion studies confirmed that tumor-derived MCP-1 elicits effector T cell chemotaxis. Moreover, MCP-1 is sufficient for in vivo T cell tumor tropism as evidenced by the selective accumulation of i.v. administered firefly luciferase-expressing T cells in intracerebral xenografts of tumor transfectants secreting MCP-1.
17709502	B Acute Lymphoblastic Leukemia	PEG10	Inhibit immunity (T cell function)	Moreover, using a short hairpin RNA to knockdown PEG10, we provide direct evidence that increased expression of PEG10 in B-ALL CD23+CD5+ B cells is involved in malignant B-T cell interaction, contributing to the up-regulation of IL-10 expression, as well as to the impairment of cytotoxicity of syngeneic CD8+ T cells.
17709502	B Acute Lymphoblastic Leukemia	IL10	Inhibit immunity (T cell function)	Here, we report that B-ALL CD23+CD5+ B cells produce IL-10 at high level, which can be further elevated by costimulation with CCL19 and CXCL13. CCL19/CXCL13-activated B-ALL CD23+CD5+ B cells, in turn, increase IL-10 expression in syngeneic CD8+ T cells in a B cell-derived IL-10-dependent manner and requiring a cell-cell contact. IL-10 secreted from B-ALL CD23+CD5+ B cells in vitro impairs tumor-specific CTL responses of syngeneic CD8+ T cells.
17709502	B Acute Lymphoblastic Leukemia	CCL19	Inhibit immunity (T cell function)	Here, we report that B-ALL CD23+CD5+ B cells produce IL-10 at high level, which can be further elevated by costimulation with CCL19 and CXCL13. CCL19/CXCL13-activated B-ALL CD23+CD5+ B cells, in turn, increase IL-10 expression in syngeneic CD8+ T cells in a B cell-derived IL-10-dependent manner and requiring a cell-cell contact. IL-10 secreted from B-ALL CD23+CD5+ B cells in vitro impairs tumor-specific CTL responses of syngeneic CD8+ T cells. The impairment of cytotoxicity of syngeneic CD8+ T cells is escalated by means of CCL19/CXCL13-induced up-regulation of IL-10 from B-ALL CD23+CD5+ B cells.
17709502	B Acute Lymphoblastic Leukemia	CXCL13	Inhibit immunity (T cell function)	Here, we report that B-ALL CD23+CD5+ B cells produce IL-10 at high level, which can be further elevated by costimulation with CCL19 and CXCL13. CCL19/CXCL13-activated B-ALL CD23+CD5+ B cells, in turn, increase IL-10 expression in syngeneic CD8+ T cells in a B cell-derived IL-10-dependent manner and requiring a cell-cell contact. IL-10 secreted from B-ALL CD23+CD5+ B cells in vitro impairs tumor-specific CTL responses of syngeneic CD8+ T cells. The impairment of cytotoxicity of syngeneic CD8+ T cells is escalated by means of CCL19/CXCL13-induced up-regulation of IL-10 from B-ALL CD23+CD5+ B cells.
17709502	B Acute Lymphoblastic Leukemia	CXCR5	Inhibit immunity (T cell function)	In a previous study, we have reported that ligation of CCL19-CCR7 and CXCL13-CXCR5 activates paternally expressed gene 10 (PEG10), resulting in an enhancement of apoptotic resistance in B-cell acute lymphocytic leukemia (B-ALL) CD23+CD5+ B cells.
17684491	Glioblastoma	TGFBR2	Inhibit immunity	We developed plasmid-transcribed small hairpin RNAs (shRNAs) to downregulate the TGF-beta type II receptor (TbetaIIR) expression, which effectively inhibited cytokine-induced signaling pathways and transcriptional responses in transiently transfected human glioblastoma cells. Silencing of TbetaIIR abolished TGF-beta-induced glioblastoma invasiveness and migratory responses in vitro. Moreover, tumorigenicity of glioblastoma cells stably expressing TbetaIIR shRNAs in nude mice was reduced by 50%.
17255258	Gastric Carcinoma	MICA	Inhibit immunity	NKG2D expression on circulating CD8(+) T cells was down-regulated and significantly correlated with IFN-gamma production in gastric cancer patients (r = 0.68; P = 0.007). Transwell experiments showed that this down-regulation was induced by direct contact between cancer cells and CD8(+) T cells and that soluble factors did not affect the NKG2D expression. This phenomenon was blocked by the addition of anti-MICA antibodies.
17251933	Liver Carcinoma	TP53	Promote immunity (T cell function)	We show that even brief reactivation of endogenous p53 in p53-deficient tumours can produce complete tumour regressions. The primary response to p53 was not apoptosis, but instead involved the induction of a cellular senescence program that was associated with differentiation and the upregulation of inflammatory cytokines. This program, although producing only cell cycle arrest in vitro, also triggered an innate immune response that targeted the tumour cells in vivo, thereby contributing to tumour clearance.
17237823	Breast Carcinoma	ESR1	Inhibit immunity (NK cell function)	In breast cancer cells, increasing concentrations of estrogen induce increasing levels of the granzyme B inhibitor, SerpinB9/proteinase inhibitor 9 (PI-9) and progressively block cell death induced by NK92 natural killer (NK) cells, but do not block killing by a second NK cell line, NKL cells. RNA interference knockdown of PI-9 abolishes estrogen's ability to block NK92 cell-induced cytotoxicity. Expressing elevated levels of estrogen receptor alpha (ERalpha) increases the induced level of PI-9, and makes tamoxifen (TAM), but not raloxifene or ICI 182,780, a potent inducer of PI-9. At elevated levels of ERalpha, induction of PI-9 by estradiol or TAM blocks killing by both NK92 and NKL cells.
17237823	Breast Carcinoma	SERPINB9	Inhibit immunity (NK cell function)	In breast cancer cells, increasing concentrations of estrogen induce increasing levels of the granzyme B inhibitor, SerpinB9/proteinase inhibitor 9 (PI-9) and progressively block cell death induced by NK92 natural killer (NK) cells, but do not block killing by a second NK cell line, NKL cells. RNA interference knockdown of PI-9 abolishes estrogen's ability to block NK92 cell-induced cytotoxicity. Expressing elevated levels of estrogen receptor alpha (ERalpha) increases the induced level of PI-9, and makes tamoxifen (TAM), but not raloxifene or ICI 182,780, a potent inducer of PI-9. At elevated levels of ERalpha, induction of PI-9 by estradiol or TAM blocks killing by both NK92 and NKL cells.
17237382	Lung Carcinoma	IL12A	Promote immunity (T cell function)	Analysis of tumor-infiltrating macrophages and distal TAMs revealed that IL-12, both in vivo and in vitro, induced a rapid (<90 min) reduction of tumor supportive macrophage activities (IL-10, MCP-1, migration inhibitory factor, and TGFbeta production) and a concomitant increase in proinflammatory and proimmunogenic activities (TNF-alpha, IL-15, and IL-18 production). Similar shifts in functional phenotype were induced by IL-12 in tumor-infiltrating macrophages isolated from the primary tumor mass and in TAMs isolated from lung containing metastases, spleen, and peritoneal cavity.
17234791	Breast Carcinoma; Melanoma	IDO1	Inhibit immunity (T cell function)	However, the D isomer was significantly more effective in reversing the suppression of T cells created by IDO-expressing dendritic cells, using both human monocyte-derived dendritic cells and murine dendritic cells isolated directly from tumor-draining lymph nodes. In vivo, the d isomer was more efficacious as an anticancer agent in chemo-immunotherapy regimens using cyclophosphamide, paclitaxel, or gemcitabine, when tested in mouse models of transplantable melanoma and transplantable and autochthonous breast cancer.
17211884	Burkitt Lymphoma	MYC	Inhibit immunity (T cell function)	Using a cell line in which EBNA2 and c-myc can be regulated at will, we show that c-MYC negatively regulates STAT1, the central player linking the Type-I and Type-II interferon response. Switching off c-myc expression leads to STAT1 induction through a direct and indirect mechanism involving induction of Type-I interferons. c-MYC thus masks an interferon-inducing activity in these cells.
17210719	Sacroma	NFKB1	Inhibit immunity	Tumor-induced oxidative stress increased cytosolic IkappaBalpha retention and inhibited NF-kappaB nuclear translocation in thymic T cells. These NF-kappaB-perturbed cells became vulnerable to tumor-secreted tumor necrosis factor (TNF)-alpha (TNF-alpha)-mediated apoptosis through the activation of TNF receptor-associated protein death domain-associated Fas-associated protein death domain and caspase-8. When T cells were overexpressed with NF-kappaB, the cells became resistant to tumor-induced apoptosis.
17210719	Sacroma	NFKBIA	Inhibit immunity (T cell function)	Tumor-induced oxidative stress increased cytosolic IkappaBalpha retention and inhibited NF-kappaB nuclear translocation in thymic T cells. These NF-kappaB-perturbed cells became vulnerable to tumor-secreted tumor necrosis factor (TNF)-alpha (TNF-alpha)-mediated apoptosis through the activation of TNF receptor-associated protein death domain-associated Fas-associated protein death domain and caspase-8.
17200356	Ewing Sarcoma	CASP8	Promote immunity (T cell function)	Although all tested Ewing sarcoma cell lines expressed cFLIP, resistance to CD95/Fas-mediated apoptosis was only observed in two cell lines lacking caspase-8 expression.
17191072	Hepatocellular Carcinoma	IFNA1	Promote immunity	KD3-IFN expresses human IFN-alpha in concurrence with vector replication and overexpresses the adenovirus death protein (ADP; E3-11.6K). The antitumor activity of KD3-IFN was significantly higher than that of a control vector in established human hepatocellular carcinoma tumors in immunodeficient mice and in hamster kidney cancer tumors in immunocompetent Syrian hamsters.
17170077	Acute Myeloid Leukemia	TNFSF9	Promote immunity (T cell function)	Addition of 4-1BBL to cocultures of AML-DC and T cells induced a preferential increase in the proliferation of CD8(+) T cells. Increased differentiation into effector and central memory populations was observed in both CD4(+) and CD8(+) T cells in the presence of 4-1BBL. AML-DC induce a T helper 1 response, characterized by high IFN-gamma production, which is significantly increased by targeting 4-1BB.
17170077	Acute Myeloid Leukemia	TNFRSF9	Promote immunity (T cell function)	Addition of 4-1BBL to cocultures of AML-DC and T cells induced a preferential increase in the proliferation of CD8(+) T cells. Increased differentiation into effector and central memory populations was observed in both CD4(+) and CD8(+) T cells in the presence of 4-1BBL. AML-DC induce a T helper 1 response, characterized by high IFN-gamma production, which is significantly increased by targeting 4-1BB.
17159987	Glioma	PTEN	Inhibit immunity (T cell function)	Here we show that expression of the gene encoding B7-H1 increases post transcriptionally in human glioma after loss of phosphatase and tensin homolog (PTEN) and activation of the phosphatidylinositol-3-OH kinase (PI(3)K) pathway.
25049283	neuroblastoma	CD1D	Promote immunity (T cell function); essential for immunotherapy	We proposed that CAR expression in Vα24-invariant natural killer T (NKT) cells can build on the natural antitumor properties of these cells while their restriction by monomorphic CD1d limits toxicity. CAR.GD2 expression rendered NKT cells highly cytotoxic against NB cells without affecting their CD1d-dependent reactivity.
25049283	neuroblastoma	CD247	Promote immunity (T cell function); essential for immunotherapy	We compared CAR.GD2 constructs that encoded the CD3ζ chain alone, with CD28, 4-1BB, or CD28 and 4-1BB costimulatory endodomains. CAR.GD2 expression rendered NKT cells highly cytotoxic against NB cells without affecting their CD1d-dependent reactivity. We observed a striking T helper 1-like polarization of NKT cells by 4-1BB-containing CARs. Importantly, expression of both CD28 and 4-1BB endodomains in the CAR.GD2 enhanced in vivo persistence of NKT cells. These CAR.GD2 NKT cells effectively localized to the tumor site had potent antitumor activity, and repeat injections significantly improved the long-term survival of mice with metastatic NB.
25049283	neuroblastoma	CD28	Promote immunity (T cell function); essential for immunotherapy	Importantly, expression of both CD28 and 4-1BB endodomains in the CAR.GD2 enhanced in vivo persistence of NKT cells.
25046660	Leukemia	IFNG	Promote immunity	Instead, we highlight a critical and nonredundant role for IFN-γ and TNF-α production by NK cells to enhance cross-presentation by DC using two different Ag models.
25046660	Leukemia	CD34	Promote immunity	Importantly, we observed that NK cells promote cell-associated Ag cross-presentation selectively by monocytes-derived DC (Mo-DC) and CD34-derived CD11b(neg) CD141(high) DC subsets but not by myeloid CD11b(+) DC.
25046660	Leukemia	THBD	Promote immunity	Taken together, our findings point toward a novel role of human NK cells bridging innate and adaptive immunity through selective induction of cell-associated Ag cross-presentation by CD141(high) DC, a process that could be exploited to better harness Ag-specific cellular immunity in immunotherapy.
25046567	leukemia	KLRK1	Promote immunity (NK cell function)	WT already enhanced antileukemia reactivity by inducing antibody-dependent cellular cytotoxicity (ADCC) with NKG2D-Fc-ADCC mediating significantly stronger effects. Thus, NKG2D-Fc-ADCC potently enhances NK antileukemia reactivity despite the inevitable reduction of activating signals upon binding to NKG2DL and may constitute an attractive means for immunotherapy of leukemia.
25043048	Glioma	IDH1	Promote immunity (infiltration)	From an immunological perspective, IDH1(R132H) represents a potential target for immunotherapy as it is a tumour-specific potential neoantigen with high uniformity and penetrance expressed in all tumour cells.
25043048	Glioma	HLA-E	Promote immunity	Peptides encompassing the mutated region are presented on major histocompatibility complexes (MHC) class II and induce mutation-specific CD4(+) T-helper-1 (TH1) responses.
25042737	B cell lymphoma	CD14	Inhibit immunity	CD14(+) HLA-DR(low/neg) immunosuppressive monocytes affect tumor growth by suppressing host antitumor immunity.
25038326	melanoma	PMEL	Promote immunity	Patients with metastatic uveal melanoma received at least 3 vaccinations with autologous dendritic cells, professional antigen-presenting cells loaded with melanoma antigens gp100 and tyrosinase.
25038230	glioma	LGALS1	Inhibit immunity	Our findings suggest that galectin-1 suppression in human glioma could improve patient survival by restoring NK immune surveillance that can eradicate glioma cells
25038199	melanoma	CTLA4	Inhibit immunity (T cell function)	Because α-CTLA-4 Fab fragments had the same effect as the intact antibody, the higher T-cell motility does not seem to be due to CTLA-4 inhibitory signaling but rather to the release of nonproductive stable interactions between tumor-infiltrating T cells and tumor targets or antigen-presenting cells subsequent to CTLA-4 blockade.
25035397	Lung carcinomas	SPP1	Inhibit immunity (T cell function)	The matricellular protein osteopontin (OPN, Spp-1) is widely associated with cancer aggressiveness when produced by tumor cells, but its impact is uncertain when produced by leukocytes in the context of the tumor stroma.Moreover, fewer regulatory T cells accumulated at the metastatic site in Spp1(-/-) mice.
25024386	lymphoma	CD40	Promote immunity	The dependence on FcγRIIB for immunostimulatory activity was not absolute, however, because when anti-CD40 mAbs were administered systemically with the TLR3 agonist polyinosinic:polycytidylic acid or were given subcutaneously, activatory FcγR could also provide cross-linking.
25024303	lymphoma	FUT4	Inhibit immunity (infiltration)	The serum absolute lymphocyte count, the presence of tumor-infiltrating dendritic cells, CD15 expression on the malignant cells, and tumor morphology were biomarkers of outcome in MGZL.
25024217	melanoma	TNFAIP3	Inhibit immunity	The tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20) imposes a brake on antitumor activity of CD8 T cells.
25024217	melanoma	NFKB1	Promote immunity (T cell function); essential for immunotherapy	The transcription factor NF-κB is central to inflammatory signaling and activation of innate and adaptive immune responses. In contrast, relief from the A20 brake in NF-κB activation in adoptively transferred antitumor CD8 T cells led to improved control of melanoma growth. Moreover, systemic delivery of NPsiCDK1 is able to suprress tumor growth in mice bearing SUM149 and BT549 xenograft and cause no systemic toxcity or activate the innate immune response, suggesting the therapeutic promise with such nanoparticles carrying siCDK1 for c-Myc overexpressed triple negative breast cancer.
25024217	melanoma	IL2	Promote immunity (T cell function); essential for immunotherapy	A20-deleted CD8 T cells had increased sensitivity to antigen stimulation with production of large amounts of IL-2 and IFNγ, correlated with sustained nuclear expression of NF-κB components reticuloendotheliosis oncogene c-Rel and p65.
25016226	hepatocellular carcinoma	IL15	Promote immunity (T cell function); increase the efficacy of immunotherapy	Here, we studied the therapeutic effects of hyper-interleukin15 (hyper-IL-15), which is composed of IL-15 and the sushi domain of the IL-15 receptor α chain, on metastatic and autochthonous liver cancers.
25016158	Breast carcinoma	CDK1	Inhibit immunity	Moreover, systemic delivery of NPsiCDK1 is able to suppress tumor growth in mice bearing SUM149 and BT549 xenograft and cause no systemic toxicity or activate the innate immune response, suggesting the therapeutic promise with such nanoparticles carrying siCDK1 for c-Myc overexpressed triple negative breast cancer.
25015834	glioblastoma	PTEN	Promote immunity	Genetic and pharmacologic experimental approaches in vitro, as well as in vivo autoimmunity models, provide convincing evidence that PI3K/PTEN-regulated extracellular Arginase I acts as a paracrine regulator of inflammation and immunity.
25012502	Pancreatic ductal adenocarcinoma	IFNA1	Promote immunity	RIG-I-like helicases (RLH) are immunoreceptors for viral RNA that induce an antiviral response program via the production of type I interferons (IFN) and apoptosis in susceptible cells.
25012502	Pancreatic ductal adenocarcinoma	HMGB1	Promote immunity (T cell function)	In addition, tumor cells died via intrinsic apoptosis and displayed features of immunogenic cell death, such as release of HMGB1 and translocation of calreticulin to the outer cell membrane.
25012502	Pancreatic ductal adenocarcinoma	FAS	Promote immunity (T cell function)	Tumor cells treated with sublethal doses of RLH ligands upregulated Fas and MHC-I expression and were effectively sensitized towards Fas-mediated apoptosis and cytotoxic T lymphocyte (CTL)-mediated lysis.
25012502	Pancreatic ductal adenocarcinoma	IFIH1	Promote immunity (T cell function); increase the efficacy of immunotherapy	In addition, MDA5-based immunotherapy led to effective tumor control of established pancreatic tumors.
25005243	Acute Lymphoblastic Leukemia	CD19	Promote immunity (T cell function); increase the efficacy of immunotherapy	IL-12-secreting CD19-targeted cord blood-derived T cells for the immunotherapy of B-cell acute lymphoblastic leukemia.
25000978	Stage IV Squamous Cell Lung Carcinoma AJCC v7	IL2	Promote immunity (T&NK cell function)	Because of increasing interest in the removal of immunosuppressive pathways in cancer, the combination of IL-2 with Abs to neutralize TGF-β, a potent immunosuppressive cytokine, was assessed.
24994597	melanoma	MICA	Promote immunity	Associations between HLA class I antigen expression and the efficacy of a melanoma vaccine (Melacine; Corixa Corp.) were initially described in stage IV melanoma.
24992895	breast carcinoma	ERBB2	Inhibit immunity (T cell function); immunotherapy target	They were subgrouped as the mrTNBC group (n = 18), the luminal/human epidermal growth factor receptor 2 (HER2)-negative group (n = 41) and the HER2-positive group (n = 18), while the remaining two patients had not been investigated.
24990079	melanoma	IL6	Promote immunity (T cell function); increase the efficacy of immunotherapy	The HspX protein induces DC maturation and proinflammatory cytokine production (TNF-α, IL-1β, IL-6, and IFN-β) through TLR4 binding partially mediated by both the MyD88 and the TRIF signaling pathways.
24990079	melanoma	IFNA1	Promote immunity (T cell function); increase the efficacy of immunotherapy	The administration of HspX-stimulated DCs increased the activation of naive T cells, effectively polarizing the CD4(+) and CD8(+) T cells to secrete IFN-γ, as well as enhanced the cytotoxicity of splenocytes against HPV-16 E7 (E7)-expressing TC-1 murine tumor cells in therapeutic experimental animals.
24987109	melanoma	KIF2C	Promote immunity (infiltration)	Both KIF2C and POLA2 have been found to play important roles in cell proliferation.
24987057	Metastatic Gastrointestinal Carcinoma	TP53	Promote immunity (T cell function); increase the efficacy of immunotherapy	Furthermore, the frequency of PD1+ CD8+ T cells showed an inverse correlation with the peak CD8+ p53 response (P=0.02) and antibody blockade of PD1 in vitro increased the p53 immune responses detected after the second or third immunizations.
24986688	melanoma	CD247	Promote immunity	Compared with CARs containing the CD3ζ chain alone, or in tandem with the CD28 or the 4-1BB intracellular domains, ICOS signaling increased IL-17A, IL-17F, and IL-22 following antigen recognition.
24986688	melanoma	IFNA1	Promote immunity	Of note, ICOS signaling also induced the expression of IFN-γ and T-bet, consistent with a TH17/TH1 bipolarization.
24986688	melanoma	CD28	Promote immunity	When transferred into mice with established tumors, TH17 cells that were redirected with ICOS-based CARs mediated efficient antitumor responses and showed enhanced persistence compared with CD28- or 4-1BB-based CAR T cells.
24986517	melanoma & breast carcinoma	ADORA2A	Inhibit immunity immunotherapy target	Adenosine targeting is an attractive new approach to cancer treatment, but no clinical study has yet examined adenosine inhibition in oncology despite the safe clinical profile of adenosine A2A receptor inhibitors (A2ARi) in Parkinson disease.
24983365	breast carcinoma	CTCFL	Inhibit immunity	The serum levels of MAGE-A and BORIS mRNA, as well as let-7b were significantly higher in patients with invasive carcinomas than in patients with benign breast diseases or healthy women (P<0.001), whereas the levels of miR-202 were elevated in both patient cohorts (P<0.001).
24980949	carcinoma	EPCAM	Inhibit immunity	In conclusion, our data suggest that anti-EpCAM(scFv)-MAP may be of therapeutic value for the targeted elimination of EpCAM(+) carcinomas.
24975576	adenocarcinoma	NFKB1	Inhibit immunity	Both activation of the pathway and termination of the NF-κB response are tightly regulated events, which is essential to prevent exacerbated inflammatory responses.
24973443	colorectal carcinoma	CD55	Inhibit immunity	RNA interference-induced knockdown or overexpression of membrane-bound complement regulatory proteins revealed CD55 expression to be a pivotal determinant of anti-EGFR-IgG3-triggered CML and to force a switch from classical complement pathway activation to C1q-dependent alternative pathway amplification.
24970861	Cervical Carcinoma	IL6	Inhibit immunity	We show evidence of constitutive activation of the IL-6/STAT3 signaling pathway in the tumor, including TAMs, and in APCs in the spleen.
24970476	lung adenocarcinomas	VCX3A	Promote immunity	VCX3A, a member of the VCX/Y gene family, was expressed at the protein level in approximately 20% of lung adenocarcinomas and 35% of squamous cell carcinomas, but not expressed in normal lung tissues.
24970476	lung adenocarcinomas	VCX	Promote immunity	Among CT antigens with concordant mRNA and protein expression levels, four CT antigens, XAGE1, VCX, IL13RA2, and SYCE1, were expressed, alone or in combination, in about 80% of lung adenocarcinoma tumors.
24965046	Glioma	ITGAM	Inhibit immunity	Intermittent metronomic cyclophosphamide scheduling strongly increased glioma-associated CD11b+ immune cells but not CD11b+Gr1+ myeloid-derived suppressor cells, while bone marrow and spleen reservoirs of the suppressor cells were decreased.
24965046	Glioma	KDR	Promote immunity	The inhibition of immune cell recruitment and tumor regression by anti-angiogenic receptor tyrosine kinase inhibitors, previously observed in several brain tumor models, was recapitulated in the 9L tumor model with the VEGFR2-specific inhibitory monoclonal antibody DC101 (p < 0.01), implicating VEGFR2 signaling as an essential step in metronomic cyclophosphamide-stimulated immune cell recruitment.
24963846	melanoma	ROCK1	Inhibit immunity	Rounded-amoeboid cancer cells use actomyosin contractility driven by Rho-ROCK and JAK-STAT3 to migrate efficiently.
24963846	melanoma	STAT3	Inhibit immunity	MMP-9 is upregulated in a panel of rounded-amoeboid compared with elongated-mesenchymal melanoma cell lines and its levels are controlled by ROCK-JAK-STAT3 signalling.
24963042	Essential Thrombocythemia	JAK2	Promote immunity	Survival correlated with type of donor, but not with the degree of histocompatibility match, age, or JAK2(V617F) status.
24962571	osteosarcoma	USE1	Promote immunity	D12 could react with PBF A2.2 peptide-pulsed T2 cells and HLA-A2+PBF+ osteosarcoma cell lines and simultaneously demonstrated that the HLA·peptide complex was expressed on osteosarcoma cells.
24958858	Prostate Neoplasm	IFNA1	Promote immunity	We found that murine androgen deprivation in vivo elicited RNA expression patterns conducive to IFN signaling and T-cell differentiation.
24958858	Prostate Neoplasm	STAT4	Promote immunity (T cell function); increase the efficacy of immunotherapy	Interrogation of mechanism showed that testosterone regulates T-helper 1 (Th1) differentiation by inhibiting IL-12-induced Stat4 phosphorylation: in murine models, we determined that androgen receptor binds a conserved region within the phosphatase, Ptpn1, and consequent up-regulation of Ptpn1 then inhibits IL-12 signaling in CD4 T cells.
24958858	Prostate Neoplasm	PTPN1	Inhibit immunity (T cell function); resistant to immunotherapy	The clinical relevance of this mechanism, whereby the androgen milieu modulates CD4 T-cell differentiation, was ascertained as we found that androgen deprivation reduced expression of Ptpn1 in CD4 cells from patients undergoing androgen deprivation therapy for prostate cancer.
24958825	melanoma	BRAF	Resistant to immunotherapy	Targeted therapy can successfully block oncogenic signaling in BRAF(V600)-mutant melanoma with high initial clinical responses, but relapse rates are also high.
24957708	acute myeloid leukemia	IRF8	Promote immunity	Constitutive expression of Irf8 or its target gene Ccl9 identified these genes as potent inhibitors of murine and human leukemias in vivo.
24957708	acute myeloid leukemia	MN1	Inhibit immunity	Our data show that MN1 prevents activation of the immune response pathway, and suggest restoration of IRF8 signaling as therapeutic target in AML.
24957461	Ovarian Dermoid Cyst with Melanoma	PPARG	Promote immunity	Inhibition of p38 MAPK in DCs lowers expression of PPARγ, activating p50 and upregulating OX40L expression in DCs.
24957461	Ovarian Dermoid Cyst with Melanoma	TNFSF4	Promote immunity (T cell function); essential for immunotherapy	OX40L/OX40 interactions between DCs and Teff and/or Treg are critical for priming effective and therapeutic antitumour responses.
24954781	pancreatic ductal adenocarcinoma	CSF2	Promote immunity	Sequential chemoimmunotherapy included two cycles of combination chemotherapy, then an intradermal lower abdominal injection of granulocyte-macrophage colony-stimulating factor (GM-CSF; 75 μg) and GV1001 (0·56 mg; days 1, 3, and 5, once on weeks 2-4, and six monthly thereafter).
24954733	melanoma	TLR7	Promote immunity (T cell function); increase the efficacy of immunotherapy	Poly (γ-glutamic acid) based combination of water-insoluble paclitaxel and TLR7 agonist for chemo-immunotherapy.
24950910	Prostate Carcinoma	PTX3	Inhibit immunity (biomarker)	In summary, our results encourage further evaluation of PTX3 as a tissue biopsy and blood-borne biomarker to discriminate BPH from prostate cancer.
24947042	melanoma, lung carcinoma	IL6	Promote immunity	Mechanistic investigations revealed a defective induction of the γδT17 cell response in lungs of Abt mice; here, more aggressive tumor development was observed, possibly related to a reduction in IL6 and IL23 expression there.
24943214	melanoma	IL7	Promote immunity (T cell function); increase the efficacy of immunotherapy	Autologous tumor vaccine modified with recombinant new castle disease virus expressing IL-7 promotes antitumor immune response.
24943214	melanoma	IFNA1	Promote immunity (T cell function); increase the efficacy of immunotherapy	Although the tumor-infiltrating CD4(+) T cells and CD8(+) T cells were both increased and their IFN-γ productions also were upregulated, the antitumor activity of the tumor vaccine modified with LX/(IL-7) was dependent on CD8(+) T cells.
24942756	Pancreatic ductal adenocarcinoma (	CSF2	Promote immunity (infiltration)	We designed a neoadjuvant and adjuvant clinical trial comparing an irradiated, granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting, allogeneic PDAC vaccine (GVAX) given as a single agent or in combination with low-dose cyclophosphamide to deplete regulatory T cells (Treg) as a means to study how the TME is altered by immunotherapy.
24938765	melanoma	CSF2	Promote immunity	Here, we report potent antitumor activity for a novel fusion cytokine generated by N-terminal coupling of GM-CSF to IL4, generating a fusokine termed GIFT4.
24938524	melanoma	IL4	Promote immunity (T cell function); increase the efficacy of immunotherapy	Circulating CD4+ T cells that produce IL4 or IL17 when stimulated by melan-A but not by NY-ESO-1 have negative impacts on survival of patients with stage IV melanoma.
24938524	melanoma	MLANA	Promote immunity	In contrast, recognition of Melan-A by CD4(+) T cells was associated with reduced survival in our cohort of patients preselected for NY-ESO-1 and/or Melan-A reactivity (that is, in patients with exceptionally long survival).
24938283	postsurgical lung metastasis, fibrosarcoma	VEGFA	Inhibit immunity (T cell function); immunotherapy target	Underscoring the potency of stroma-targeted costimulation and the broad spectrum of tumors secreting VEGF, in preclinical murine tumor models, systemic administration of the VEGF-targeted 4-1BB aptamer conjugates engendered potent antitumor immunity against multiple unrelated tumors in subcutaneous, postsurgical lung metastasis, methylcholantrene-induced fibrosarcoma, and oncogene-induced autochthonous glioma models, and exhibited a superior therapeutic index compared with nontargeted administration of an agonistic 4-1BB Ab or 4-1BB aptamer.
24937677	Breast Carcinoma	CASP3	Promote immunity	Contrary to ILC, IDC patients frequently expressed higher cleaved caspase-3 and Ki67, which was prognostic.
24935874	Hodgkin lymphoma	DNER	Inhibit immunity	Transfection of HEK293T and Hela cells to express DNER coupled to an enhanced green fluorescent protein tag using a plasmid previously used to detect human DNER antibodies. We also confirm that DNER is the target antigen of the anti-Tr immune response.
24935458	leukemia	SPP1	Promote immunity (infiltration)	A high level of OPN in EL4-v10 tumors supported leukocyte recruitment and tumor-infiltrating T-cell activation.
24935458	leukemia	CD44	Inhibit immunity (infiltration)	Blockade of CD44 is considered a therapeutic option for the elimination of leukemia-initiating cells.
24935257	leukemia	CD1C	Promote immunity (T cell function); increase the efficacy of immunotherapy	mLPA-specific T cells efficiently kill CD1c(+) acute leukemia cells, poorly recognize nontransformed CD1c-expressing cells, and protect immunodeficient mice against CD1c(+) human leukemia cells.
24931170	breast adenocarcinoma	WNT1	Promote immunity	The present study was designed to determine whether the WNT1-inducible signaling pathway protein 2 (WISP2, also referred to as CCN5), a key regulator of tumor cell plasticity, interferes with tumor susceptibility to cytotoxic T-lymphocyte (CTL)-mediated lysis.
24931170	breast adenocarcinoma	WISP2	Promote immunity (T cell function)	These studies indicate for the first time that WISP2 acts as an activator of CTL-induced killing and suggests that the loss of its function promotes evasion of immunosurveillance and the ensuing progression of the tumor.
24928851	Pancreatic Carcinoma	IL15	Promote immunity	In vitro assays of lymphocyte activation and proliferation demonstrated that IL15 produced by MSCs was biofunctional.
24923299	Breast Carcinoma	CD34	Promote immunity (T cell function); increase the efficacy of immunotherapy	Grafts included CD34(+) cells (mean 9.7 × 10(6)/kg), Tregs (mean 2.5 × 10(6)/kg), and Tcons (mean 1.1 × 10(6)/kg).
24919843	Breast Carcinoma	ERBB2	Inhibit immunity (T cell function); immunotherapy target	However, a large number of HER2+ tumors are not responsive to, or become resistant to, trastuzumab-based therapy, and thus more effective therapies targeting HER2 are needed.
24919843	Breast Carcinoma	IFNG	Promote immunity	An interferon γ and interleukin 2 enzyme-linked immunosorbent assay and a chromium-51 release assay were used to evaluate the antitumor immune response of CAR T cells in coculture with tumor cells.
24919807	leukemia	CD19	Promote immunity	The best example of this is represented by the anti-CD19 chimeric antigen receptor (CD19.CAR) T cells.
24919154	leukaemia	PIK3CD	Inhibit immunity (T cell function); immunotherapy target	We demonstrate that p110δ inactivation in regulatory T cells unleashes CD8(+) cytotoxic T cells and induces tumour regression.
24916698	breast carcinoma; Malignant Ovarian Neoplasm	ERBB2	Inhibit immunity	Basal-like and HER2-enriched tumors exhibited more BCR sequence variants in regions consistent with SHM.
24916506	chronic lymphocytic leukemia	PTK2	Inhibit immunity	This retrospective analysis from 2 independent trials revealed that increased PTK2 expression is associated with improved outcomes for CLL patients treated with R-FC vs FC. PTK2 expression may be a useful biomarker for patient selection in future trials.
24916470	adenocarcinoma	TNFRSF8	Inhibit immunity (T cell function); decrease the efficacy of immunotherapy	Brentuximab vedotin represents a first-in-class ADC directed against CD30(+) malignancies.
24916470	adenocarcinoma	CTLA4	Inhibit immunity (infiltration)	We observed substantial therapeutic synergies when combining dolastatins with tumor antigen-specific vaccination or blockade of the PD-1-PD-L1 and CTLA-4 coinhibitory pathways.
24913717	breast carcinoma	CASP3	Promote immunity (T cell function); increase the efficacy of immunotherapy	Low doses of c-di-GMP significantly increased the production of IL12 by MDSCs, in correlation with improved T-cell responses to Mage-b, whereas a high dose of c-di-GMP (range, 0.3-3 mmol/L) activated caspase-3 in the 4T1 tumor cells and killed the tumor cells directly.
24912675	Hepatocellular Carcinoma	TM4SF5	Inhibit immunity	Cross talk between the TM4SF5/focal adhesion kinase and the interleukin-6/STAT3 pathways promotes immune escape of human liver cancer cells.
24912675	Hepatocellular Carcinoma	IL6	Inhibit immunity	We found that interleukin-6 (IL-6) was differentially expressed in hepatocytes depending on cancerous malignancy and TM4SF5 expression.
24912675	Hepatocellular Carcinoma	STAT3	Inhibit immunity (T cell function); resistant to immunotherapy	suppression abolished the IL-6-mediated effects in normal Chang cells, but it did not recover the TM4SF5-dependent FAK activity that was inhibited by IL-6 treatment in cancerous SNU761-TM4SF5 cells.
24907636	breast carcinoma	CSF2	Promote immunity (infiltration)	The studies were conducted as dose escalation/schedule optimization trials enrolling node-positive and high-risk node-negative patients with tumors expressing any degree of HER2 (immunohistochemistry 1-3+).
24907636	breast carcinoma	ERBB2	Inhibit immunity	We have conducted phase I/II clinical trials vaccinating breast cancer patients with nelipepimut-S and granulocyte-macrophage colony-stimulating factor (GM-CSF) in the adjuvant setting to prevent disease recurrence.
24907635	Pancreatic Carcinoma	CTLA4	Inhibit immunity (infiltration)	Tremelimumab (CP-675,206) is a fully human monoclonal antibody binding to cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) on T cells that stimulates the immune system by blocking the CTLA4-negative regulatory signal.
24907378	melanoma and Kidney Carcinoma	IL2	Promote immunity (infiltration)	The growth of large numbers of tumor-infiltrating lymphocytes with in vitro anti-cancer activity in IL-2 has led to the development of cell transfer therapies that are highly effective in patients with melanoma.
24907113	melanoma	CD14	Inhibit immunity	Suppression of NK-cell activity by PGE2-treated monocytes was compared with that of freshly isolated CD14(+)HLA-DR(low/-) monocytic MDSCs (moMDSC) from patients with melanoma.
24907113	melanoma	TGFB1	Inhibit immunity (NK cell function); decrease the efficacy of immunotherapy	Patient-derived moMDSCs inhibited NK-cell activity through the production of TGFβ. In vitro, binding of PGE2 to EP2 and EP4 receptors on monocytes activated the p38MAPK/ERK pathway and resulted in elevated secretion of TGFβ.
24907113	melanoma	ITGAM	Inhibit immunity	Furthermore, silencing COX-2 in murine 4T1 tumor cells reduced the accumulation of CD11b(+)Gr1(+) MDSCs in the spleen, resulting in concomitant improved in vivo clearance of NK-cell sensitive YAC-1 cells.
24903480	Burkitt lymphoma	CD55	Inhibit immunity	We developed a novel strategy to enhance CDC using bispecific antibodies (bsAbs) that neutralize the C-regulators CD55 and CD59 to enhance C-mediated functions.
24895997	melanoma	CD1C	Promote immunity (T cell function); increase the efficacy of immunotherapy	They are activated by a host of ligands including stress-induced self-antigens, glycolipids presented by CD1c/d, and potentially many others that currently remain unidentified.
24895110	melanoma	STAT2	Promote immunity (T cell function); increase the efficacy of immunotherapy	Here we show in a syngeneic tumor transplantation model that STAT2 reduces tumor growth.Gene expression analysis revealed a small subset of immunomodulatory genes to be downregulated in tumors established in Stat2(-/-) mice.
24895110	melanoma	IFNA1	Promote immunity	We observed that an increase in the number of CD4(+) and CD8(+) T cells in the draining lymph nodes of IFN-β-treated tumor-bearing WT mice was absent in IFN-β treated Stat2(-/-) mice.
24894093	lung carcinoma	MUC1	Inhibit immunity	The goals of the present study were to define the effects of simultaneous cisplatin/tecemotide therapy on tumor development in a human mucin 1 (MUC1) transgenic lung cancer mouse model and to examine the effects of radiotherapy (RTX) on splenocytes, serum cytokines, and immune response to tecemotide.
24894091	Melanoma	IL6	Inhibit immunity	Immunohistochemical data of infiltrating (suppressive) cells, such as T cells, regulatory T cells, myeloid-derived suppressor cells, and mast cells, or the expression of T-cell inhibitory factors (PD-1/PD-L1, IDO, and galectins), cytotoxic molecules (granzyme-B), melanocyte differentiation antigens, HLA class-I and tolerogenic cytokines [interleukin (IL)-1, IL-6, IL-10, TNF-α, and TGF-β] were correlated statistically to clinical outcome and overall survival (OS).
24893628	Skin Basal Cell Carcinoma	TLR7	Promote immunity	Imiquimod is a Toll-like receptor 7 agonist used topically to treat external genital warts and basal cell carcinoma.
24893628	Skin Basal Cell Carcinoma	CALR	Promote immunity	We examined the combination of topical imiquimod with intramuscular administration of CRT/E7, a therapeutic human papillomavirus (HPV) vaccine comprised of a naked DNA vector expressing calreticulin fused to HPV16 E7.
24893628	Skin Basal Cell Carcinoma	CXCL9	Promote immunity (infiltration)	Intravaginal imiquimod deposition induced upregulation of CXCL9 and CXCL10 mRNA expression in the genital tract, which are produced in response to IFNγ receptor signaling and attract cells expressing their ligand, CXCR3.
24893628	Skin Basal Cell Carcinoma	CXCR3	Promote immunity (T cell function); increase the efficacy of immunotherapy	Our results indicate that intramuscular CRT/E7 vaccination in conjunction with intravaginal imiquimod deposition recruits antigen-specific CXCR3(+) CD8(+) T cells to the genital tract.
24892809	biliary atresia	IL13	Inhibit immunity	The IL-33-dependent proliferative response was mediated by an increase in the number of type 2 innate lymphoid cells (ILC2s), which released high levels of IL-13 that in turn promoted cholangiocyte hyperplasia.
24892809	biliary atresia	AKT1	Inhibit immunity	Induction of the IL-33/ILC2/IL-13 circuit in a murine biliary injury model promoted epithelial repair; however, induction of this circuit in mice with constitutive activation of AKT and YAP in bile ducts induced cholangiocarcinoma with liver metastases.
24892807	T-Cell Non-Hodgkin Lymphoma	CTLA4	Inhibit immunity (infiltration)	These data demonstrate that a CTLA4(apt)-based siRNA delivery strategy allows gene silencing in both tumor-associated T cells and tumor cells and inhibits tumor growth and metastasis.
24892261	myeloid leukemia	CD34	Promote immunity (T cell function); increase the efficacy of immunotherapy	Results of multivariate analysis showed that PBPC from HLA-matched siblings containing <4 × 10(6) CD34(+)/kg was associated with higher nonrelapse mortality (hazard ratio [HR], 2.03; P = .001), overall mortality (HR, 1.48; P = .008), and lower neutrophil (odds ratio [OR], .76; P = .03) and platelet (OR, .76; P = .03) recovery.
24891322	acute myeloid leukemia	CD14	Promote immunity; increase the efficacy of immunotherapy	In these mice, CD14 was aberrantly overexpressed on granulocytes in a cell-autonomous manner, leading to a hypersensitive innate immune response to lipopolysaccharide (LPS) stimuli through CD14/Toll-like receptor 4 signaling.
24891322	acute myeloid leukemia	DIAPH1	Inhibit immunity	Mechanistically, mDia1 deficiency led to a downregulation of membrane-associated genes and a specific upregulation of CD14 messenger RNA in granulocytes, but not in other lineages.
24890832	breast carcinoma	MYC	Inhibit immunity (T&NK cell function); resistant to immunotherapy	Hence, tumors appear to be "addicted" to MYC because of both tumor cell-intrinsic, cell-autonomous and host-dependent, immune cell-dependent mechanisms.
24888813	glioma	EPHA2	Inhibit immunity	GAAs were EphA2, interleukin-13 receptor alpha 2 (IL-13Rα2), and survivin, and their peptide epitopes were emulsified in Montanide-ISA-51 and given every 3 weeks with intramuscular polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose for eight courses, followed by booster vaccinations every 6 weeks.
24886523	Ovarian Carcinoma	MUC16	Inhibit immunity	The importance of MUC16/CA125 in the diagnosis, progression and therapy of ovarian cancer warrants the need for in-depth research on the biochemistry and biology of this mucin.
24886523	Ovarian Carcinoma	WFDC2	Inhibit immunity	However, CA125 continues to be, with the recent exception of HE4, the only clinically reliable diagnostic marker for ovarian cancer.
24884733	melanoma	USP18	Promote immunity (T cell function); increase the efficacy of immunotherapy	USP18 expression in B16 melanoma tumor cells regulated IFN-γ-mediated immunoediting, including upregulating MHC class-I expression, reducing tumor cell-mediated inhibition of T cell proliferation and activation, and suppressing PD-1 expression in CD4+ and CD8+ T cells in tumor-bearing mice.
24884733	melanoma	IFNA1	Promote immunity (T cell function); increase the efficacy of immunotherapy	Interferon (IFN)-γ-mediated immune response plays an important role in tumor immunosurveillance.
24883121	metastatic disease indicator	RIT1	Promote immunity	RIT has become an attractive strategy in cancer treatment, but still faces important drawbacks due to poor tumor penetration and undesirable pharmacokinetics of the targeting vehicles.
24883121	metastatic disease indicator	MYC	Inhibit immunity (T cell function); resistant to immunotherapy	Dynamic planar imaging of Wistar rats with 111In-DTPA-nanobodies revealed that untagged nanobodies showed a 70% drop in kidney accumulation compared to Myc-His-tagged nanobodies at 50 min p.i..
24882582	melanoma	MTOR	Inhibit immunity (T cell function); decrease the efficacy of immunotherapy	Activation of mTOR pathway in myeloid-derived suppressor cells stimulates cancer cell proliferation and metastasis in lal(-/-) mice.
24882582	melanoma	LIPA	Inhibit immunity	Our results indicate that LAL has a critical role in regulating MDSCs' ability to directly stimulate cancer cell proliferation and overcome immune rejection of cancer metastasis in allogeneic mice through modulation of the mTOR pathway, which provides a mechanistic basis for targeting MDSCs to reduce the risk of cancer metastasis.
24882582	melanoma	TNF	Promote immunity (T&NK cell function); essential for immunotherapy	tumor necrosis factor-α Cytokines, that is, interleukin-1β and tumor necrosis factor-α from MDSCs are required for B16 melanoma cell
24880020	acute myeloid leukemia	CD34	Promote immunity (T cell function); increase the efficacy of immunotherapy	Autologous stem cell transplantation (ASCT) was performed in patients collecting ≥3 × 10(6) CD34(+)/kg and low-dose gemtuzumab ozogamicin (GO) was performed in poor mobilizers (collecting <3 × 10(6) CD34(+)/kg).
24879823	melanoma	SOAT1	Promote immunity	These immunogenic effects include modulation of STAT signaling; induction of an immunogenic type of cancer cell death through exposure of calreticulin and release of ATP and high-mobility group protein box-1 (HMGB-1); and enhancement of the effector immune response through modulation of programmed death receptor 1-ligand and mannose-6-phosphate receptor expression.
24878583	myeloma	PDE5A	Promote immunity	Here, we show how the addition of the PDE5 inhibitor, tadalafil, in a patient with end-stage relapsed/refractory multiple myeloma reduced MDSC function and generated a dramatic and durable antimyeloma immune and clinical response.
24867687	Ovarian Carcinoma	NFKB1	Inhibit immunity (T cell function); immunotherapy target	NF-κB is involved in the immunosuppression induced by human EOC, and its inhibitor may restore antitumour immune responses, indicating that NF-κB is an attractive target for EOC treatment.
29686284	Prostate Carcinoma	PTEN	Promote immunity	Here we show that a patient-derived prostate-specific microbe, CP1, in combination with anti-PD-1 immunotherapy, increases survival and decreases tumor burden in orthotopic MYC- and PTEN-mutant prostate cancer models.
29686284	Prostate Carcinoma	VEGFA	Inhibit immunity	CP1 also decreases intra-tumoral regulatory T cells and VEGF.
29686080	Prostate Carcinoma	FXYD3	Promote immunity	FXYD3 and CEACAM5 were validated as cell-surface antigens enriched in PrAd and NEPC, respectively.
29686080	Prostate Carcinoma	CEACAM5	Promote immunity	As a proof of concept, engineered chimeric antigen receptor T cells targeting CEACAM5 induced antigen-specific cytotoxicity in NEPC cell lines.
29685162	Colon Carcinoma	IDO1	Inhibit immunity (T cell function); decrease the efficacy of immunotherapy	These findings indicate that miR-153 inhibits IDO1 expression in colon cancer cells and is a tumor-suppressive miRNA that enhances CAR T cell immunotherapy.
29685162	Colon Carcinoma	CD19	Promote immunity	The Food and Drug Administration has approved CAR T cells that target CD19 for treatment of advanced B cell leukemia and lymphoma.
29684277	breast carcinoma; prostate carcinoma	PRLR	Inhibit immunity	Prolactin receptor (PRLR) is overexpressed in breast and prostate cancers and is a new target for cancer therapy.
29683892	Esophageal squamous cell carcinoma	KLRK1	Promote immunity (NK cell function); essential for immunotherapy	Blocking of NKG2D with anti-NKG2D monoclonal antibody dampened expanded NK cell cytotoxicity, suggesting that the NKG2DLs-NKG2D interaction is crucial for NK cells to eliminate ESCC cells.
29683892	Esophageal squamous cell carcinoma	IL2	Promote immunity (NK cell function); essential for immunotherapy	The cytotoxicity of resting and of IL-2-activated NK cells against ESCC cell lines was compared with that of expanded NK cells.
29683683	melanoma	MMP2	Promote immunity (T cell function); increase the efficacy of immunotherapy	To achieve this, an amphiphilic peptide, consisting of a functional 3-diethylaminopropyl isothiocyanate (DEAP) molecule, a peptide substrate of matrix metalloproteinase-2 (MMP-2), and DPPA-1, was synthesized and coassembled with NLG919.
29682201	melanoma	CXCR4	Promote immunity (T cell function); increase the efficacy of immunotherapy	In immunological responder patients, increased protein levels of the chemokine receptor CXCR4 and the Fc-receptor CD32 were observed on cell membranes of CD8+ T and B cells and the monocyte population, respectively, confirming gene expression results.
29681426	breast carcinoma	IFNA1	Promote immunity (infiltration)	In support of a link between IFN signaling and immunotherapeutic response, the combination of type I interferon inducers with checkpoint immunotherapy has recently been demonstrated critical for a sustained anti-tumor response in aggressive breast cancer models.
29678874	melanoma	TNFRSF9	Promote immunity (T cell function); increase the efficacy of immunotherapy	Collectively, these data point to a critical link between mitochondrial morphology and function and enhanced antitumor effector activity upon CD137 costimulation of T cells.
29678298	melanoma	CTNNB1	Inhibit immunity	We propose that targeting Wnt/β-catenin signaling would potentially improve clinical outcomes of cancer patients by overcoming the primary, adaptive, and acquired resistance to immunotherapy.
29678144	Epstein-Barr virus	IFNA1	Promote immunity (infiltration)	Although more promising results have been obtained with allo-HSCT, inhaled IFN-alpha may also be a therapeutic option in patients with CAEBV and a concomitant IP.
29676849	malignant glioma	HOXC10	Inhibit immunity	In two glioma cell lines, HOXC10 knock-down inhibited cell proliferation, colony formation, migration and invasion, and promoted apoptosis.
29675003	Gastric Carcinoma	S100A8	Inhibit immunity	Exosomes have been shown to deliver not only various types of genetic information, mainly miRNAs, but also cytotoxin-associated gene A (CagA), a major H. pylori virulence factor.
29675003	Gastric Carcinoma	PDLIM7	Inhibit immunity	In addition, a growing body of evidence demonstrates that exosomes contain genetic material of viruses and viral miRNAs and proteins such as EBV latent membrane protein 1 (LMP1) which are delivered into recipient cells.
29674509	melanoma	MEX3B	Inhibit immunity (T cell function); immunotherapy target	MEX3B is a post-transcriptional regulator of HLA-A, validating the critical role of tumor-intrinsic antigen presentation in T cell immunotherapy and indicating a new putative molecular target.
29674449	lung carcinoma	ITGAX	Promote immunity (T&NK cell function); increase the efficacy of immunotherapy	The ihv-DCs are a subset of CD11c+/CD205+ DCs that constitutively display costimulatory molecules.
29674449	lung carcinoma	MAGEA3	Promote immunity	The ihv-DCs, which are engineered to express MAGEA3 and high levels of 4-1BBL and MICA, induce simultaneous production of both HLA-A2-restricted, MAGEA3-specific CTLs and NK cells from HLA-A2+ donor peripheral blood mononuclear cells.
29673712	Prostate Carcinoma	ESR1	Inhibit immunity (T cell function); immunotherapy target	Update on Systemic Prostate Cancer Therapies: Management of Metastatic Castration-resistant Prostate Cancer in the Era of Precision Oncology.
29673644	Squamous Cell Carcinoma	NOC2L	Promote immunity	When illuminating with NIR light, PIT can induce highly-selective cancer cell death while leaving most of tumor blood vessels unharmed, leading to an effect termed super-enhanced permeability and retention (SUPR), which can significantly improve the effectiveness of anti-cancer drug.
29672836	Colorectal Carcinoma; urothelial carcinoma; urachal adenocarcinomas	TP53	Promote immunity	Sequence variations were observed in TP53 (66%), KRAS (21%), BRAF (4%), PIK3CA (4%), FGFR1 (1%), MET (1%), NRAS (1%), and PDGFRA (1%).
29672836	Colorectal Carcinoma; urothelial carcinoma; urachal adenocarcinomas	EGFR	Inhibit immunity (T cell function); immunotherapy target	EGFR Gene amplifications were found in EGFR (5%), ERBB2 (2%), and MET (2%).
29672836	Colorectal Carcinoma; urothelial carcinoma; urachal adenocarcinomas	ERBB2	Inhibit immunity (T cell function); immunotherapy target	Less frequent potentially actionable genetic alterations were additionally detected in ERBB2 (HER2), MET, FGFR1, and PDGFRA.
29672044	Colorectal Carcinoma	ROS1	Inhibit immunity	Andrographolide Antagonizes TNF-α-Induced IL-8 via Inhibition of NADPH Oxidase/ROS/NF-κB and Src/MAPKs/AP-1 Axis in Human Colorectal Cancer HCT116 Cells.
29672044	Colorectal Carcinoma	TNF	Promote immunity (T&NK cell function); essential for immunotherapy	We found that andrographolide concentration-dependently inhibited TNF-α-induced IL-8 mRNA (2.23 ± 0.15 fold at 20 μM) and protein expression (4.78 ± 0.31 fold at 20 μM) and reduced the IL-8 transcriptional activity (2.59 ± 0.25 fold at 20 μM).
29672044	Colorectal Carcinoma	NFKB1	Inhibit immunity (T cell function); immunotherapy target	We found that NF-κB and AP-1 were the critical transcription factors for TNF-α-induced IL-8 expression.
29671006	Colon Carcinoma	CXCL9	Promote immunity (infiltration)	Treg depletion also resulted in increased levels of the chemokines CXCL9 and CXCL10 specifically in the tumors.
29670692	prostate carcinoma	HDAC1	Promote immunity	In order to take advantage of both immunotherapeutic and epigenetic antitumor agents, the first generation of dual indoleamine 2,3-dioxygenase 1 (IDO1) and histone deacetylase (HDAC) inhibitors were designed.
29670692	prostate carcinoma	HDAC1	Promote immunity	The highly active dual inhibitor 10 showed excellent and balanced activity against both IDO1 (IC50 = 69.0 nM) and HDAC1 (IC50 = 66.5 nM), whose dual targeting mechanisms were validated in cancer cells.
29670088	Metastatic Malignant Neoplasm	BRD4	Inhibit immunity	PVAX is developed by encapsulating JQ1 (a BRD4 inhibitor) and indocyanine green (ICG) co-loaded tumor cells with a hydrogel matrix.
29670088	Metastatic Malignant Neoplasm	NOC2L	Promote immunity	A mechanical study reveals that NIR light-triggered antigen release and JQ1-mediated PD-L1 checkpoint blockade cumulatively contribute to the satisfied therapeutic effect.
29669721	B16 Malignant Melanoma	PPARG	Promote immunity	Peroxisome proliferator activated receptor-γ (PPARγ) is a lipid-activated nuclear receptor that promotes immune tolerance through effects on macrophages, dendritic cells (DCs), and regulatory T cells (Tregs).
29669721	B16 Malignant Melanoma	CSF2	Promote immunity (infiltration)	Together, these results highlight a key role for myeloid cell PPARγ in GM-CSF-stimulated antitumor immunity and suggest that PPARγ agonists might be useful in cancer immunotherapy.
29669721	B16 Malignant Melanoma	CCL17	Inhibit immunity	PPARγ agonists similarly attenuated Treg induction and decreased CCL17 and CCL22 levels in cultures of human peripheral blood mononuclear cells with GM-CSF-secreting tumor cells.
29669207	melanoma	TLR3	Promote immunity (T cell function); essential for immunotherapy	ROS-Inducing Micelles Sensitize Tumor-Associated Macrophages to TLR3 Stimulation for Potent Immunotherapy.
29669207	melanoma	ROS1	Inhibit immunity	The outcomes revealed that ROS-inducing ZnPP PM demonstrated specificity for the in vitro and in vivo targeting of macrophages, elevated the level of ROS, and lowered STAT3 expression in BM-TAMs.
29668679	breast carcinoma; ovarian carcinoma and glioblastoma	TNF	Promote immunity	After 2 days of co-culture, monocytes exposed to cancer cell lines showed markedly upregulated expression of M1-associated (TNF-α, IL-1β), M2-associated (CCL13, CD206), Mreg-associated (IL-10, TGF-β), and angiogenesis associated (MMP9, VEGF) genes.
29668679	breast carcinoma; ovarian carcinoma and glioblastoma	CCL13	Inhibit immunity	After 2 days of co-culture, monocytes exposed to cancer cell lines showed markedly upregulated expression of M1-associated (TNF-α, IL-1β), M2-associated (CCL13, CD206), Mreg-associated (IL-10, TGF-β), and angiogenesis associated (MMP9, VEGF) genes. Similar to cancer cell lines, but less dramatically, mf altered the mRNA expression of IL-1β, CCL13, TGM2 and MMP9.
29668679	breast carcinoma; ovarian carcinoma and glioblastoma	GZMA	Promote immunity (T cell function)	In contrast to exposure to mf, exposure to cancer cell lines increased the phagocytic ability of monocytes and reduced their ability to induce T cell proliferation and to expand Granzyme A+ CD8+ T cells.
29668066	colon adenocarcinoma	MR1	Promote immunity (T&NK cell function); essential for immunotherapy	Accordingly, MAIT cells are capable of lysing MR1-expressing cells infected with a variety of pathogenic bacteria in in vitro settings and may also mount cytotoxic responses during microbial infections in vivo.
29668066	colon adenocarcinoma	IFNG	Promote immunity (T cell function); increase the efficacy of immunotherapy	Consequently, they release potent immunomodulatory mediators, including IFN-γ, TNF-α, and/or IL-17.
29668066	colon adenocarcinoma	PRF1	Promote immunity	They display several NK cell-associated receptors, carry granules containing cytotoxic effector molecules, and swiftly upregulate perforin and granzymes upon activation.
29667169	lung carcinoma	MARCO	Promote immunity (infiltration)	On the transcriptomic level, we found a positive association between MARCO gene expression and general immune response pathways including strong links to immunosuppressive TAMs, T-cell infiltration and immune checkpoint molecules.
29667169	lung carcinoma	CD68	Inhibit immunity	We observed a large variation in macrophage density between cases and a strong correlation between CD68 and CD163, suggesting that the majority of TAMs present in NSCLC exhibit a protumor phenotype.
29666124	melanoma	FGF1	Inhibit immunity	Fgf1 Nuclear transcriptional profiling of neutrophils, performed as they respond to the earliest precursors of melanoma in vivo, revealed an intricate landscape of regulatory factors that may promote progression to melanoma, including Serpinb1l4, Fgf1, Fgf6, Cathepsin H, Galectin 1 and Galectin 3.
29666026	Cervical Carcinoma	VEGFA	Inhibit immunity (T cell function)	Vascular endothelial growth factor Vascular endothelial growth factor (VEGF) has emerged as a therapeutic target in several malignancies, including cervical cancer.
29664568	melanoma	IL15	Promote immunity (T cell function); essential for immunotherapy	These phases of a T-cell response and the ensuing maintenance of memory T cells are shaped by cytokines, most notably interleukin-2 (IL-2), IL-7, and IL-15 that share the common γ chain (γc ) cytokine receptor.
29664568	melanoma	IL7	Promote immunity (T cell function); essential for immunotherapy	Steady-state production of IL-7 and IL-15 is necessary for background proliferation and homeostatic survival of CD4+ and CD8+ memory T cells.
29664568	melanoma	IL2	Promote immunity (T cell function); increase the efficacy of immunotherapy	During immune responses, augmented levels of IL-2, IL-15, IL-21, IL-12, IL-18, and type-I interferons determine the memory potential of antigen-specific effector CD8+ cells, while increased IL-2 and IL-15 cause bystander proliferation of heterologous CD4+ and CD8+ memory T cells.
29664018	breast carcinoma	IFNA1	Promote immunity	Mechanistically, CD8+ T cell depletion, IFN-γ neutralization, or implantation of tumors in IFN-γ receptor knockout mice abrogated the vessel perfusion enhancement and antitumor effects of ICB.
29664013	melanoma	THBD	Promote immunity	This poor-prognosis subgroup exhibited expression profiles consistent with β-catenin-mediated failure to recruit CD141+ DCs.
29664013	melanoma	CTNNB1	Inhibit immunity	The 6 subgroups were replicated in The Cancer Genome Atlas (TCGA) melanomas, where β-catenin signaling was also associated with low immune scores predominantly related to hypomethylation.
29663369	Squamous Cell Carcinoma	NT5E	Inhibit immunity (T cell function); immunotherapy target	Altogether, these findings highlight the immunoregulatory role of CD73 in the development of HNSCC and we propose that CD73 may prove to be a promising immunotherapeutic target for the treatment of HNSCC.
29663369	Squamous Cell Carcinoma	CTLA4	Inhibit immunity (infiltration)	Whereas the population of CD4+ CD73hi /CD8+ CD73hi T cells expressed higher CTLA-4 and PD-1 as compared to untreated controls.
29662549	lung adenocarcinoma	IFNA1	Promote immunity (infiltration)	The aim of this study was to evaluate potential prognostic and predictive biomarkers interferon-gamma (IFN-γ), tumour necrosis factor-alpha (TNF-α) and a panel of interleukins (ILs) in the peripheral blood, and assess any correlation with response to anti-PD-1 inhibition, progression-free survival and OS in NSCLC patients.
29662549	lung adenocarcinoma	TNF	Promote immunity (infiltration)	Increased cytokine values (IFN-γ, TNF-α, IL-1β, IL-2, IL-4, IL-6 and IL-8) at the time of diagnosis and at 3 months after initiation of treatment were significantly correlated with improved response to immunotherapy and prolonged OS.
29662549	lung adenocarcinoma	IFNG	Promote immunity (infiltration)	TNF-α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10 and IL-12 were analyzed by flow cytometry at the time of diagnosis and at 3 months after initiation of anti-PD-1 inhibition.
29662483	lung adenocarcinoma	HOXA1	Promote immunity	HOXA transcript antisense RNA myeloid-specific 1 (HOTAIRM1) is a long non-coding RNA that has been shown to be a key regulator of myeloid cell development by targeting HOXA1.
29662190	Ovarian Carcinoma	JAK2	Inhibit immunity immunotherapy target	These findings not only identify a novel ROS-IL-11-JAK2-mediated platinum resistance mechanism but also provide a new strategy for using LY2784544- or IL-11-mediated immunotherapy to treat platinum-resistant ovarian cancer.
29662190	Ovarian Carcinoma	IL11	Inhibit immunity	Significantly, clinic studies also confirm the activated IL-11-JAK2 pathway in platinum-resistant ovarian cancer patients, which highly correlates with poor prognosis.
29661854	Skin Carcinoma	TLR4	Inhibit immunity immunotherapy target	Given the tremendous cancer burden incurred by NMSC, further exploration of the use of TLR4 antagonists in NMSC chemoprevention strategies is certainly warranted.
29661826	melanoma	ICOS	Promote immunity (T cell function); essential for immunotherapy	We find that calcineurin, although largely dispensable for suppressive activity in vitro, is essential for upregulation of ICOS and CTLA-4 in Treg, as well as for expression of chemokine receptors driving their accumulation in tumors.
29661826	melanoma	CD28	Promote immunity (T cell function); essential for immunotherapy	Accordingly, although deletion of either CnB or CD28 strongly impairs Treg-mediated tumor tolerance, lack of CnB has an even more pronounced impact than lack of CD28.
29661791	melanoma	IFNG	Promote immunity (infiltration)	IFN-γ production is largely restricted to T lymphocytes and natural killer (NK) cells and can ultimately lead to the generation of a polarized immune response composed of T helper (Th)1 CD4+ T cells and CD8+ cytolytic T cells.
29661791	melanoma	IFNA1	Promote immunity (infiltration)	In contrast, the temporally distinct elaboration of IFN-γ in progressively growing tumors also promotes a state of adaptive resistance caused by the up-regulation of inhibitory molecules, such as programmed-death ligand 1 (PD-L1) on tumor cell targets, and additional host cells within the tumor microenvironment.
29661778	ovarian carcinoma	IFNA1	Promote immunity	Loss of chemokine and IFN-γ pathway genes is frequent in ovarian cancer and is significantly associated with low immune score and poor outcome.
29661776	myeloma	TMEM37	Promote immunity	Following PR1 cross-presentation, we are able to target multiple myeloma with PR1-CTL and anti-PR1/HLA-A2 antibody both in vitro and in vivoConclusions: Collectively, our data demonstrate that PR1 is a novel tumor-associated antigen target in multiple myeloma and that multiple myeloma is susceptible to immunotherapies that target cross-presented antigens.
29661773	pancreatic ductal adenocarcinoma	FOXP3	Inhibit immunity	Three PDAC subtypes were identified: the immune escape (54%), poor in T and B cells and enriched in FOXP3+ regulatory T cells (Treg), with high-grade budding, frequent CDKN2A, SMAD4, and PIK3CA mutations, and poor outcome; the immune rich (35%), rich in T and B cells and poorer in FOXP3+ Tregs, with infrequent budding, lower CDKN2A and PIK3CA mutation rate, and better outcome and a subpopulation with tertiary lymphoid tissue (TLT), mutations in DNA damage response genes (STK11 and ATM), and the best outcome; and the immune exhausted (11%), with immunogenic microenvironment and two subpopulations-one with PD-L1 expression and a high PIK3CA mutation rate and a microsatellite-unstable subpopulation with a high prevalence of JAK3 mutations.
29661773	pancreatic ductal adenocarcinoma	CDKN2A	Promote immunity	Three PDAC subtypes were identified: the immune escape (54%), poor in T and B cells and enriched in FOXP3+ regulatory T cells (Treg), with high-grade budding, frequent CDKN2A, SMAD4, and PIK3CA mutations, and poor outcome; the immune rich (35%), rich in T and B cells and poorer in FOXP3+ Tregs, with infrequent budding, lower CDKN2A and PIK3CA mutation rate, and better outcome and a subpopulation with tertiary lymphoid tissue (TLT), mutations in DNA damage response genes (STK11 and ATM), and the best outcome; and the immune exhausted (11%), with immunogenic microenvironment and two subpopulations-one with PD-L1 expression and a high PIK3CA mutation rate and a microsatellite-unstable subpopulation with a high prevalence of JAK3 mutations.
29661225	melanoma	CD27	Promote immunity (T cell function); essential for immunotherapy	There was differential expression of PD-1 by CD27 status, with expression being higher in the B and T cell subsets associated with memory status (CD27+ and CD27-, respectively; p < 0.001).
29659677	Colorectal carcinoma	ERBB2	Inhibit immunity immunotherapy target& oncogene	While the role of HER2 as a biomarker for prognosis in CRC remains uncertain, its relevance as a therapeutic target has been established.
29657128	lung adenocarcinoma	CTLA4	Inhibit immunity (infiltration)	TMB should be incorporated in future trials examining PD-(L)1 with CTLA-4 blockade in NSCLC.
29656892	melanoma	CTLA4	Inhibit immunity (infiltration)	We validate this gene expression signature in an independent anti-CTLA-4-treated cohort and show its specificity to the CTLA-4 pathway with two independent anti-PD-1-treated cohorts.
29656749	lung adenocarcinoma	FGF9	Inhibit immunity (T cell function)	We have developed a mouse model of lung cancer that is initiated through an inducible overexpression of fibroblast growth factor 9 (FGF9) in type-2 pneumocytes.
29656749	lung adenocarcinoma	VEGFA	Inhibit immunity	TAMs had high expression of Tgf-β, Vegf, Fgf2, Fgf10, Fgfr2 and several matrix metalloproteinases; factors that play multiple roles in supporting tumor growth, immune protection, fibroblast activation and angiogenesis.
29656492	melanoma	CD274	Inhibit immunity (T cell function)	Cancer cells resist to the host immune antitumor response via multiple suppressive mechanisms, including the overexpression of PD-L1 that exhausts antigen-specific CD8+ T cells through PD-1 receptors.
29655625	colon carcinoma	TXN	Promote immunity	First, the immunogenicity of the previously employed bacterial thioredoxin (TRX) was reduced by using a truncated from (TRXtr).
29655625	colon carcinoma	FN1	Promote immunity	This technology was used for vaccination against a marker of the tumor vasculature, the well-known extra domain B (EDB) of fibronectin.
29653983	squamous cell carcinoma	CASP1	Inhibit immunity	Taken together, our findings demonstrated that caspase-1 in MDSCs is a direct T cell-independent mediator of tumor proliferation.
29653983	squamous cell carcinoma	CD14	Inhibit immunity	To better define their T cell-independent functions within the tumor, sorted monocytic CD14+CD11b+HLA-DRlow/- MDSCs (mMDSC) from squamous cell carcinoma patients showed upregulated caspase-1 activity, which was associated with increased IL1β and IL18 expression.
29653983	squamous cell carcinoma	MYD88	Promote immunity (T cell function); essential for immunotherapy	In mice with wild-type caspase-1, MyD88-silenced tumors displayed reduced growth rate, but in chimeric mice with caspase-1 null bone marrow cells, MyD88-silenced tumors did not display differential tumor growth rate.
29653690	colon carcinoma	GLB1	Promote immunity	We used a pCMV-LacZ plasmid (expressing β-galactosidase) and a pcDNA-hNIS plasmid (expressing the human sodium/iodide symporter [hNIS] gene) as non-secreted visual-imaging markers.
29653690	colon carcinoma	IFNG	Promote immunity	High levels of INF-γ-secreting cells were identified in ELISpot and increased IFN-γ levels were found in cytokine ELISAs.
29651051	colon carcinoma	CCL7	Inhibit immunity	Subsequent functional analyses implicated both MEK/ERK and PI3K signaling upstream of CCL7 upregulation and identified CCL7 (but not CCL5) as a critical migration/invasion factor, acting via the chemokine receptor CCR3.
29651051	colon carcinoma	CCL5	Inhibit immunity	Chemokine CCL5 was identified as a regulator of the T-cell immune response in the liver.
29650805	melanoma	DNER	Inhibit immunity	We show that BET proteins are overexpressed in NRAS-mutant melanoma and that high levels of the BET family member BRD4 are associated with poor patient survival.
29650805	melanoma	MAP2K7	Inhibit immunity	Transcriptomic and proteomic analysis revealed that combining BET and MEK inhibitors mitigates a MAPK and checkpoint inhibitor resistance transcriptional signature, downregulates the transcription factor TCF19, and induces apoptosis.
29650000	lung adenocarcinoma	POLE	Inhibit immunity	POLE-mutant LUAD patients with high expression of PD-L1 (Mut-High, n = 6) exhibited improved OS (P = 0.024) when compared to POLE-mutant patients with low PD-L1 expression (Mut-Low, n = 24) and other patients without POLE mutation (n = 476). This benefit was not due to the high content of the tumor infiltrating lymphocytes. Instead, the antitumor immune response was activated in Mut-High patients so that these patients were likely responding more effectively to immuno-oncology (IO) treatments; whereas genes involved with metabolic pathways were enriched in Mut-Low group, which may cause the decreased OS of these patients.
29644393	carcinoma in situ	EGFR	Inhibit immunity immunotherapy target	Intravesical instillation of 213Bi-anti-EGFR monoclonal antibody was well tolerated and showed therapeutic efficacy.
29642948	melanoma	IL6	Promote immunity (infiltration)	Among the immune-profile biomarkers analyzed, only interleukin-6 was associated with the risk of toxicity.
29637789	Acute myeloid leukemia	CD99	Inhibit immunity	Expert opinion/commentary: Cytotoxic CD99 monoclonal antibodies represent promising stem cell-directed therapies that have the potential to markedly improve clinical outcomes for these difficult-to-treat hematologic malignancies.
29636826	lung carcinoma	STAT3	Inhibit immunity	We have actively worked on the role of STAT3, a transcriptional factor that causes innate resistance to targeted therapies in oncogene-addicted tumors.
29636751	colorectal carcinoma	ITGAM	Inhibit immunity	MDSCs comprise a heterogeneous population of immature myeloid cells that can be distinct in two subtypes: CD11b+Ly6G+Ly6Clow with granulocytic phenotype (G-MDSCs) and CD11b+Ly6G-Ly6Chigh with monocytic phenotype (M-MDSCs).
29635363	glioma	SPRY2	Inhibit immunity	The present study highlights an antitumoral effect of SPRY2 inhibition that is based on excessive activation of ERK signaling and DNA damage response, resulting in reduced cell proliferation and increased cytotoxicity, proposing SPRY2 as a promising pharmacological target in GBM patients.
29635163	Acute Lymphoblastic Leukemia	HLA-E	Promote immunity (T cell function); increase the efficacy of immunotherapy	CAR T-cells and bsAb represent the most powerful tools for major-histocompatibility complex (MHC) independent T-cell immune response against cancer.
29635163	Acute Lymphoblastic Leukemia	CD19	Promote immunity	CD19 loss is infrequent after blinatumomab, preserving the option for alternative CD19-direct treatments.
29634978	Squamous Cell Carcinoma	HGF	Inhibit immunity	MET/hepatocyte growth factor (HGF) signaling and transcription factors involved in epithelial-to-mesenchymal transition (EMT) upregulate PD-L1, which can contribute to clinical outcome.
29634978	Squamous Cell Carcinoma	SNIP1	Inhibit immunity	SNIP1 overexpression, unmethylated TWIST1, smoking, and poorly-differentiated tumors were predictive for PD-L1 overexpression.
29634944	Pancreatic Carcinoma	CD40	Promote immunity (T cell function); increase the efficacy of immunotherapy	CD40 activation plays a critical role in generating T cell immunity, by activating dendritic cells, and converting cold tumors to hot.
29634348	hepatocellular carcinoma	NOS2	Inhibit immunity	It is becoming increasingly evident that nitric oxide synthase 2 (NOS2)-mediated NO/reactive nitrogen oxide species (RNS) are heavily involved in cancer progression and metastasis in different types of tumor.
29634345	lung carcinoma	CXCL1	Inhibit immunity	Moreover, 34 immune response genes were significantly upregulated in tumors from Nrf2 KO mice, especially a series of cytokines (Cxcl1, Csf1, Ccl9, Cxcl12, etc.) and major histocompatibility complex antigens that promote tumor growth.
29634251	lung carcinoma	CCL22	Inhibit immunity	It is shown that GNPs can be specifically internalized by TAMs via lectin receptors, which results in upregulation of immunostimulatory IL-12 and downregulation of immunosuppressive IL-10, arginase 1, and CCL22, indicating functional reversion of protumor TAMs toward antitumor phenotype.
29634251	lung carcinoma	STAT6	Promote immunity	The reversion of TAMs is proved to be mainly controlled by suppressing STAT6 and activating NF-κB phosphorylation.
29633523	carcinoma	MUC1	Promote immunity	Synthetic vaccines based on MUC1 tandem repeat motifs, comprising tumor-associated 2,3-sialyl-T antigen, conjugated to the immunostimulating tetanus toxoid, are reported herein.
29633386	acute lymphoblastic leukemia	CD19	Promote immunity	A total of 18 R/R ALL patients with or without prior murine CD19 CAR-T therapy were treated with humanized CD19-targeted CAR-T cells (hCART19s).
29632734	bladder carcinoma	DEPDC1	Promote immunity	Here, we aimed to identify long peptides (LPs) derived from DEPDC1 and MPHOSPH1 that induced both T-helper (Th) cells and tumor-reactive cytotoxic T lymphocytes (CTLs).
29632730	Renal Cell Carcinoma	PDCD1	Inhibit immunity (T cell function)	Programmed cell death protein 1 (PD-1) immune checkpoint inhibitors have shown activity in patients with advanced renal cell carcinoma (RCC).
29632728	glioblastoma	STAT3	Inhibit immunity	Mass spectrometry analysis demonstrated that the GDEs contain a variety of components, including members of the signal transducer and activator of transcription 3 (STAT3) pathway that functionally mediate this immune suppressive switch.
29632726	Gastric Carcinoma	RAG1	Promote immunity	Despite minimal in vitro cytotoxic activity, the adoptive transfer of CD8+ memory stem T cells into Rag1-/- tumor bearing mice enhanced tumor regression compared to CD8+ central or effector memory T cell counterparts.
29632721	B16 Malignant Melanoma	CIRBP	Promote immunity (T cell function); increase the efficacy of immunotherapy	In vitro, CIRP induced dendritic cell activation, migration and enhanced presentation of CIRP-bound antigens to T-cells.
29632721	B16 Malignant Melanoma	CTLA4	Inhibit immunity (infiltration)	Moreover, immunogenicity of this vaccination platform was enhanced not only by combination with additional adjuvants, but also with antibodies blocking PD-1/PD-L1, CTLA-4 and IL-10, immunosuppressive molecules usually present in the tumor environment and also induced by the vaccine.
29632715	breast carcinoma	HLA-E	Promote immunity	Since recombinant DCN also elevated MHC class I surface expression in BGNlow/neg HER-2/neu+ cells, both proteoglycans might act synergistically.
29632715	breast carcinoma	BGN	Promote immunity	Furthermore, BGN expression in HER-2/neu+ cells was accompanied by an increased expression of the proteoglycan decorin (DCN). Since recombinant DCN also elevated MHC class I surface expression in BGNlow/neg HER-2/neu+ cells, both proteoglycans might act synergistically.
29632714	breast carcinoma	TGFB1	Inhibit immunity	Murine studies have suggested that countering immune suppressive effects of TGFβ may be sufficient to inhibit tumor growth.
29632714	breast carcinoma	SMAD4	Promote immunity	In vitro the 4-1BB-Smad4 conjugate rendered T cells partially resistant to TGFβ inhibition, and treatment of tumor bearing mice with systemically administered 4-1BB-Smad4 conjugate enhanced vaccine- and irradiation-induced antitumor immunity.
29632713	breast carcinoma	CD47	Inhibit immunity	These results provide a rationale for an innovative preclinical combination immunotherapy based on PD-1/PD-L1 and CD47 blockade along with EMT inhibitors in patients with highly aggressive, mesenchymal, and metastatic breast cancer.
29632713	breast carcinoma	SNAI1	Inhibit immunity	The phagocytosis of EMT-activated cells was rescued by using CD47 blocking antibody or by genetic targeting of SNAI1, ZEB1 or CD47.
29632709	breast carcinoma	ERBB2	Inhibit immunity	Despite substantial clinical progress with targeted therapies, current antibody-based approaches have limited efficacy at controlling HER2/neu-positive breast cancers, especially in the absence of chemotherapies.
29632708	hepatocellular carcinoma	S100A4	Promote immunity	S100A4 blockage alleviates agonistic anti-CD137 antibody-induced liver pathology without disruption of antitumor immunity.
29632708	hepatocellular carcinoma	TNFRSF9	Inhibit immunity (T cell function); immunotherapy target	Here, we found that anti-CD137 monoclonal antibody (mAb) treatment in mice induced the infiltration of a large number of S100A4+ macrophages into the liver.
29632540	Burkitt’s lymphoma; acute myeloid leukemia	KIR2DL2	Inhibit immunity	We found that DAC upregulated KIR2DL2/3 expression in KIR2DL2/3-negative γδ T cells by inhibiting KIR2DL2/3 promoter methylation, which enhances the binding of KIR2DL2/3 promoter to Sp-1 and activates KIR2DL2/3 gene expression.
29632537	ovarian carcinoma	TNFRSF1B	Inhibit immunity (T cell function); immunotherapy target	These studies clearly show that TNFR2-targeting pharmacological agents represent an effective approach to modulating the function of Tregs and thus may be useful in the treatment of major human diseases such as autoimmune disorders, graft-versus-host disease (GVHD), and cancer.
29632319	neuroblastoma	MYCN	Inhibit immunity	In this review, we will summarize and discuss the latest progress in the study of TNFR2-targeting pharmacological agents and their therapeutic potential based on upregulation or downregulation of Treg activity.
29632317	Breast carcinoma	PLAC1	Inhibit immunity	EO771 "knockdown" (KD) resulted in 50% reduction in proliferation in vitro and impaired tumor growth in syngeneic mice; however, tumor growth in SCID mice was equivalent to tumor cells expressing a non-silencing control RNA, suggesting that Plac1 regulated adaptive immunity.
29632317	carcinoma	CXCL1	Inhibit immunity	Gene expression profiling of Plac1 KD cells indicated reduction in several inflammatory and immune factors, including Cxcl1, Ccl5, Ly6a/Sca-1, Ly6c and Lif.
29632317	carcinoma	CXCR2	Inhibit immunity	Treatment of mice engrafted with wild-type EO771 cells with a Cxcr2 antagonist impaired tumor growth, reduced myeloid-derived suppressor cells and regulatory T cells, while increasing macrophages, dendritic cells, NK cells and the penetration of CD8+ T cells into the tumor bed.
29632307	plasma cell myeloma	IFNA1	Promote immunity	Migration and secretion of IL12p70 and IFN-γ (in DC-T cell co-cultures) were significantly reduced in MM-DCs.
29632307	plasma cell myeloma	IL6	Promote immunity	This impairment could be attributed to autocrine secretion of IL6 by MM-monocytes and activation of their P38 MAPK pathway.
29632196	Squamous Cell Carcinoma	CSF1R	Inhibit immunity (infiltration)	Our results reveal that a CSF-1R blockade enhances CD8 T cell migration and infiltration into tumor islets.
29632186	B16 Malignant Melanoma	ANXA5	Promote immunity (T cell function)	Fusion of ANXA5 to pMHC augments lymphocyte activation by several orders of magnitude (>1,000-fold), bypasses the need for costimulation, and breaks tolerance against a model self-antigen in vivo.
29631966	adenocarcinomas; squamous Cell Carcinoma	RET	Inhibit immunity	The receptor tyrosine kinase MET is implicated in malignant transformation, tumor progression, metastasis, and acquired treatment resistance.
29631966	adenocarcinomas; squamous Cell Carcinoma	MET	Inhibit immunity immunotherapy target	High MET expression correlated with activation markers of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathways only in cases without Kirsten rat sarcoma viral oncogene homolog (KRAS), epidermal growth factor receptor (EGFR), v-Raf murine sarcoma viral oncogene homolog B (BRAF), anaplastic lymphoma kinase (ALK) and proto-oncogene tyrosine-protein kinase ROS (ROS1) aberrations.
29630987	ovarian carcinoma	CD209	Promote immunity	In this present work, we evaluated the capacity of LPR functionalized with a tri-antenna of α-d-mannopyranoside (triMN-LPR) concerning (i) their binding to CD209/DC-SIGN and CD207/Langerin expressing cell lines, human and mouse DCs and other hematopoietic cell populations, (ii) the nature of induced immune response after in vivo immunization and (iii) their therapeutic anti-cancer vaccine efficiency.
29630987	ovarian carcinoma	CCR7	Promote immunity (T cell function); increase the efficacy of immunotherapy	This was associated with skin production of CCR7 and CXCR4 at vaccination sites driving DC migration.
29630898	Pancreatic ductal adenocarcinoma; melanoma; colon carcinoma	RAG1	Promote immunity (T function); essential for immunotherapy	However, depletion of gut microbiome did not reduce tumor growth in Rag1-knockout mice, which lack mature T and B cells.
29630898	Pancreatic ductal adenocarcinoma; melanoma; colon carcinoma	IFNG	Promote immunity (T cell function); increase the efficacy of immunotherapy	Flow cytometry analyses demonstrated that gut microbiome depletion led to significant increase in interferon gamma-producing T cells with corresponding decrease in interleukin 17A and interleukin 10-producing T cells.
29628923	melanoma	FOLR1	Promote immunity	To establish this, we selected Folate Receptor alpha (FRα) as a model antigen and a mouse B cell line, expressing both the soluble and the membrane-bound forms of a human/mouse chimeric antibody (MOv18 IgG1) specific for FRα, as test antibody-expressing cells.
29628923	melanoma	ERBB2	Inhibit immunity	In PBMC pools, beads conjugated to recombinant antigens FRα and HER2 bound antigen-specific anti-FRα MOv18 and anti-HER2 Trastuzumab antibody-expressing cells, respectively.
29628419	melanoma; squamous Cell Carcinoma	IRF1	Promote immunity (T cell function); increase the efficacy of immunotherapy	We identified reduced levels of IRF1 and CXCL10 immunostimulatory molecules in highly glycolytic melanoma cells.
29628320	lung adenocarcinoma	EGFR	Inhibit immunity immunotherapy target	We collected 105 surgically resected (50 EGFR mutated and 55 EGFR wild-type), treatment-na?ve lung adenocarcinoma tissues with clinical data to investigate the landscape and compartmentalization of tumor-infiltrating immune cells with respect to EGFR status by immunohistochemistry.
29628320	lung adenocarcinoma	MMP9	Promote immunity	In the RNA-Seq analysis, MMP9 and VEGFA showed higher levels in wild-type EGFR than in mutant cases.
29628320	lung adenocarcinoma	CD68	Promote immunity (infiltration)	CD68-positive cells within the tumor niche exhibited more intensive infiltration in wild-type EGFR than in mutations, and was related to lymph node invasion.
29628290	all cancer types	IFNA1	Promote immunity	Across cancer types, we identified six immune subtypes-wound healing, IFN-γ dominant, inflammatory, lymphocyte depleted, immunologically quiet, and TGF-β dominant-characterized by differences in macrophage or lymphocyte signatures, Th1:Th2 cell ratio, extent of intratumoral heterogeneity, aneuploidy, extent of neoantigen load, overall cell proliferation, expression of immunomodulatory genes, and prognosis.
29628290	all cancer types	IDH1	Promote immunity	Specific driver mutations correlated with lower (CTNNB1, NRAS, or IDH1) or higher (BRAF, TP53, or CASP8) leukocyte levels across all cancers.
29626519	breast carcinoma	BMI1	Inhibit immunity	These DEGs were enriched with reductions in immunological processes, indicating a role of BMI1 in downregulation of the immune surveillance.
29626119	breast carcinoma	FAP	Inhibit immunity	Fibroblast activation protein (FAP) is overexpressed in cancer associated fibroblasts and is involved in a variety of tumor promoting activities such as matrix remodeling, angiogenesis, chemotherapy resistance and immunosuppression.
29625896	hepatocellular carcinoma	VTCN1	Inhibit immunity (T cell function); decrease the efficacy of immunotherapy	Collectively, B7S1 initiates dysfunction of tumor-infiltrating CD8+ T cells and may be targeted for cancer immunotherapy.
29625896	hepatocellular carcinoma	MUC5AC	Inhibit immunity (infiltration)	Putative B7S1 receptor was co-expressed with PD-1 but not T cell immunoglobulin and mucin-domain containing-3 (Tim-3) at an activated state of early tumor-infiltrating CD8+ T cells, and B7S1 promoted T cell exhaustion, possibly through Eomes overexpression.
29622580	breast carcinoma	ERBB2	Inhibit immunity	To understand the role of endogenous IFN-I in spontaneous, oncogene-driven carcinogenesis, we characterized tumors arising in HER2/neu transgenic (neuT) mice carrying a nonfunctional mutation in the IFNI receptor (IFNAR1).
29622580	breast carcinoma	IFNAR1	Promote immunity	IFNAR-neuT tumors exhibited deregulation of genes having adverse prognostic value in breast cancer patients, including the breast cancer stem cell (BCSC) marker aldehyde dehydrogenase-1A1 (ALDH1A1).
29622464	breast carcinoma	ESR1	Inhibit immunity	We found functionally significant estrogen receptor-regulated long non-coding RNAs (lncRNAs) and gene/lncRNA interaction networks.
29620951	B-cell leukemia; lymphoma	CD19	Promote immunity	Early trials with anti-CD19 CAR T cells have achieved spectacular remissions in B-cell leukemia and lymphoma, so far refractory, very recently resulting in the Food and Drug Administration approval of CD19 CAR T cells for therapy.
29619980	lung adenocarcinoma	VEGFA	Inhibit immunity	Through the downregulation of vascular endothelial growth factor (VEGF), AHFRT inhibited VEGF/VEGF receptor signaling, which was essential for MDSC recruitment.
29619406	Melanoma	PDCD1	Inhibit immunity (T cell function)	Programmed cell death protein 1 Monoclonal antibodies targeting two such molecules, Programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) have shown clinical benefit in the treatment of advanced malignancies, including metastatic melanoma.
29619406	Melanoma	CD163	Promote immunity	A thyroid biopsy was performed based on ultrasound findings and cytopathology revealed unique features including abundant clusters of necrotic cells, lymphocytes and CD163-positive histiocytes.
29619024	Melanoma	NGFR	Promote immunity	In conclusion, we have demonstrated that the incorporation of the NGFR marker gene within the CAR sequence allows for a single molecule to simultaneously work as a therapeutic and selection/tracking gene.
29618525	Melanoma	CRK	Promote immunity (Nk cell function); increase the efficacy of immunotherapy	The diminished function of Crk x CrkL-double-deficient NK cells correlated with decreased phosphorylation of STAT4 and STAT1 in response to IL-12 and IFN-α stimulation, respectively.
29618525	Melanoma	IFNA1	Promote immunity (Nk cell function); increase the efficacy of immunotherapy	However, Crk family proteins were required for optimal activation, IFN-γ production, expansion, and differentiation of Ly49H+ NK cells, as well as host defense during mouse CMV infection.
29618524	melanoma	IL2	Inhibit immunity (T cell function)	Our results show that it is enough to transiently inhibit IL-2 signaling to bias E and Treg cell balance in vivo toward immunity.
29618523	Large B-Cell Cell Lymphoma	CD5	Inhibit immunity	Phenotypic examination of both lines revealed a substantial difference in their surface of expression of CD5, which serves as a dependable readout of the self-reactivity of a cell.
29617862	melanoma	PMEL	Promote immunity	Combining these technologies, we efficiently generated gp100-specific PD-1(-) CD8+ T cells, and demonstrated that the genetically engineered CD8+ T cells have high avidity against melanoma cells both in vitro and in vivo.
29617574	Non-Small Cell Lung Carcinoma	CCR5	Inhibit immunity	The frequency of C-C chemokine receptor 5 (CCR5) expression on circulating M-MDSCs was significantly higher in the patients than in the HDs.
29616326	Lung Carcinoma; Non-small cell lung carcinoma; Small cell lung carcinoma	IL2	Promote immunity (Nk cell function); increase the efficacy of immunotherapy	Recent clinical trials on NK cell-based novel therapies such as cytokines including interleukin (IL)-15, IL-12 and IL-2, NK-92 cell lines and allogenic NK cell immunotherapy showed promising results with less adverse effects on the lung cancer survival.
29616191	breast carcinoma	BECN1	Inhibit immunity	Genetic inactivation of Beclin-1, an autophagy regulator, significantly reverses mitochondrial abnormalities and tumor development in ATM-null mice, independently of DDR.
29616191	breast carcinoma	ERBB2	Inhibit immunity	Furthermore, ATM sustains cancer stem cells survival by promoting the autophagic flux and ATM kinase activity is enhanced in HER2-dependent tumors.
29615432	Medulloblastoma	PRAME	Inhibit immunity (T cell function); immunotherapy target	Altogether, these data indicate that T cells genetically modified with a high-affinity, PRAME-specific TCR and iC9 may represent a promising innovative approach for treating HLA-A*02+ medulloblastoma patients.
29615063	breast carcinoma	ESR1	Inhibit immunity	Estrogen receptor, progesteron receptor, human epidermal growth factor receptor 2, Ki67, PD-L1, PDL-2 and PD-1 status were assessed by immunohistochemistry.
29614981	Colorectal cancer	ICOS	Promote immunity (T function); essential for immunotherapy	Furthermore, the activation/suppression marker values of the lymphocytes (i.e., such as PD-1, ICOS, Granzyme B and the PD-1/CD8 ratio) in the primary tumor were correlated with values in the metastatic tumor.
29606356	hepatocellular carcinoma	PTPRC	Promote immunity (T cell function); increase the efficacy of immunotherapy	Here, we report one population of tumor-inducible, erythroblast-like cells (Ter-cells) deriving from megakaryocyte-erythroid progenitor cells with a unique Ter-119+CD45-CD71+ phenotype.
29606356	hepatocellular carcinoma	SMAD3	Promote immunity	Transforming growth factor β (TGF-β) and Smad3 activation are important in Ter-cell generation.
29605760	lymphoma	CD19	Promote immunity	Remarkable responses have been observed in patients receiving autologous CD19-redirected T cells for the treatment of B-lymphoid malignancies.
29604293	Pancreatic ductal adenocarcinoma; melanoma; colon carcinoma	IL17A	Promote immunity	Immune cells that produce interleukin 17A (IL17A) in the chronically inflamed pancreas (chronic pancreatitis) contribute to pancreatic interepithelial neoplasia (PanIN) initiation and progression.
29604293	Pancreatic ductal adenocarcinoma; melanoma; colon carcinoma	KRAS	Inhibit immunity	We performed studies with Mist1Cre;LSLKras;Rosa26mTmG (KCiMist;G) and Kras(G12D);Trp53(R172H);Pdx1-Cre (KPC) mice (which upon tamoxifen induction spontaneously develop PanINs) and control littermates.
29604293	Pancreatic ductal adenocarcinoma; melanoma; colon carcinoma	DCLK1	Inhibit immunity	In human pancreatic tumor tissues, high levels of DCLK1 associated with a shorter median survival time of patients (17.7 months, compared with 26.6 months of patients whose tumors had low levels of DCLK1).
29604063	colorectal carcinoma； endometrial cancer	TP53	Promote immunity	Genomic instability, which is a hallmark of cancer, is generally thought to occur in the middle to late stages of tumourigenesis, following the acquisition of permissive molecular aberrations such as TP53 mutation or whole genome doubling.
29604063	colorectal carcinoma； endometrial cancer	POLE	Inhibit immunity (T cell function); immunotherapy target	Using genome and exome sequencing, we found that multiple driver mutations in POLE-mutant cancers show the characteristic POLE mutational signature, including those in genes conventionally regarded as initiators of tumourigenesis.
29603746	Colon Carcinoma	MBD2	Promote immunity	As environmental interactions within the intestine can alter DNA methylation patterns, we propose that Mbd2 plays a key role in determining whether these interactions are anti- or pro-tumourigenic and this makes it a useful new epigenetic model for inflammation-associated carcinogenesis.
29603856	colorectal carcinoma	CD274	Inhibit immunity (T cell function)	Immune checkpoint inhibitors (ICIs) block CTLA-4, PD-1 and PD-L1, or other molecules that control antitumour activities of lymphocytes.
29603739	glioblastoma	TNFSF14	Promote immunity	Thus, peptide-mediated LIGHT targeting is a highly translatable approach in primary brain cancer to reduce vascular leakiness and enhance immunotherapy.
29603739	glioblastoma	RGR	Inhibit immunity	We assessed the ability of micelle-tagged, vascular homing peptides RGR, CGKRK and NGR to specifically bind to blood vessels in syngeneic orthotopic GBM models.
29603739	glioblastoma	TNF	Promote immunity (infiltration)	By using the peptide CGKRK to deliver the tumour necrosis factor (TNF) superfamily member LIGHT (also known as TNF superfamily member 14; TNFSF14) to angiogenic tumour vessels, we have generated a reagent that normalizes the brain cancer vasculature by inducing pericyte contractility and re-establishing endothelial barrier integrity.
29602801	mesothelioma	ITGAM	Inhibit immunity	Characterization of the whole blood at diagnosis identified similar, circulating, immunosuppressive CD11b+CD15+HLADR- granulocytes at increased frequency compared with healthy controls.
29602801	mesothelioma	CYBB	Inhibit immunity (T cell function)	Culture of healthy-donor granulocytes with human mesothelioma cells showed that GM-CSF upregulates NOX2 expression and the release of reactive oxygen species (ROS) from granulocytes, resulting in T-cell suppression.
29602801	mesothelioma	CSF2	Inhibit immunity (T cell function); immunotherapy target	Blockade of GM-CSF with neutralizing antibody, or ROS inhibition, restored T-cell proliferation, suggesting that targeting of GM-CSF could be of therapeutic benefit in these patients.Conclusions: Our study presents the mechanism behind the cross-talk between mesothelioma tumors and the immune microenvironment and indicates that targeting GM-CSF could be a novel treatment strategy to augment immunotherapy in patients with mesothelioma.
29602773	melanoma	TYRP1	Promote immunity (T cell function); increase the efficacy of immunotherapy	Previously, we showed that tumor-specific, cytotoxic CD4+ T cells from tyrosinase-related protein 1 transgenic mice could overcome secondary resistance to recurring melanoma when anti-programmed cell death 1 ligand (PD-L1) checkpoint blockade was combined with either anti-lymphocyte-activated gene 3 (LAG-3) Abs or depletion of tumor-specific regulatory T (Treg) cells.
29602773	melanoma	LAG3	Inhibit immunity (T cell function); immunotherapy target	Because LAG-3 negatively regulates effector T cell function and activates Treg cells, LAG-3 blockade may be more beneficial in overcoming primary resistance in combination immunotherapies using adoptive cellular therapy and irradiation than blockade of PD-L1.
29601471	hepatocellular carcinoma	HMGB1	Promote immunity	uch effects may be responsible for release of danger-associated molecular patterns, including ATP, calreticulin, and high mobility group box 1 (HMBG1) from 4T1-Luc cells to induce immunogenic cell death (ICD).
29600445	melanoma	BIRC5	Promote immunity	By characterizing nine different GBCCLs and several fresh tumor tissues, we found that they expressed some tumor-associated antigens such as CEA, MUC-1, CA19-9, Erb2, Survivin, and several carcinoembryonic antigens.
29600445	melanoma	HMGB1	Promote immunity	Moreover, heat-shock treatment of GBCCLs induced calreticulin translocation and release of HMGB1 and ATP, both known to act as danger signals.
29599908	Pancreatic ductal adenocarcinoma; melanoma; colon carcinoma	IL18	Inhibit immunity immunotherapy target	Our results show that IL-18 and PD-1/PD-L1 could be therapeutic targets in pancreatic cancer.
29599411	melanoma	CD69	Promote immunity (T cell function); increase the efficacy of immunotherapy	Durable responses, however, occur in less than half of those treated, and efforts to improve treatment efficacy are confounded by a lack of understanding of the characteristics of the cells that initiate antitumor immune response.Experimental Design: We performed multiparameter flow cytometry and quantitative multiplex immunofluorescence staining on tumor specimens from immunotherapy-na?ve melanoma patients and longitudinal biopsy specimen obtained from patients undergoing anti-PD-1 therapy.Results: Increased numbers of CD69+CD103+ tumor-resident CD8+ T cells were associated with improved melanoma-specific survival in immunotherapy-na?ve melanoma patients.
29599411	melanoma	IL15	Promote immunity (T cell function); increase the efficacy of immunotherapy	Local IL15 expression levels strongly correlated with these tumor-resident T-cell numbers.
29599411	melanoma	LAG3	Inhibit immunity (T cell function); immunotherapy target	The expression of several immune checkpoints including PD-1 and LAG3 was highly enriched in this subset, and these cells significantly expanded early during anti-PD-1 immunotherapy.Conclusions: Tumor-resident CD8+ T-cell numbers are more prognostic than total CD8+ T cells in metastatic melanoma.
29596939	melanoma	CTLA4	Inhibit immunity (infiltration)	Two inhibitory molecules, cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1), got high attention, as inhibition of CTLA-4 or PD-1 signaling provides the first immune therapy that significantly improves the survival of patients with metastatic solid cancers.
29596910	Recurrent Non-Small Cell Lung Carcinoma	EGFR	Inhibit immunity immunotherapy target	Furthermore, treatment of NSCLC cell lines that harbor such driver oncogenes with corresponding EGFR or ALK tyrosine kinase inhibitors or depletion of EGFR or ALK by small interfering RNA transfection suppressed expression of PD-L2, demonstrating that activating EGFR mutations or echinoderm microtubule associated protein like 4 gene (EML4)-ALK receptor tyrosine kinase gene (ALK) fusion intrinsically induce PD-L2 expression.
29596910	Recurrent Non-Small Cell Lung Carcinoma	IFNG	Inhibit immunity (T cell function)	We also found that interferon gamma (IFN-γ) extrinsically induced expression of PD-L2 through signal transducer and activator of transcription 1 signaling in NSCLC cells.
29596910	Recurrent Non-Small Cell Lung Carcinoma	STAT3	Inhibit immunity (T cell function)	Oncogene-driven expression of PD-L2 in NSCLC cells was inhibited by knockdown of the transcription factors signal transducer and activator of transcription 3 (STAT3) or c-FOS.
29596890	ovarian carcinoma; Pancreatic ductal adenocarcinoma; mesothelioma	MSLN	Promote immunity	The results indicate that an MSLN-specific DNA vaccine combined with immuno-modulators may be an effective immunotherapeutic strategy to control MSLN-expressing tumors including ovarian and pancreastic cancers, and malignant mesothelioma.
29596890	ovarian carcinoma; Pancreatic ductal adenocarcinoma; mesothelioma	CTGF	Promote immunity	The anti-tumor effects of the CTGF/MSLN DNA vaccine combined with anti-CD40 Ab and toll-like receptor 3 ligand-poly(I:C) were validated in an MSLN-expressing model.
29596783	multiple cancer types	MYC	Inhibit immunity	Using computational approaches, we define genomic and proteomic features associated with MYC and the PMN across the 33 cancers of The Cancer Genome Atlas.
29596783	multiple cancer types	PIK3CA	Inhibit immunity	MYC alterations were mutually exclusive with PIK3CA, PTEN, APC, or BRAF alterations, suggesting that MYC is a distinct oncogenic driver.
29595533	Esophageal Carcinoma	IDO1	Inhibit immunity immunotherapy target	IDO1 expression was associated with an unfavorable clinical outcome in esophageal cancer, supporting its role as a prognostic biomarker.
29594389	melanoma	FSTL1	Promote immunity	FSTL1 is involved in multiple signaling pathways and biological processes, including vascularization and regulation of the immune response, a feature that complicates its study.
29594038	Lung Carcinoma	CD40	Promote immunity	Overall, 60% of mice treated with SRBs showed complete tumor regression during the observation period, compared to 10% for cohorts administered with anti-CD40 mAbs, but no SRB.
29593283	breast carcinoma; Pancreatic ductal adenocarcinoma	IRF8	Promote immunity	Breast and pancreatic cancer interrupt IRF8-dependent dendritic cell development to overcome immune surveillance.
29587865	Adenocarcinoma of the Mouse Pulmonary System; colorectal adenocarcinoma	KRT7	Inhibit immunity	The combination of CK7+/CDX2+ immunostaining and the distinctive genetic signatures, including low incidence of sensitivity genes mutations and high tumor mutation burden, is an important supplementary to the clinical differential diagnosis of primary PEACs.
29587865	Adenocarcinoma of the Mouse Pulmonary System; colorectal adenocarcinoma	KRAS	Inhibit immunity	The primary PEACs harbor a high incidence of KRAS mutation but almost absent of EGFR mutation.
29587679	breast carcinoma	KLRG1	Promote immunity	Tumour infiltrating ILC were found to show an activated phenotype with higher expression of MHC-II, KLRG1, early activation marker CD69 and CD44.
29581846	Non-Small Cell Lung Carcinoma	SHH	Inhibit immunity; immunotherapy target	Collectively, our results provide early demonstration of the antitumor utility of antibodies specific for the C-terminal region of Shh, and support continued development to evaluate their potential efficacy in cancers in which Shh activity is elevated.
29581358	colorectal carcinoma	FOXP3	Inhibit immunity	With histopathological analysis, Foxp3+ Tregs were preferentially located in stroma.
29581358	colorectal carcinoma	CCR1	Promote immunity	Concurrent transcriptome analysis of epithelial cells, stromal cells, and T cell subsets obtained from carcinomatous and normal intestinal samples from patients revealed a distinct gene expression signature in colorectal adenocarcinoma-associated Tregs, with overexpression of CCR1, CCR8, and TNFRSF9, whereas their ligands CCL4 and TNFSF9 were found upregulated in cancerous epithelium.
29581358	colorectal carcinoma	WNT2	Inhibit immunity	Overexpression of WNT2 and CADM1, associated with carcinogenesis and metastasis, in cancer-associated stromal cells suggests that both cancer cells and stromal cells play important roles in the development and progression of colorectal cancer through the formation of a tumor microenvironment.
29581297	hepatocellular carcinoma	EZH2	Inhibit immunity (NK cell function); resistant to immunotherapy	The inhibition of EZH2 by small-molecule inhibitors or genetic means enhanced HCC cell eradication by NK cells in a NKG2D ligand-dependent manner.
29581297	hepatocellular carcinoma	KLRK1	Promote immunity (NK cell function); essential for immunotherapy	Because the down-regulation of NKG2D ligands occurred at the transcriptional level, we tested 32 chemical inhibitors of epigenetic regulators for their ability to re-express NKG2D ligands and enhance HCC cell eradication by NK cells and found that Enhancer of zeste homolog 2 (EZH2) was a transcriptional repressor of NKG2D ligands.
29581255	Colon Carcinoma	CTLA4	Inhibit immunity (infiltration)	The VHH H11 lacks an Fc portion, binds monovalently to CTLA-4, and inhibits interactions between CTLA-4 and its ligand by occluding the ligand-binding motif on CTLA-4 as shown crystallographically.
29581255	Colon Carcinoma	HSPB8	Promote immunity	Installation of the murine IgG2a constant region on H11 dramatically enhances its antitumor response.
29580868	Melanoma	TRPV1	Promote immunity	Altogether, our study demonstrates that TRPV1 is a potential tumor suppressor in melanoma.
29580807	breast carcinoma	ERBB2	Inhibit immunity	In this study, the AE37 (Ii-Key/HER-2/neu 776-790) peptide derived from HER2 (human epidermal growth factor receptor protein) was used as a fused peptide to the lambda phage (λF7) coat protein gpD, and the phage nanoparticles were used to induce antitumor immunogenicity in a TUBO model of breast cancer in mice.
29580288	Plasma Cell Myeloma	CD274	Inhibit immunity (T cell function)	Drugs modulating the transcriptional and post-transcriptional regulation of PD-L1 could represent new therapeutic strategies for the treatment of multiple myeloma, help potentiate the action of other drugs or be combined to PD-1/PD-L1 inhibitors in order to avoid the potentially problematic combination with immunomodulators.
29577276	Plasma Cell Myeloma	IL2	Promote immunity (T function); essential for immunotherapy	This is due to the modulation of IL-2 and IL-15 signaling, which is required for expansion and survival of CD8+ T cells as well as for optimal cytotoxic activity.
29576376	Pancreatic Carcinoma	CD40	Promote immunity	Here we determined characteristics of nine hCD40 mAbs engaging epitopes throughout the CD40 extracellular region expressed as varying isotypes.
29576376	Pancreatic Carcinoma	FCGR1A	Promote immunity	Fc gamma receptor All mAb formats were strong agonists when hyper-crosslinked; however, only those binding the membrane-distal cysteine-rich domain 1 (CRD1) retained agonistic activity with physiological Fc gamma receptor crosslinking or as human immunoglobulin G2 isotype; agonistic activity decreased as epitopes drew closer to the membrane.
29576376	Pancreatic Carcinoma	CD40LG	Promote immunity	In addition, all CRD2-4 binding mAbs blocked CD40 ligand interaction and were potent antagonists.
29574275	Malignant Ovarian Neoplasm	ANXA5	Promote immunity	The fusion protein combines annexin V (ANXA5), an ovarian tumor and tumor vasculature targeting protein, with mutated cystathionine gamma-lyase (mCTH), an enzyme that converts selenomethionine (SeMet) into toxic methylselenol, which generates reactive oxygen species and eventual tumor cell death.
29574275	Malignant Ovarian Neoplasm	NT5E	Inhibit immunity (T cell function); immunotherapy target	In order to further enhance the therapeutic efficacy, anti-CD73 and anti-OX40 immunostimulants were combined with mCTH-ANXA5, resulting in an increase of survival by 100% from 12 to 24 days post-therapy and decrease tumor burden in mice with orthotopic metastatic ovarian cancer.
29573941	melanoma	BRAF	Inhibit immunity	We investigated encorafenib, a BRAF inhibitor with unique target-binding properties, alone or in combination with the MEK inhibitor binimetinib, versus vemurafenib in patients with advanced BRAFV600-mutant melanoma.
29573850	all types of cancer	TNF	Promote immunity	Ten patients required additional immunosuppression beyond corticosteroids, with TNF-inhibitors and/or methotrexate.
29573820	lymphoma	TLR7	Promote immunity	Small molecule TLR7/8 agonist hold high potential for this purpose, but suffer from an undesirable pharmacokinetic profile, resulting in systemic inflammatory responses.
29572968	breast carcinoma	IFNA1	Promote immunity (T cell function); increase the efficacy of immunotherapy	These therapeutic outcomes are achieved through the inhibition of immunosuppressive MDSCs in tumors and spleens by releasing gemcitabine and recruitment/activation of dendritic cells, enhanced population of CD4+ and CD8+ T cells, and increased IFN-γ production by cancer vaccines from the iCD.
29572701	melanoma	DGKA	Inhibit immunity (T cell function); decrease the efficacy of immunotherapy	Diacylglycerol kinase α Diacylglycerol kinase α inactivation is an integral component of the costimulatory pathway that amplifies TCR signals.
29572701	melanoma	LCK	Promote immunity (T function); essential for immunotherapy	In contrast with enhanced activation triggered by pharmacological inhibition, DGKα silencing/genetic deletion led to impaired Lck (lymphocyte-specific protein tyrosine kinase) activation and limited costimulation responses.
29572232	Plasma Cell Myeloma	IL18	Inhibit immunity (T cell function); decrease the efficacy of immunotherapy	IL18 drives bone marrow MDSC function to suppress T-cell activity and accelerate multiple myeloma.
29572003	Non-Small Cell Lung Carcinoma	POLE	Inhibit immunity	POLE mutation may thus represent a candidate biomarker for response to immunotherapy in patients with NSCLC.
27925176	Breast Carcinoma	CD274	Inhibit immunity (T cell function)	The expression of PD-L1 and tumor-infiltrating lymphocytes (TILs) in residual breast cancer cells was assessed by immunohistochemistry in surgical specimens. High expression of PD-L1 was correlated to worse survival. The expression of PD-L1 was more commonly observed in patients with low levels of total TILs (p?<?0.001), high levels of FOXP3+ TILs (p?<?0.001) and low levels of CD8+ TILs (p?<?0.001)
27923823	Nasopharyngeal Carcinoma	IDO1	Inhibit immunity; immunotherapy target	Indoleamine 2,3-dioxygenase (IDO), an IFNγ-inducible enzyme, is a major inducer of immune tolerance during tumor development; therefore, inhibition of the IDO pathway is an important modality for cancer treatment.
27923823	Nasopharyngeal Carcinoma	STAT1	Inhibit immunity; immunotherapy target	bortezomib, a proteasomal inhibitor, inhibited the pathways leading to STAT1 and IRF-1 activation, both of which are necessary for IDO expression.
27923823	Nasopharyngeal Carcinoma	IRF1	Inhibit immunity; immunotherapy target	bortezomib, a proteasomal inhibitor, inhibited the pathways leading to STAT1 and IRF-1 activation, both of which are necessary for IDO expression.
27923823	Nasopharyngeal Carcinoma	NFKB1	Inhibit immunity	Negative feedback inhibited the transcription of NF-κB, which is important for activating IRF-1 expression.
27922598	Pre-B Acute Lymphoblastic Leukemia	EPHA3	Essential for immunotherapy	We use two models of human pre-B-ALL to examine EphA3 function. No antitumor effect in the xenografts with no EphA3 expression providing evidence that EphA3 is a functional therapeutic target in pre-B-ALL.
27913437	Breast Carcinoma	LRRC32	Inhibit immunity (T cell function)	GARP encoded by the Lrrc32 gene is the cell surface docking receptor for latent TGFβ. Although Lrrc32 is amplified frequently in breast cancer. We report that GARP exerts oncogenic effects, promoting immune tolerance by enriching and activating latent TGFβ in the tumor microenvironment. We found that human breast, lung, and colon cancers expressed GARP aberrantly. In genetic studies in normal mammary gland epithelial and carcinoma cells, GARP expression increased TGFβ bioactivity and promoted malignant transformation in immunodeficient mice. In breast carcinoma-bearing mice that were immunocompetent, GARP overexpression promoted Foxp3+ Treg activity.
27913437	Lung Carcinoma, Colon Carcinoma	LRRC32	Inhibit immunity (T cell function)	GARP encoded by the Lrrc32 gene is the cell surface docking receptor for latent TGFβ. We report that GARP exerts oncogenic effects, promoting immune tolerance by enriching and activating latent TGFβ in the tumor microenvironment. We found that human breast, lung, and colon cancers expressed GARP aberrantly.
27913437	Breast Carcinoma; Lung Carcinoma; Colon Carcinoma	TGFB1	Inhibit immunity (T cell function)	GARP encoded by the Lrrc32 gene is the cell surface docking receptor for latent TGFβ, which is expressed naturally by platelets and regulatory T cells (Treg). We report that GARP exerts oncogenic effects, promoting immune tolerance by enriching and activating latent TGFβ in the tumor microenvironment. In genetic studies in normal mammary gland epithelial and carcinoma cells, GARP expression increased TGFβ bioactivity and promoted malignant transformation in immunodeficient mice.
27913437	Breast Carcinoma	FOXP3	Inhibit immunity (T cell function)	In breast carcinoma-bearing mice that were immunocompetent, GARP overexpression promoted Foxp3+ Treg activity, which in turn contributed to enhancing cancer progression and metastasis.
27890932	Chronic lymphocytic leukemia	IGH	Inhibit immunity	Chronic lymphocytic leukemias (CLLs) with unmutated (U-CLL) or mutated (M-CLL) IGHV have variable features of immunosuppression, possibly influenced by those CLL cells activated to produce interleukin 10 (IL-10). We have now found that levels of IL-10 produced by activated CLL cells were highly variable. Levels were higher in M-CLL than in U-CLL.
27890932	Chronic lymphocytic leukemia	SYK	Inhibit immunity; immunotherapy target	A functional signal transducer and activator of transcription 3 (STAT3) binding site in CLL-VMR2 was confirmed by proximity ligation and luciferase assays, whereas inhibition of SYK-mediated STAT3 activation resulted in suppression of IL10. The observation that SYK inhibition also suppresses IL-10 provides a potential new rationale for therapeutic targeting and immunological rescue by SYK inhibitors in CLL.
27890932	Chronic lymphocytic leukemia	STAT3	Inhibit immunity	A functional signal transducer and activator of transcription 3 (STAT3) binding site in CLL-VMR2 was confirmed by proximity ligation and luciferase assays, whereas inhibition of SYK-mediated STAT3 activation resulted in suppression of IL10.
27879269	Melanoma	CCL3	Promote immunity (infiltration)	Intratumoral basophils enhanced CD8+ T-cell infiltration via production of chemokines CCL3 and CCL4; antibody-based blocking of these chemokines inhibited CD8+ T-cell infiltration.
27879269	Melanoma	CCL4	Promote immunity (infiltration)	Intratumoral basophils enhanced CD8+ T-cell infiltration via production of chemokines CCL3 and CCL4; antibody-based blocking of these chemokines inhibited CD8+ T-cell infiltration.
27879269	Melanoma	IL3	Promote immunity (infiltration)	Therapeutic induction of basophilia by IL3/anti-IL3 antibody complexes, combined with transfer of CD8+ T cells, resulted in enhanced T-cell infiltration and tumor rejection.
27879265	Breast Carcinoma	IL6	Inhibit immunity	IL6 is a pleiotropic cytokine with both pro- and anti-inflammatory properties, which acts directly on cancer cells to promote their survival and proliferation. How IL6 modulates the host immune response in cancer patients is unclear. Here, we show the IL6 signaling response in peripheral blood T cells is impaired in breast cancer patients and is associated with blunted Th17 differentiation. The mechanism identified involved downregulation of gp130 and IL6Rα in breast cancer patients and was independent of plasma IL6 levels.
27879258	Lymphoma; Lung Carcinoma; Neuroblastoma	ALK	Inhibit immunity	Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase physiologically expressed by fetal neural cells. However, aberrantly expressed ALK is involved in the pathogenesis of diverse malignancies, including distinct types of lymphoma, lung carcinoma, and neuroblastoma. NPM-ALK co-opts several intracellular signal transduction pathways, foremost being the STAT3 pathway, normally activated by cytokines from the interleukin-2 (IL-2) family to promote cell proliferation and to inhibit apoptosis. Many genes and proteins modulated by NPM-ALK are also involved in evasion of antitumor immune response. NPM-ALK uses epigenetic silencing mechanisms to downregulate tumor suppressor genes to maintain its own expression. NPM-ALK is capable of transforming primary human CD4+ T cells into immortalized cell lines indistinguishable from patient-derived ALK+ ALCL.
27879258	Lymphoma; Lung Carcinoma; Neuroblastoma	NPM1	Inhibit immunity	Many genes and proteins modulated by NPM-ALK are also involved in evasion of antitumor immune response. NPM-ALK uses epigenetic silencing mechanisms to downregulate tumor suppressor genes to maintain its own expression. NPM-ALK is capable of transforming primary human CD4+ T cells into immortalized cell lines indistinguishable from patient-derived ALK+ ALCL.
27875523	Non-Small Cell Lung Carcinoma; Gastric Carcinoma; Colorectal Carcinoma; Esophageal Squamous Cell Carcinoma	TOP1	Promote immunity	The production of autoantibodies against tumour-associated antigens (TAAs) is believed to reflect greater immunologic reactivity in cancer patients and enhanced immune surveillance for cancer cells. Here we describe a novel TAA that was a fragment derived from human DNA-topoiomerase I and an autoantibody against the novel TAA with relatively high positive frequency in the sera of early-stage non-small-cell lung cancer (NSCLC), gastric cancer (GC), colorectal cancer (CRC) and oesophageal squamous cell carcinoma (ESCC). We identified the novel TAA as a fragment derived from human DNA-topoiomerase I (TOP1). We observed that the immune response against the novel TAA was associated with early stage ESCC, GC, CRC and NSCLC.
27873300	Bladder Carcinoma	CTLA4	Immunotherapy target	Here, we investigated the efficacy of a local low-dose anti-CTLA-4 administration for treatment of subcutaneous or orthotopic murine bladder 49 (MB49) bladder carcinoma in C57BL/6 mice. In addition, p.t. anti-CTLA-4 therapy was potentiated by depletion of regulatory T cells. Our results demonstrate that local anti-CTLA-4 antibody therapy is equally effective as systemic administration, but reduces systemic antibody levels and cytokine release, and enhances the response to anti-PD1 therapy.
27872087	Renal Cell Carcinoma	HAVCR2	Inhibit immunity (T cell function)	Inhibitory receptors expressed by T cells mediate tolerance to tumor antigens, with coexpression of these receptors exacerbating this dysfunctional state. Using the VectraR automated multiparametric immunofluorescence technique, we quantified intratumoral CD8+ T cells coexpressing the inhibitory receptors PD-1 and Tim-3 from patients with renal cell carcinoma (RCC). The percentage of tumor-infiltrating CD8+ T cells coexpressing PD-1 and Tim-3 correlated with an aggressive phenotype and a larger tumor size at diagnosis.
27872087	Renal Cell Carcinoma	PDCD1	Inhibit immunity (T cell function)	Inhibitory receptors expressed by T cells mediate tolerance to tumor antigens, with coexpression of these receptors exacerbating this dysfunctional state. Using the VectraR automated multiparametric immunofluorescence technique, we quantified intratumoral CD8+ T cells coexpressing the inhibitory receptors PD-1 and Tim-3 from patients with renal cell carcinoma (RCC). The percentage of tumor-infiltrating CD8+ T cells coexpressing PD-1 and Tim-3 correlated with an aggressive phenotype and a larger tumor size at diagnosis.
27869649	Skin Squamous Cell Carcinoma	TSLP	Promote immunity	Actinic keratosis is a precursor to cutaneous squamous cell carcinoma. Thymic stromal lymphopoietin (TSLP) is an epithelium-derived cytokine that induces a robust antitumor immunity in barrier-defective skin. The mechanism of calcipotriol action against skin carcinogenesis was examined in genetically engineered mouse models. Calcipotriol suppressed skin cancer development in mice in a TSLP-dependent manner.
27863995	Melanoma	STAT3	Inhibit immunity	To effectively treat this aggressive tumor, a multi-target receptor tyrosine kinase inhibitor, sunitinib base, was efficiently encapsulated into a targeted polymeric micelle nano-delivery system (SUNb-PM), working in a synergistic manner with vaccine therapy in an advanced mouse melanoma model. Inhibition of the Stat3 and AKT signaling pathways by SUNb-PM may induce tumor cell apoptosis or decrease tumor immune evasion.
27863995	Melanoma	AKT1	Inhibit immunity	To effectively treat this aggressive tumor, a multi-target receptor tyrosine kinase inhibitor, sunitinib base, was efficiently encapsulated into a targeted polymeric micelle nano-delivery system (SUNb-PM), working in a synergistic manner with vaccine therapy in an advanced mouse melanoma model. Inhibition of the Stat3 and AKT signaling pathways by SUNb-PM may induce tumor cell apoptosis or decrease tumor immune evasion.
27863995	Melanoma	TXK	Inhibit immunity (infiltration)	To effectively treat this aggressive tumor, a multi-target receptor tyrosine kinase inhibitor, sunitinib base, was efficiently encapsulated into a targeted polymeric micelle nano-delivery system (SUNb-PM), working in a synergistic manner with vaccine therapy in an advanced mouse melanoma model. SUNb-PM not only increased cytotoxic T-cell infiltration and decreased the number and percentage of MDSCs and Tregs in the TME, but also induced a shift in cytokine expression from Th2 to Th1 type while remodeling the tumor-associated fibroblasts, collagen, and blood vessels in the tumor.
27863199	Malignant Mesothelioma; Pancreatic Adenocarcinoma; Ovarian Adenocarcinoma; Lung Adenocarcinoma	MSLN	Promote immunity	Mesothelin is a tumor antigen that is highly expressed in many human cancers, including malignant mesothelioma and pancreatic, ovarian, and lung adenocarcinomas. It is an attractive target for cancer immunotherapy because its normal expression is limited to mesothelial cells, which are dispensable.
27859048	Chronic Lymphocytic Leukemia	HLA-E	Inhibit immunity	HLA-E allelic genotype correlates with HLA-E plasma levels and predicts early progression in chronic lymphocytic leukemia. In vitro, sHLA-E inhibited degranulation and interferon-γ production by natural killer (NK) cells when cocultivated with tumor cells.
27853178	Hepatocellular Carcinoma	FASLG	Promote immunity	Environmental semimature dendritic cells, but not macrophages, can operate in a CD95L-dependent pathway to generate FcγRIIlow/- activated B cells.
27853178	Hepatocellular Carcinoma	IL10	Inhibit immunity (T cell function)	More importantly, the activated FcγRIIlow/- B cells from HCC tumours, but not the resting FcγRIIhigh B cells, without external stimulation suppress autologous tumour-specific cytotoxic T-cell immunity via IL-10 signals.
27851914	Colorectal Carcinoma; small cell lung cancinoma	IL1R2	Promote immunity (T cell function)	Transcriptomes of T helper 1 (Th1), Th17, and Treg cells infiltrating colorectal or non-small-cell lung cancers were compared to transcriptomes of the same subsets from normal tissues and validated at the single-cell level. We found that tumor-infiltrating Treg cells were highly suppressive, upregulated several immune-checkpoints, and expressed on the cell surfaces specific signature molecules such as interleukin-1 receptor 2 (IL1R2), programmed death (PD)-1 Ligand1, PD-1 Ligand2, and CCR8 chemokine, which were not previously described on Treg cells.
27851914	Colorectal Carcinoma; Small Cell Lung Cancinoma	CCR8	Inhibit immunity	Transcriptomes of T helper 1 (Th1), Th17, and Treg cells infiltrating colorectal or non-small-cell lung cancers were compared to transcriptomes of the same subsets from normal tissues and validated at the single-cell level. We found that tumor-infiltrating Treg cells were highly suppressive, upregulated several immune-checkpoints, and expressed on the cell surfaces specific signature molecules such as interleukin-1 receptor 2 (IL1R2), programmed death (PD)-1 Ligand1, PD-1 Ligand2, and CCR8 chemokine, which were not previously described on Treg cells.
27851914	Colorectal Carcinoma; Small Cell Lung Cancinoma	LAYN	Inhibit immunity (T cell function)	We found that tumor-infiltrating Treg cells were highly suppressive, upregulated several immune-checkpoints. Remarkably, high expression in whole-tumor samples of Treg cell signature genes, such as LAYN, MAGEH1, or CCR8, correlated with poor prognosis.
27851914	Colorectal Carcinoma; Small Cell Lung Cancinoma	MAGEH1	Inhibit immunity (T cell function)	We found that tumor-infiltrating Treg cells were highly suppressive, upregulated several immune-checkpoints. Remarkably, high expression in whole-tumor samples of Treg cell signature genes, such as LAYN, MAGEH1, or CCR8, correlated with poor prognosis.
27832300	Melanoma	IL9	Promote immunity (T cell function)	However, the links between IL-9 and cancer progression have been recently revisited following the discovery of TH9 cells. TH9 cells, which have been characterized in 2008 as a proinflammatory CD4 T cell subset that promotes protection against parasites and drives tissue inflammation in colitis, actually harbor potent IL-9-dependent anti-cancer properties in solid tumors and especially melanoma. While the molecular mechanisms underlying these observations are still being investigated, TH9 cells were demonstrated to activate both innate and adaptive immune responses, thereby favoring anti-cancer immunity and tumor elimination.
27829137	Colorectal Cancinoma; Pancreatic Ductal Adenocarcinoma	IL6	Inhibit immunity; resistant to immunotherapy	Here, we describe tumor-induced alterations of the host metabolic response to caloric deficiency that cause intratumoral immune suppression. In pre-cachectic mice with transplanted colorectal cancer or autochthonous pancreatic ductal adenocarcinoma (PDA), we find that IL-6 reduces the hepatic ketogenic potential through suppression of PPARalpha, the transcriptional master regulator of ketogenesis. Therefore, tumor-induced IL-6 impairs the ketogenic response to reduced caloric intake, resulting in a systemic metabolic stress response that blocks anti-cancer immunotherapy.
27821498	Head and Neck Squamous Cell Carcinoma	TMEM173	Promote immunity	Lack of induction of innate immunity through pattern-recognition receptors, such as the stimulator of interferon (IFN) genes (STING) receptor, may represent a significant barrier to the development of effective antitumor immunity. STING activation resulted in increased tumor microenvironment type 1 and type 2 IFN and greater expression of PD-1 pathway components in vivo.
27821498	Head and Neck Squamous Cell Carcinoma	PDCD1	Inhibit immunity; immunotherapy target	These findings suggest that PD-1 pathway blockade may reverse adaptive immune resistance following cyclic dinucleotide treatment, enhancing both local and systemic antitumor immunity.
27813511	Colorectal Cancinoma	CD274	Inhibit immunity; immunotherapy target	The CD274 (PD-L1)/PDCD1 (PD-1) pathway is crucial for the modulation of immune responses and self-tolerance. Aberrantly expressed CD274 allows tumor cells to evade host immune system and is considered to be a mechanism of adaptive immune resistance. Inhibition of the CD274/PDCD1 immune checkpoint offers a promising new therapeutic strategy. In this study, 454 primary colorectal carcinomas were analyzed histologically and immunohistochemically for CD274, mismatch repair (MMR) proteins, intestinal differentiation marker (CDX2), and stem cell markers (ALCAM, ALDH1A1, and SALL4). Thus, colorectal carcinomas defined by CD274 positivity displayed features associated with tumors arising via the serrated neoplasia pathway.
27813511	Colorectal Cancinoma	CDX2	Promote immunity	Aberrantly expressed CD274 allows tumor cells to evade host immune system and is considered to be a mechanism of adaptive immune resistance. Moreover, colorectal carcinomas characterized by lack of CDX2 and prominent expression of ALCAM frequently (71%) showed CD274 positivity. This might suggest association of CD274 expression with 'stem-like' phenotype.
27813511	Colorectal Cancinoma	ALCAM	Inhibit immunity	Moreover, colorectal carcinomas characterized by lack of CDX2 and prominent expression of ALCAM frequently (71%) showed CD274 positivity. This might suggest association of CD274 expression with 'stem-like' phenotype.
27680685	Breast cancinoma; Oral Squamous Cell Carcinoma	CCR2	Inhibit immunity (T cell function)	The CCL2 chemokine receptor CCR2 drives cancer by mediating the recruitment of monocytes and myeloid-derived suppressor cells to the tumor microenvironment. Following tumor initiation, an expanded population of CCR2+ Tregs required CCR2 expression to traffic between draining lymph nodes (dLN) and the tumor. Notably, in mouse models, low-dose cyclophosphamide treatment preferentially depleted CCR2+ Treg, enhancing priming of tumor-specific CD8+ T cells. In the MMTV-PyMT transgenic mouse model of breast cancer and in oral squamous cell carcinoma patients, tumor development was associated with decreased blood frequency and inversely increased tumor frequency of CCR2+ Tregs. Our results define a novel subset of CCR2+ Treg involved in tumoral immune escape.
27680683	Melanoma	TMEM173	Promote immunity (T cell function)	The innate immunoregulator STING stimulates cytokine production in response to the presence of cytosolic DNA, which can arise following DNA damage. Extrinsic STING signaling is also needed for antigen-presenting cells to stimulate antitumor T-cell immunity. Here, we show that STING signaling is recurrently suppressed in melanoma cells, where this event may enable immune escape after DNA damage. Mechanistically, STING signaling was suppressed most frequently by epigenetic silencing of either STING or the cyclic GMP-AMP synthase. Loss of STING function rendered melanoma cells unable to produce type I IFN and other immune cytokines after exposure to cytosolic DNA species.
27601131	Prostate Adenocarcinoma	SPP1	Promote immunity	Osteopontin has a protective role in prostate tumor development in mice. Osteopontin (OPN) is a protein, generally considered to play a pro-tumorigenic role, whereas several reports have demonstrated the anti-tumorigenic function of OPN during tumor development. Here, we report that host-derived OPN plays an anti-tumorigenic role in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model and a TRAMP tumor transplant model. Tumor suppression mediated by OPN in Rag2-/- mice suggests that OPN is dispensable in the adaptive immune response.
27807435	Melanoma; Squamous Cell Carcinoma; Colorectal cancinoma	CCR10	Promote immunity (NK cell function)	It is observed that drugs used to treat multiple sclerosis such as glatiramer acetate, dimethyl fumarate, and monomethyl fumarate upregulate the expression of chemokines receptor 10 (CCR10) on the surface of human IL-2-activated NK cells. It is also demonstrated that these three drugs enhance NK cell cytotoxicity against tumor target cells, an activity that is abrogated by prior incubation of the cells with anti-CCR10 antibody. Because CCL27 and CCL28 are secreted by selective tumor types such as malignant melanoma, squamous cell carcinomas, and colorectal cancer, respectively.
27803062	Acute Myeloid Leukemia	CALR	Promote immunity	In these patients, high levels of surface-exposed CRT correlated with an increased proportion of natural killer cells and effector memory CD4+ and CD8+ T cells in the periphery. Moreover, CRT exposure on the plasma membrane of malignant blasts positively correlated with the frequency of circulating T cells specific for leukemia-associated antigens, indicating that ecto-CRT favors the initiation of anticancer immunity in patients with AML.
27737879	Pancreatic Ductal Adenocarcinoma	CXCR2	Inhibit immunity (T cell function)	Evidence from various murine models has shown that the chemokine receptor CXCR2 attracts neutrophil into tumors and, therefore, represents a tractable therapeutic target. Host CXCR2 inhibition by genetic ablation prevented neutrophil accumulation in pancreatic tumors and led to a T cell-dependent suppression of tumor growth. In the absence of neutrophils, activated and functional T cells infiltrated pancreatic tumors otherwise devoid of effector T cells. Thus, the CXCR2-ligand axis helps establish an immunosuppressive microenvironment in PDA, highlighting the potential utility of targeting this axis as a novel therapy for this deadly disease.
27737879	Pancreatic Ductal Adenocarcinoma	CXCL5	Inhibit immunity (T cell function)	CXCL5 was the most prominently expressed CXCR2 ligand in human PDA, and its expression was higher in PDA than in any other common tumor represented in The Cancer Genome Atlas. Cxcl5 expression was associated with mutant Kras expression and regulated by NF-κB activation.
27688020	Prostate Carcinoma	CSF2	Promote immunity (infiltration); Promote immunity (T cell function) increase efficacy of immunotherapy	Granulocytic-macrophage colony-stimulating factor (GM-CSF) is used as an adjuvant in cancer vaccine trials and has the potential to enhance antitumor efficacy with immunotherapy. GM-CSF treatment increased the numbers of circulating mature myeloid dendritic cells, proliferating conventional CD4 T cells, proliferating CD8 T cells, and to a lesser magnitude FoxP3+ regulatory CD4 T cells. Although GM-CSF treatment did not augment antigen-presenting cell localization to the prostate, treatment was associated with recruitment of CD8+ T cells to the tumor. These results suggest that systemic GM-CSF can modulate T-cell infiltration in the tumor microenvironment.
27638840	Germ Cell Tumor	PDCD1	Inhibit immunity; immunotherapy target	Clinical Response of a Patient to Anti-PD-1 Immunotherapy and the Immune Landscape of Testicular Germ Cell Tumors. Anti-Programed Death 1 (PD-1) is standard immunotherapy for multiple cancers, and the expression of one of its ligands, PD-L1, has been described in germ cell tumors (GCT). Neither the clinical activity of anti-PD-1 nor the incidence of an immunoresponsive tumor microenvironment has been described for GCTs. These data suggest that GCTs can respond to anti-PD-1 and that gene expression profiling supports investigation of immunotherapy for treatment of GCTs.
27638840	Germ Cell Tumor	AFP	Inhibit immunity (infiltration)	Expression of alpha-fetoprotein (AFP) RNA correlated with lack of the T-cell signature, with increasing AFP RNA inversely correlating with the inflamed signature and expression of IFNγ-associated genes.
27634754	Melanoma	CCL22	Promote immunity (T cell function)	Ccl22 Diverts T Regulatory Cells and Controls the Growth of Melanoma. A 5-fold increase was documented in the Treg chemoattractants CCL22 and CCL1 in melanoma-affected skin versus unaffected skin, as accompanied by infiltrating FoxP3+ T cells. In assessing this hypothesis, we observed a marked increase in skin Treg in mice vaccinated with Ccl22, with repetitive vaccination sufficient to limit Treg accumulation and melanoma growth in the lungs of animals challenged by tumor cell injection. Overall, our findings offered a preclinical proof of concept for the potential use of CCL22 delivered by local injection as a strategy to enhance the efficacious response to immune checkpoint therapy while suppressing its autoimmune side effects.
27256566	Head and Neck Squamous Cell Carcinoma	LYN	Inhibit immunity	Next, we analyzed LYN expression by immunostaining and found that it was overexpressed in the human HNSCC specimens. Moreover, LYN expression in stromal cells positively correlated with myeloid-derived suppressor cells (MDSCs) makers CD11b and CD33 in human HNSCC. The dual positive expression of LYN in epithelial and stromal cells (EPI+ SRT+ ) was associated with unfavorable overall survival of HNSCC patients.
27797936	Pancreatic Ductal Adenocarcinoma	IL6	Inhibit immunity; decrease the efficacy of immunotherapy	Limited efficacy of immune checkpoint inhibitors in pancreatic ductal adenocarcinoma (PDAC) has prompted investigation into combination therapy. We hypothesised that interleukin 6 (IL-6) blockade would modulate immunological features of PDAC and enhance the efficacy of anti-programmed death-1-ligand 1 (PD-L1) checkpoint inhibitor therapy. These preclinical results indicate that targeted inhibition of IL-6 may enhance the efficacy of anti-PD-L1 in PDAC.
27797936	Pancreatic Ductal Adenocarcinoma	CD274	Immunotherapy target	These preclinical results indicate that targeted inhibition of IL-6 may enhance the efficacy of anti-PD-L1 in PDAC.
27756784	Neuroblastoma	TGFB1	Inhibit immunity (NK cell function)	The impact of galunisertib on TGFβ1-induced inhibition of aNK cytotoxicity and ADCC in vitro and on anti-neuroblastoma activity in NOD-scid gamma (NSG) mice was determined. Neuroblastomas express TGFB1 and TGFBR1 mRNA. Galunisertib suppressed SMAD activation in neuroblastoma cells induced by exogenous TGFβ1 or by patient blood and bone marrow plasma, and suppressed SMAD2 phosphorylation in human neuroblastoma cells growing in NSG mice.
27756784	Neuroblastoma	SMAD2	Promote immunity	Galunisertib suppressed SMAD activation in neuroblastoma cells induced by exogenous TGFβ1 or by patient blood and bone marrow plasma, and suppressed SMAD2 phosphorylation in human neuroblastoma cells growing in NSG mice. In NK cells treated in vitro with exogenous TGFβ1, galunisertib suppressed SMAD2 phosphorylation. Galunisertib suppresses activation of SMAD2 in neuroblastomas and aNK cells, restores NK cytotoxic mechanisms, and increases the efficacy of dinutuximab with aNK cells against neuroblastoma tumors.
27742794	Renal Cell Carcinoma	FCGR2A	Promote immunity	FCGR Polymorphisms Influence Response to IL2 in Metastatic Renal Cell Carcinoma. Fc-gamma receptors (FCGRs) are expressed on immune cells, bind to antibodies, and trigger antibody-induced cell-mediated antitumor responses when tumor-reactive antibodies are present. The affinity of the FCGR/antibody interaction is variable and dependent upon FCGR polymorphisms. When higher-affinity genotypes for FCGR2A, FCGR3A, and FCGR2C were considered together, they were associated with significantly increased tumor shrinkage and prolonged survival in response to HD-IL2.
27742794	Renal Cell Carcinoma	FCGR3A	Promote immunity	FCGR Polymorphisms Influence Response to IL2 in Metastatic Renal Cell Carcinoma. Fc-gamma receptors (FCGRs) are expressed on immune cells, bind to antibodies, and trigger antibody-induced cell-mediated antitumor responses when tumor-reactive antibodies are present. The affinity of the FCGR/antibody interaction is variable and dependent upon FCGR polymorphisms. When higher-affinity genotypes for FCGR2A, FCGR3A, and FCGR2C were considered together, they were associated with significantly increased tumor shrinkage and prolonged survival in response to HD-IL2.
27742794	Renal Cell Carcinoma	FCGR2C	Promote immunity	FCGR Polymorphisms Influence Response to IL2 in Metastatic Renal Cell Carcinoma. Fc-gamma receptors (FCGRs) are expressed on immune cells, bind to antibodies, and trigger antibody-induced cell-mediated antitumor responses when tumor-reactive antibodies are present. The affinity of the FCGR/antibody interaction is variable and dependent upon FCGR polymorphisms. When higher-affinity genotypes for FCGR2A, FCGR3A, and FCGR2C were considered together, they were associated with significantly increased tumor shrinkage and prolonged survival in response to HD-IL2.
27742794	Renal Cell Carcinoma	IL2	Promote immunity	FCGR Polymorphisms Influence Response to IL2 in Metastatic Renal Cell Carcinoma. We hypothesize that endogenous antitumor antibodies may engage immune cells through their FCGRs, and HD-IL2 may enhance antibody-induced tumor destruction, or antibody-enhanced tumor antigen presentation, via augmented activation of innate or adaptive immune responses.
27793879	Chronic Myeloid Leukemia	IFNG	Promote immunity	Interferon γ (IFN-γ) stimulation resulted in an upregulation of CIITA and MHC-II in CML stem/progenitor cells. Moreover, mixed lymphocyte reactions revealed that exposure of CD34+ CML cells to IFN-γ or RUX significantly enhanced proliferation of the responder CD4+CD69+ T cells.
27785783	Lung Carcinoma	B2M	Promote immunity	Tumor tissues obtained from 57 patients diagnosed with lung carcinomas were analyzed for HLA expression and leukocyte infiltration. The HLA-I negative phenotype was produced by a combination of HLA haplotype loss and a transcriptional downregulation of β2-microglobulin (β2-m) and LMP2 and LMP7 antigen presentation machinery genes.
27785783	Lung Carcinoma	PSMB9	Promote immunity	The absence of HLA class I expression in non-small cell lung cancer correlates with the tumor tissue structure and the pattern of T cell infiltration. Tumor tissues obtained from 57 patients diagnosed with lung carcinomas were analyzed for HLA expression and leukocyte infiltration. The HLA-I negative phenotype was produced by a combination of HLA haplotype loss and a transcriptional downregulation of β2-microglobulin (β2-m) and LMP2 and LMP7 antigen presentation machinery genes. In contrast, another pattern defined as non-immune-permissive TME was found in HLA-I negative tumors with strong stromal-matrix interaction, T-CD8+ cells surrounding tumor nests, a dense layer of FAP+ fibroblasts and M2/repair-type macrophages.
27785783	Lung Carcinoma	PSMB8	Promote immunity	The absence of HLA class I expression in non-small cell lung cancer correlates with the tumor tissue structure and the pattern of T cell infiltration. Tumor tissues obtained from 57 patients diagnosed with lung carcinomas were analyzed for HLA expression and leukocyte infiltration. The HLA-I negative phenotype was produced by a combination of HLA haplotype loss and a transcriptional downregulation of β2-microglobulin (β2-m) and LMP2 and LMP7 antigen presentation machinery genes. In contrast, another pattern defined as non-immune-permissive TME was found in HLA-I negative tumors with strong stromal-matrix interaction, T-CD8+ cells surrounding tumor nests, a dense layer of FAP+ fibroblasts and M2/repair-type macrophages.
27784674	Acute Lymphoblastic Leukemia	CD19	Promote immunity	Resistance to anti-CD19/CD3 BiTE in acute lymphoblastic leukemia may be mediated by disrupted CD19 membrane trafficking. The CD19 antigen is a promising target for immunotherapy of acute lymphoblastic leukemia (ALL), but CD19- relapses remain a major challenge in about 10% to 20% of patients.
27668655	Melanoma	CTLA4	Immunotherapy target	Here we show that somatic mutations in SERPINB3 and SERPINB4 are associated with survival after anti-CTLA4 immunotherapy in two independent cohorts of patients with melanoma.
27668655	Melanoma	SERPINB3	Promote immunity (T cell function); essential for immunotherapy	Here we show that somatic mutations in SERPINB3 and SERPINB4 are associated with survival after anti-CTLA4 immunotherapy in two independent cohorts of patients with melanoma. Interestingly, serpins are homologs of the well-known ovalbumin antigen and are associated with autoimmunity.
27668655	Melanoma	SERPINB4	Promote immunity (T cell function); essential for immunotherapy	Here we show that somatic mutations in SERPINB3 and SERPINB4 are associated with survival after anti-CTLA4 immunotherapy in two independent cohorts of patients with melanoma. Interestingly, serpins are homologs of the well-known ovalbumin antigen and are associated with autoimmunity.
24068730	Medulloblastoma	STAT3	Inhibit immunity	For example, myeloid derived suppressor cells (MDSCs) are thought to promote tumor growth by several mechanisms, including the suppression of T cell activity. It has been suggested that STAT3 activation in myeloid cells modulates multiple aspects of MDSC physiology, including their expansion and activity. In fully developed tumors, pSTAT3 was found in the majority of these cells. Conditional STAT3 gene disruption in myeloid cells resulted in an enhanced proinflammatory phenotype of macrophages in Smo* mice.
24068664	Bladder Carcinoma	EEF1A2	Essential for immunotherapy	In vitro studies were conducted to determine the interaction of BCG with high-grade bladder cancer cell line overexpressing sTn. sTn or s6T expression was associated with BCG response (P=0.024; P<0.0001) and with increased recurrence-free survival (P=0.001). Multivariate analyses showed that sTn and/or s6T were independent predictive markers of recurrence after BCG immunotherapy (HR=0.296; (0.148-0.594); P=0.001). Our data strongly suggest that BCG immunotherapy is efficient against sTn- and s6T-positive tumours.
24055012	Melanoma	CTLA4	Immunotherapy target	Two distinct approaches have emerged to try to extend survival in patients with metastatic melanoma: immunomodulation with anti-CTLA4 monoclonal antibodies, and targeted therapy with BRAF inhibitors or MEK inhibitors for BRAF-mutated melanoma.
24055012	Melanoma	CD274	Immunotherapy target	Anti-PD1 and anti-PDL1 antibodies have emerged as breakthrough drugs for melanoma that have high response rates and long durability.
24055012	Melanoma	PDCD1	Immunotherapy target	Anti-PD1 and anti-PDL1 antibodies have emerged as breakthrough drugs for melanoma that have high response rates and long durability.
24048332	Castration-Resistant Prostate Carcinoma	TWIST1	Immunotherapy target	Male C57BL/6 or TRAMP (transgenic adenocarcinoma of the mouse prostate) prostate cancer model mice were exposed to enzalutamide and/or a therapeutic vaccine targeting Twist, an antigen involved in epithelial-to-mesenchymal transition and metastasis. Twist was confirmed as a valid tumor antigen in TRAMP mice by immunohistochemistry. The combination of enzalutamide and Twist-vaccine resulted in significantly increased overall survival of TRAMP mice compared with other treatment groups (27.5 vs. 10.3 weeks).
24045666	Head and Neck Squamous Cell Carcinoma	EGFR	Inhibit immunity (T cell function); immunotherapy target	Epidermal growth factor receptor (EGFR)-targeted therapy is an attractive strategy alternative to conventional cancer treatments for HNSCC, but its efficacy remains controversial. The results provide support for a novel strategy to treat HNSCC by combining EGFR-targeted therapy with T-cell-based immunotherapy. Among several predicted peptide epitopes, EGFR875-889 elicited CD4 T-cell responses that were restricted by HLA-DR4, DR15, or DR53 molecules, indicating that the peptide functions as a promiscuous T-cell epitope. The peptide-reactive T cells responded to autologous dendritic cells loaded with EGFR-expressing tumour cell lysates, indicating that these epitopes are naturally processed.
24045666	Head and Neck Squamous Cell Carcinoma	HLA-DRB4	Inhibit immunity (T cell function)	Among several predicted peptide epitopes, EGFR875-889 elicited CD4 T-cell responses that were restricted by HLA-DR4, DR15, or DR53 molecules, indicating that the peptide functions as a promiscuous T-cell epitope.
24045181	Ovarian Cancinoma; Melanoma	TNFRSF9	Promote immunity (T cell function)	Upregulation of CD137 (4-1BB) on recently activated CD8(+) T cells has been used to identify rare viral or tumor antigen-specific T cells from peripheral blood. CD137(pos) TILs also mediated superior antitumor effects in vivo, compared with CD137(neg) TILs. An HLA-dependent increase in CD137 expression was observed following incubation of fresh enzyme-digested tumor or ascites in IL-7 and IL-15 cytokines, but not IL-2. Enriched CD137(pos) TILs, but not PD-1(pos) or PD-1(neg) CD137(neg) cells, possessed autologous tumor reactivity in vitro and in vivo.
24045181	Melanoma	SEPT4	Promote immunity (T cell function)	In melanoma studies, all MART-1-specific CD8(+) TILs upregulated CD137 expression after incubation with HLA-matched, MART-expressing cancer cells and antigen-specific effector function was restricted to the CD137(pos) subset in vitro.
24039573	Kaposi Sarcoma	ICAM1	Promote immunity (infiltration)	Further analysis also identified that KSHV miRNAs can modulate activity or expression of upstream regulatory factors, resulting in suppressed activation of a protein involved in leukocyte recruitment (ICAM1) following lysophosphatidic acid treatment, as well as up-regulation of a pro-angiogenic protein (HIF1α), and up-regulation of a protein involved in stimulating angiogenesis (HMOX1).
24037725	Follicular Lymphoma	TP53	Promote immunity	Abnormalities associated with transformation of the disease likely impair immune surveillance, activate the nuclear factor-κB pathway, and deregulate p53 and B-cell transcription factors.
24030977	Glioma	IL4R	Inhibit immunity (T cell function)	Interleukin-4 receptor-α (IL-4Rα) mediates the immunosuppressive functions of myeloid cells, and polymorphisms in the IL-4Rα gene are associated with altered glioma risk and prognosis. In both mouse de novo gliomas and human glioblastoma cases, IL-4Rα was upregulated on glioma-infiltrating myeloid cells but not in the periphery or in normal brain. Mice genetically deficient for IL-4Rα exhibited a slower growth of glioma associated with reduced production in the glioma microenvironment of arginase, a marker of myeloid suppressor cells, which is critical for their T-cell inhibitory function.
24030977	Glioma	IL13	Inhibit immunity (T cell function)	Mice genetically deficient for IL-4Rα exhibited a slower growth of glioma associated with reduced production in the glioma microenvironment of arginase, a marker of myeloid suppressor cells, which is critical for their T-cell inhibitory function. Supporting this result, investigations using bone marrow-derived myeloid cells showed that IL-4Rα mediates IL-13-induced production of arginase.
24030977	Glioma	CSF2	Inhibit immunity (T cell function)	Granulocyte macrophage colony-stimulating factor (GM-CSF) plays a central role for the induction of IL-4Rα expression on myeloid cells, and we found that GM-CSF is upregulated in both human and mouse glioma microenvironments compared with normal brain or peripheral blood samples. Together, our findings establish a GM-CSF-induced mechanism of immunosuppression in the glioma microenvironment via upregulation of IL-4Rα on MDSCs.
24030703	Hepatocellular Carcinoma	CD274	Inhibit immunity (T cell function)	Anti-B7-H1 (PD-L1) monoclonal antibodies (mAb) block a critical inhibitory pathway in T cells, whereas anti-CD137 and OX40 mAbs provide T-cell costimulation.
24030703	Hepatocellular Carcinoma	TNFRSF4	Inhibit immunity (T cell function)	Anti-B7-H1 (PD-L1) monoclonal antibodies (mAb) block a critical inhibitory pathway in T cells, whereas anti-CD137 and OX40 mAbs provide T-cell costimulation.
24030703	Hepatocellular Carcinoma	TNFRSF9	Inhibit immunity (T cell function)	Anti-B7-H1 (PD-L1) monoclonal antibodies (mAb) block a critical inhibitory pathway in T cells, whereas anti-CD137 and OX40 mAbs provide T-cell costimulation.
24030378	Acute Myeloid Leukemia	IL3RA	Promote immunity	The interleukin-3 receptor α chain (CD123) has been identified as a potential immunotherapeutic target because it is overexpressed in AML compared with normal hematopoietic stem cells. Additionally, T cells obtained from patients with active AML can be modified to express CD123 CARs and are able to lyse autologous AML blasts in vitro. Finally, CD123 CAR T cells exhibited antileukemic activity in vivo against a xenogeneic model of disseminated AML. These results suggest that CD123 CAR T cells are a promising immunotherapy for the treatment of high-risk AML.
24030378	Acute Myeloid Leukemia	CD28	Promote immunity	Therefore, we developed 2 chimeric antigen receptors (CARs) containing a CD123-specific single-chain variable fragment, in combination with a CD28 costimulatory domain and CD3-ζ signaling domain, targeting different epitopes on CD123.
24030378	Acute Myeloid Leukemia	CD28	Promote immunity	Therefore, we developed 2 chimeric antigen receptors (CARs) containing a CD123-specific single-chain variable fragment, in combination with a CD28 costimulatory domain and CD3-ζ signaling domain, targeting different epitopes on CD123.
24023259	B16 Malignant Melanoma	CTNNB1	Inhibit immunity (T cell function)	B16 melanoma-bearing mice, when vaccinated with DC-targeting anti-DEC-205 mAb fused with tumor antigens, exhibited dampened CD8? immunity, similar to DC-β-catenin(active) mice.
24018560	Prostate Carcinoma	KLRK1	Promote immunity (NK cell function); essential for immunotherapy	The activating receptor NK cell group 2 member D (NKG2D) mediates antitumor immunity in experimental animal models. Bi-Tg TRAMP/MICB mice exhibited a markedly increased incidence of progressed carcinomas and metastasis, whereas TRAMP/MICB.A2 mice enjoyed long-term tumor-free survival conferred by sustained NKG2D-mediated antitumor immunity. Our findings suggest that the impact of soluble NKG2D ligands should be considered in NK cell-based cancer immunotherapy
24016461	Acute Myeloid Leukemia; Plasma Cell Myeloma	CD28	Increase the efficacy of immunotherapy	Accordingly, T cells targeted to CD44v6 by means of a chimeric antigen receptor containing a CD28 signaling domain mediated potent antitumor effects against primary AML and MM while sparing normal hematopoietic stem cells and CD44v6-expressing keratinocytes. Importantly, in vitro activation with CD3/CD28 beads and interleukin (IL)-7/IL-15 was required for antitumor efficacy in vivo.
24016461	Acute Myeloid Leukemia; Plasma Cell Myeloma	IL7	Essential for immunotherapy	Accordingly, T cells targeted to CD44v6 by means of a chimeric antigen receptor containing a CD28 signaling domain mediated potent antitumor effects against primary AML and MM while sparing normal hematopoietic stem cells and CD44v6-expressing keratinocytes. Importantly, in vitro activation with CD3/CD28 beads and interleukin (IL)-7/IL-15 was required for antitumor efficacy in vivo.
24016461	Acute Myeloid Leukemia; Plasma Cell Myeloma	IL15	Essential for immunotherapy	Accordingly, T cells targeted to CD44v6 by means of a chimeric antigen receptor containing a CD28 signaling domain mediated potent antitumor effects against primary AML and MM while sparing normal hematopoietic stem cells and CD44v6-expressing keratinocytes. Importantly, in vitro activation with CD3/CD28 beads and interleukin (IL)-7/IL-15 was required for antitumor efficacy in vivo.
24013874	Malignant Central Nervous System Neoplasm	CD276	Inhibit immunity (infiltration)	B7-H3 (CD276), a newly identified member of the B7 family of molecules, is often induced in human tumors and its overexpression is closely correlated with survival, prognosis or tumor grade. Despite ample evidence implicating B7-H3 in tumor immune escape, a steady flow of reports have suggested that it may also have antitumor effects under certain circumstances. The safety and efficacy of targeting B7-H3 with a monoclonal antibody for the treatment of advanced-stage central nervous system cancer in children has been proven, making B7-H3 an attractive therapeutic target for this kind of tumor. In addition, B7-H3 was shown to promote invasion and accelerate carcinogenesis in tumor progression according to its nonimmunological regulatory roles.
24009233	Chronic Lymphocytic Leukemia	LCP1	Promote immunity	Lymphocyte cytosolic protein 1 is a chronic lymphocytic leukemia membrane-associated antigen critical to niche homing. Our analysis unveiled lymphocyte cytosolic protein 1 (LCP1), a lymphocyte-specific target that is highly expressed in CLL. LCP1 plays a critical role in B-cell biology by crosslinking F-actin filaments, thereby solidifying cytoskeletal structures and providing a scaffold for critical signaling pathways. Small interfering RNA knockdown of LCP1 blocked migration toward CXCL12 in transwell assays and to bone marrow in an in vivo xenotransplant model, confirming a role for LCP1 in leukemia migration. In addition, we identify LCP1 as a membrane-associated target in CLL with confirmed pathogenic significance.
24004885	Melanoma	DCT	Promote immunity (T cell function)	Multifunctional nanoparticles co-delivering Trp2 peptide and CpG adjuvant induce potent cytotoxic T-lymphocyte response against melanoma and its lung metastasis. Compared with free Trp2 peptide/CpG, vaccination with LCP encapsulating p-Trp2 and CpG resulted in superior inhibition of tumor growth in both B16F10 subcutaneous and lung metastasis models. An IFN-γ production assay and in vivo CTL response study revealed that the improved efficacy was a result of a Trp2-specific immune response.
24004819	Breast Carcinoma	PTGS2	Inhibit immunity (T cell function)	Systemic inhibition of the inflammatory enzyme cyclooxygenase (COX) 2 decreases the risk of breast cancer and its recurrence. COX-2(MEC)KO tumors contained more CD4+ T helper (Th) cells and CD8+ cytotoxic immune cells (CTL) consistent with increased immune surveillance.
24004819	Breast Carcinoma	CXCL9	Promote immunity (infiltration)	Enhanced immune surveillance in COX-2(MEC)KO tumors was coincident with increased intratumoral CXCL9, a T cell chemoattractant, and decreased expression of T lymphocyte co-inhibitory receptors CTLA4 and PD-1, as well as PD-L1, the ligand for PD-1.
24004819	Breast Carcinoma	CTLA4	Inhibit immunity (T cell function)	Enhanced immune surveillance in COX-2(MEC)KO tumors was coincident with increased intratumoral CXCL9, a T cell chemoattractant, and decreased expression of T lymphocyte co-inhibitory receptors CTLA4 and PD-1, as well as PD-L1, the ligand for PD-1.
24004819	Breast Carcinoma	PDCD1	Inhibit immunity (T cell function)	Enhanced immune surveillance in COX-2(MEC)KO tumors was coincident with increased intratumoral CXCL9, a T cell chemoattractant, and decreased expression of T lymphocyte co-inhibitory receptors CTLA4 and PD-1, as well as PD-L1, the ligand for PD-1.
24004819	Breast Carcinoma	CD274	Inhibit immunity (T cell function)	Enhanced immune surveillance in COX-2(MEC)KO tumors was coincident with increased intratumoral CXCL9, a T cell chemoattractant, and decreased expression of T lymphocyte co-inhibitory receptors CTLA4 and PD-1, as well as PD-L1, the ligand for PD-1.
24004819	Breast Carcinoma	IFNG	Promote immunity (T cell function)	PD-L1 was also decreased in IFNγ-treated COX-2KD mouse mammary cancer cells in vitro and, compared to control cells, growth of COX-2KD cells as orthotopic tumors in immune competent mice was markedly suppressed.
24004671	Plasma Cell Myeloma	FAS	Promote immunity (T cell function)	Further analyses revealed that adhesion to accessory cells downregulated Fas and upregulated the caspase-3 inhibitor survivin in multiple myeloma cells. Reconstitution of Fas expression with bortezomib enhanced the CTL-mediated lysis of multiple myeloma cells.
24004671	Plasma Cell Myeloma	BIRC5	Inhibit immunity	Thus showing the induction of a cell adhesion-mediated immune resistance (CAM-IR) against CTL lysis. Further analyses revealed that adhesion to accessory cells downregulated Fas and upregulated the caspase-3 inhibitor survivin in multiple myeloma cells. Repressing survivin with the small-molecule YM155 synergized with CTLs and abrogated CAM-IR in vitro and in vivo.
23995793	Skin Basal Cell Carcinoma	TLR7	Promote immunity (T cell function)	It is reported to be a TLR7 and TLR8 agonist and, as such, initiates a Th1 immune response by activating sentinel cells in the vicinity of the tumour.
23995793	Skin Basal Cell Carcinoma	TLR8	Promote immunity (T cell function)	It is reported to be a TLR7 and TLR8 agonist and, as such, initiates a Th1 immune response by activating sentinel cells in the vicinity of the tumour.
23986581	Kaposi Sarcoma	MZB1	Inhibit immunity	Plasma cell-induced-endoplasmic reticulum (ER)-resident protein 1 (pERP1) is a cellular chaperone that is preferentially expressed in marginal-zone B cells and is highly upregulated during plasma cell differentiation. While initially identified as a dedicated factor for the assembly of secreted IgM, pERP1 has since been implicated in suppressing calcium mobilization, and its expression is misregulated in multiple tumors.
23986400	Melanoma	IDO1	Inhibit immunity (infiltration)	In the current report, we show that it is the subset of T cell-inflamed tumors that showed high expression of three defined immunosuppressive mechanisms: indoleamine-2,3-dioxygenase (IDO), PD-L1/B7-H1, and FoxP3(+) regulatory T cells (T(regs)), suggesting that these inhibitory pathways might serve as negative feedback mechanisms that followed, rather than preceded, CD8(+) T cell infiltration.
23986400	Melanoma	CD274	Inhibit immunity (T cell function)	In the current report, we show that it is the subset of T cell-inflamed tumors that showed high expression of three defined immunosuppressive mechanisms: indoleamine-2,3-dioxygenase (IDO), PD-L1/B7-H1, and FoxP3(+) regulatory T cells (T(regs)), suggesting that these inhibitory pathways might serve as negative feedback mechanisms that followed, rather than preceded, CD8(+) T cell infiltration.
23986400	Melanoma	FOXP3	Inhibit immunity (infiltration)	In the current report, we show that it is the subset of T cell-inflamed tumors that showed high expression of three defined immunosuppressive mechanisms: indoleamine-2,3-dioxygenase (IDO), PD-L1/B7-H1, and FoxP3(+) regulatory T cells (T(regs)), suggesting that these inhibitory pathways might serve as negative feedback mechanisms that followed, rather than preceded, CD8(+) T cell infiltration.
23986400	Melanoma	IFNG	Inhibit immunity	Mechanistic studies in mice revealed that up-regulated expression of IDO and PD-L1, as well as recruitment of T(regs), in the tumor microenvironment depended on the presence of CD8(+) T cells. The former was driven by interferon-γ and the latter by a production of CCR4-binding chemokines along with a component of induced proliferation.
23986400	Melanoma	CCL2	Inhibit immunity	Mechanistic studies in mice revealed that up-regulated expression of IDO and PD-L1, as well as recruitment of T(regs), in the tumor microenvironment depended on the presence of CD8(+) T cells. The former was driven by interferon-γ and the latter by a production of CCR4-binding chemokines along with a component of induced proliferation.
23975756	Ovarian Cancinoma	PDCD1	Inhibit immunity (infiltration)	The tumor microenvironment mediates induction of the immunosuppressive programmed cell death-1 (PD-1) pathway, and targeted interventions against this pathway can help restore antitumor immunity. Exhaustion of tumor-infiltrating lymphocytes (TIL) correlated with expression of PD-1 ligands by tumor cells and tumor-derived myeloid cells, including tumor-associated macrophages (TAM), dendritic cells, and myeloid-derived suppressor cells (MDSC). Overall, PD-1/PD-L1 blockade enhanced the amplitude of tumor immunity by reprogramming suppressive and stimulatory signals that yielded more powerful cancer control.
23975756	Ovarian Cancinoma	CSF2	Promote immunity (T cell function)	When combined with GVAX or FVAX vaccination (consisting of irradiated ID8 cells expressing granulocyte macrophage colony-stimulating factor or FLT3 ligand) and costimulation by agonistic α-4-1BB or TLR 9 ligand, antibody-mediated blockade of PD-1 or PD-L1 triggered rejection of ID8 tumors in 75% of tumor-bearing mice. This therapeutic effect was associated with increased proliferation and function of tumor antigen-specific effector CD8(+) T cells, inhibition of suppressive regulatory T cells (Treg) and MDSC, upregulation of effector T-cell signaling molecules, and generation of T memory precursor cells.
23975756	Ovarian Cancinoma	FLT3	Promote immunity (T cell function)	When combined with GVAX or FVAX vaccination (consisting of irradiated ID8 cells expressing granulocyte macrophage colony-stimulating factor or FLT3 ligand) and costimulation by agonistic α-4-1BB or TLR 9 ligand, antibody-mediated blockade of PD-1 or PD-L1 triggered rejection of ID8 tumors in 75% of tumor-bearing mice. This therapeutic effect was associated with increased proliferation and function of tumor antigen-specific effector CD8(+) T cells, inhibition of suppressive regulatory T cells (Treg) and MDSC, upregulation of effector T-cell signaling molecules, and generation of T memory precursor cells.
23975756	Ovarian Cancinoma	TNFRSF9	Promote immunity (T cell function)	When combined with GVAX or FVAX vaccination (consisting of irradiated ID8 cells expressing granulocyte macrophage colony-stimulating factor or FLT3 ligand) and costimulation by agonistic α-4-1BB or TLR 9 ligand, antibody-mediated blockade of PD-1 or PD-L1 triggered rejection of ID8 tumors in 75% of tumor-bearing mice. This therapeutic effect was associated with increased proliferation and function of tumor antigen-specific effector CD8(+) T cells, inhibition of suppressive regulatory T cells (Treg) and MDSC, upregulation of effector T-cell signaling molecules, and generation of T memory precursor cells.
23975756	Ovarian Cancinoma	TLR9	Promote immunity (T cell function)	When combined with GVAX or FVAX vaccination (consisting of irradiated ID8 cells expressing granulocyte macrophage colony-stimulating factor or FLT3 ligand) and costimulation by agonistic α-4-1BB or TLR 9 ligand, antibody-mediated blockade of PD-1 or PD-L1 triggered rejection of ID8 tumors in 75% of tumor-bearing mice. This therapeutic effect was associated with increased proliferation and function of tumor antigen-specific effector CD8(+) T cells, inhibition of suppressive regulatory T cells (Treg) and MDSC, upregulation of effector T-cell signaling molecules, and generation of T memory precursor cells.
23975435	B16 Malignant Melanoma	TP53	Promote immunity	Interestingly, this tumor-promoting effect by p53-deficient MSCs was not observed in non-obese diabetic/severe combined immunodeficiency mice, indicating the immune response has a critical role. Indeed, in the presence of inflammatory cytokines, p53-deficient MSCs expressed more inducible nitric oxide synthase (iNOS) and exhibited greater immunosuppressive capacity. Importantly, tumor promotion by p53-deficient MSCs was abolished by administration of S-methylisothiourea, an iNOS inhibitor.
23975435	B16 Malignant Melanoma	NOS2	Inhibit immunity	Interestingly, this tumor-promoting effect by p53-deficient MSCs was not observed in non-obese diabetic/severe combined immunodeficiency mice, indicating the immune response has a critical role. Indeed, in the presence of inflammatory cytokines, p53-deficient MSCs expressed more inducible nitric oxide synthase (iNOS) and exhibited greater immunosuppressive capacity. Importantly, tumor promotion by p53-deficient MSCs was abolished by administration of S-methylisothiourea, an iNOS inhibitor.
23974006	Anaplastic Large Cell Lymphoma; Hodgkin Lymphoma	TNFRSF8	Inhibit immunity (T/NK cell function); immunotherapy target	Immunotherapy of CD30-expressing lymphoma using a highly stable ssDNA aptamer. CD30 is highly expressed on Hodgkins lymphoma and anaplastic large cell lymphoma, making it an attractive target for therapy. The multivalent aptamer was able to induce oligomerization of CD30 receptors and, in effect, activate downstream signaling, which led to apoptosis of ALCL cells.
23964122	B16 Malignant Melanoma	NT5E	Inhibit immunity	CD73 inhibits antitumor immunity through the activation of adenosine receptors expressed on multiple immune subsets. CD73 also enhances tumor metastasis, although the nature of the immune subsets and adenosine receptor subtypes involved in this process are largely unknown.
23964122	B16 Malignant Melanoma	ADORA2A	Inhibit immunity (NK cell function)	In this study, we revealed that A2A/A2B receptor antagonists were effective in reducing the metastasis of tumors expressing CD73 endogenously (4T1.2 breast tumors) and when CD73 was ectopically expressed (B16F10 melanoma). A2A(-/-) mice were strongly protected against tumor metastasis, indicating that host A2A receptors enhanced tumor metastasis. A2A blockade enhanced natural killer (NK) cell maturation and cytotoxic function in vitro, reduced metastasis in a perforin-dependent manner, and enhanced NK cell expression of granzyme B in vivo, strongly suggesting that the antimetastatic effect of A2A blockade was due to enhanced NK cell function.
23964122	B16 Malignant Melanoma	GZMB	Promote immunity	A2A blockade enhanced natural killer (NK) cell maturation and cytotoxic function in vitro, reduced metastasis in a perforin-dependent manner, and enhanced NK cell expression of granzyme B in vivo, strongly suggesting that the antimetastatic effect of A2A blockade was due to enhanced NK cell function.
23960231	Cervical Carcinoma	LTB4R	Promote immunity (infiltration)	Expression of leukotriene B? receptor-1 on CD8? T cells is required for their migration into tumors to elicit effective antitumor immunity. In this study, we investigated the role of BLT1 in antitumor immunity using syngeneic TC-1 cervical cancer model, and observed accelerated tumor growth and reduced survival in BLT1?/? mice compared with BLT1?/? mice. Gene expression profiling confirmed the dramatic decrease of IFN-γ, granzyme B, and IL-2 in tumors growing in BLT1?/? mice. Furthermore, depletion of CD8? T cells enhanced the tumor growth in BLT1?/? but not in BLT1?/? mice. These results suggest that BLT1 expression on CD8? T cells plays an important role in their trafficking to tumors.
23960017	Hepatocellular Carcinoma	IL10	Inhibit immunity (T cell function)	Human CD14+ CTLA-4+ regulatory dendritic cells suppress T-cell response by cytotoxic T-lymphocyte antigen-4-dependent IL-10 and indoleamine-2,3-dioxygenase production in hepatocellular carcinoma. CD14(+) DCs significantly suppress T-cell response in vitro through interleukin (IL)-10 and indoleamine-2,3-dioxygenase (IDO). Unexpectedly, CD14(+) DCs expressed high levels of cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death-1, and CTLA-4 was found to be essential to IL-10 and IDO production. So, we identified a novel human tumor-induced regulatory DC subset, which suppresses antitumor immune response through CTLA-4-dependent IL-10 and IDO production, thus indicating the important role of nonregulatory T-cell-derived CTLA-4 in tumor-immune escape or immunosuppression.
23960017	Hepatocellular Carcinoma	IDO1	Inhibit immunity (T cell function)	Human CD14+ CTLA-4+ regulatory dendritic cells suppress T-cell response by cytotoxic T-lymphocyte antigen-4-dependent IL-10 and indoleamine-2,3-dioxygenase production in hepatocellular carcinoma. CD14(+) DCs significantly suppress T-cell response in vitro through interleukin (IL)-10 and indoleamine-2,3-dioxygenase (IDO). Unexpectedly, CD14(+) DCs expressed high levels of cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death-1, and CTLA-4 was found to be essential to IL-10 and IDO production. So, we identified a novel human tumor-induced regulatory DC subset, which suppresses antitumor immune response through CTLA-4-dependent IL-10 and IDO production, thus indicating the important role of nonregulatory T-cell-derived CTLA-4 in tumor-immune escape or immunosuppression.
23960017	Hepatocellular Carcinoma	CTLA4	Inhibit immunity (T cell function)	Human CD14+ CTLA-4+ regulatory dendritic cells suppress T-cell response by cytotoxic T-lymphocyte antigen-4-dependent IL-10 and indoleamine-2,3-dioxygenase production in hepatocellular carcinoma. CD14(+) DCs significantly suppress T-cell response in vitro through interleukin (IL)-10 and indoleamine-2,3-dioxygenase (IDO). Unexpectedly, CD14(+) DCs expressed high levels of cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death-1, and CTLA-4 was found to be essential to IL-10 and IDO production. So, we identified a novel human tumor-induced regulatory DC subset, which suppresses antitumor immune response through CTLA-4-dependent IL-10 and IDO production, thus indicating the important role of nonregulatory T-cell-derived CTLA-4 in tumor-immune escape or immunosuppression.
23958949	Lymphoma	CD83	Promote immunity	First, DD modulated DCs toward tolerance by downregulating costimulatory receptors such as CD83 and CD25 while upregulating tolerance-associated proteins/pathways including Stat-3, β-catenin, and class II transactivator-dependent antigen presentation.
23958949	Lymphoma	STAT3	Inhibit immunity	First, DD modulated DCs toward tolerance by downregulating costimulatory receptors such as CD83 and CD25 while upregulating tolerance-associated proteins/pathways including Stat-3, β-catenin, and class II transactivator-dependent antigen presentation.
23958949	Lymphoma	CTNNB1	Inhibit immunity	First, DD modulated DCs toward tolerance by downregulating costimulatory receptors such as CD83 and CD25 while upregulating tolerance-associated proteins/pathways including Stat-3, β-catenin, and class II transactivator-dependent antigen presentation.
23958683	Sarcoma	STAT1	Promote immunity (T cell function)	Signal transducer and activator of transcription 1 (Stat1) mediates anti-viral responses and cytokine-driven anti-proliferative, apoptotic and immunomodulatory activities. Knockout of Stat1 enhanced the development of sarcomas induced by the chemical carcinogen 3-methylcholanthrene (MCA). Interestingly, restoration of Stat1 expression in Stat1?/? tumours resulted in diminished involvement of NK cells and increased contribution of CD8? T cells in anti-tumour responses.
23958683	Sarcoma	STAT1	Inhibit immunity (NK cell function)	Interestingly, restoration of Stat1 expression in Stat1?/? tumours resulted in diminished involvement of NK cells and increased contribution of CD8? T cells in anti-tumour responses.
23955389	Prostate Carcinoma	TGFB1	Inhibit immunity (T cell function)	Blockade of TGF-β signaling greatly enhances the efficacy of TCR gene therapy of cancer. Treatment of mice with advanced prostate cancer with T cells genetically engineered to express a tumor-reactive TCR and a dominant-negative TGF-β receptor II induces complete and sustained tumor regression, enhances survival, and leads to restored differentiation of prostate epithelium.
23939024	Glioblastoma	ERBB2	Inhibit immunity (T/NK cell function); immunotherapy target	This mathematical model demonstrated that cotargeting HER2 and IL-13Rα2 could maximally expand the therapeutic reach of the T cell product in all primary tumors studied. Further, T cells coexpressing HER2 and IL-13Rα2-CARs exhibited accentuated yet antigen-dependent downstream signaling and a particularly enhanced antitumor activity.
23939024	Glioblastoma	IL13RA2	Promote immunity	This mathematical model demonstrated that cotargeting HER2 and IL-13Rα2 could maximally expand the therapeutic reach of the T cell product in all primary tumors studied. Further, T cells coexpressing HER2 and IL-13Rα2-CARs exhibited accentuated yet antigen-dependent downstream signaling and a particularly enhanced antitumor activity.
23935194	Melanoma	MAPK8	Promote immunity	We also show that the AICD in TCReng CD4 T cells is a death receptor-independent process and that JNK and p53 play critical roles in this process as pharmacological inhibitors targeting JNK activation and p-53-mediated transcription-independent mitochondria-centric death cascade rescued a significant fraction of TCReng CD4 T cells from undergoing AICD without affecting their effector function.
23935194	Melanoma	TP53	Inhibit immunity (T cell function)	We also show that the AICD in TCReng CD4 T cells is a death receptor-independent process and that JNK and p53 play critical roles in this process as pharmacological inhibitors targeting JNK activation and p-53-mediated transcription-independent mitochondria-centric death cascade rescued a significant fraction of TCReng CD4 T cells from undergoing AICD without affecting their effector function.
23929302	Glioblastoma; Glioma	LGALS1	Inhibit immunity (T/NK cell function); immunotherapy target	We demonstrated that the absence of tumor-derived but not of host-derived galectin-1 significantly prolonged the survival of glioma-bearing mice as such and in combination with dendritic cell (DC)-based immunotherapy. Both flow cytometric and pathological analysis revealed that the silencing of glioma-derived galectin-1 significantly decreased the amount of brain-infiltrating macrophages and myeloid-derived suppressor cells (MDSC) in tumor-bearing mice. Furthermore, the prolonged survival observed in untreated and DC-vaccinated glioma-bearing mice upon the silencing of tumor-derived galectin-1 strongly suggest that the in vivo targeting of tumor-derived galectin-1 might offer a promising and realistic adjuvant treatment modality in patients diagnosed with GBM.
23925295	Breast Carcinoma; Melanoma	TGFBR3	Promote immunity	Using murine models of breast cancer and melanoma, we elucidated a tumor immunoevasion mechanism whereby loss of tumor-expressed TGFBR3/sTGFBR3 enhanced TGF-β signaling within locoregional DC populations and upregulated both the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) in plasmacytoid DCs and the CCL22 chemokine in myeloid DCs. Alterations in these DC populations mediated Treg infiltration and the suppression of antitumor immunity.
23925295	Breast Carcinoma; Melanoma	IDO1	Inhibit immunity	Using murine models of breast cancer and melanoma, we elucidated a tumor immunoevasion mechanism whereby loss of tumor-expressed TGFBR3/sTGFBR3 enhanced TGF-β signaling within locoregional DC populations and upregulated both the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) in plasmacytoid DCs and the CCL22 chemokine in myeloid DCs. Alterations in these DC populations mediated Treg infiltration and the suppression of antitumor immunity.
23925295	Breast Carcinoma; Melanoma	CCL22	Inhibit immunity	Using murine models of breast cancer and melanoma, we elucidated a tumor immunoevasion mechanism whereby loss of tumor-expressed TGFBR3/sTGFBR3 enhanced TGF-β signaling within locoregional DC populations and upregulated both the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) in plasmacytoid DCs and the CCL22 chemokine in myeloid DCs. Alterations in these DC populations mediated Treg infiltration and the suppression of antitumor immunity.
23922331	Melanoma; Colon Carcinoma	STIM1	Promote immunity	Patients with loss-of-function mutations in the CRAC channel genes ORAI1 or STIM1 are immunodeficient and are prone to develop virus-associated tumours. Using conditional knock out mice lacking STIM1 and its homologue STIM2, we find that SOCE in CD8(+) T cells is required to prevent the engraftment of melanoma and colon carcinoma cells and to control tumour growth.
23922331	Melanoma; Colon Carcinoma	ORAI1	Promote immunity	Patients with loss-of-function mutations in the CRAC channel genes ORAI1 or STIM1 are immunodeficient and are prone to develop virus-associated tumours. Using conditional knock out mice lacking STIM1 and its homologue STIM2, we find that SOCE in CD8(+) T cells is required to prevent the engraftment of melanoma and colon carcinoma cells and to control tumour growth.
23913973	Uveal melanoma	CTLA4	Inhibit immunity (T cell function)	The anticytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) antibody ipilimumab is a standard of care for metastatic melanoma; however, the clinical activity of CTLA-4 inhibition in patients with metastatic uveal melanoma is poorly defined.
23904461	Melanoma	CD40LG	Promote immunity (T cell function); essential for immunotherapy	Autologous monocyte-derived dendritic cells (DCs) electroporated with synthetic messenger RNA (mRNA) encoding a CD40 ligand, a constitutively active Toll-like receptor 4 and CD70, together with mRNA encoding fusion proteins of a human leukocyte antigen (HLA)-class II targeting signal (DC-LAMP) and a melanoma-associated antigen (MAA); either MAGE-A3, MAGE-C2, tyrosinase or gp100) (TriMixDC-MEL) are superiorly immunogenic.
23904461	Melanoma	TLR4	Promote immunity (T cell function); essential for immunotherapy	Autologous monocyte-derived dendritic cells (DCs) electroporated with synthetic messenger RNA (mRNA) encoding a CD40 ligand, a constitutively active Toll-like receptor 4 and CD70, together with mRNA encoding fusion proteins of a human leukocyte antigen (HLA)-class II targeting signal (DC-LAMP) and a melanoma-associated antigen (MAA); either MAGE-A3, MAGE-C2, tyrosinase or gp100) (TriMixDC-MEL) are superiorly immunogenic.
23904461	Melanoma	CD70	Promote immunity (T cell function); essential for immunotherapy	Autologous monocyte-derived dendritic cells (DCs) electroporated with synthetic messenger RNA (mRNA) encoding a CD40 ligand, a constitutively active Toll-like receptor 4 and CD70, together with mRNA encoding fusion proteins of a human leukocyte antigen (HLA)-class II targeting signal (DC-LAMP) and a melanoma-associated antigen (MAA); either MAGE-A3, MAGE-C2, tyrosinase or gp100) (TriMixDC-MEL) are superiorly immunogenic.
23904461	Melanoma	MAGEC2	Promote immunity (T cell function); essential for immunotherapy	Autologous monocyte-derived dendritic cells (DCs) electroporated with synthetic messenger RNA (mRNA) encoding a CD40 ligand, a constitutively active Toll-like receptor 4 and CD70, together with mRNA encoding fusion proteins of a human leukocyte antigen (HLA)-class II targeting signal (DC-LAMP) and a melanoma-associated antigen (MAA); either MAGE-A3, MAGE-C2, tyrosinase or gp100) (TriMixDC-MEL) are superiorly immunogenic.
23904461	Melanoma	MAGEA3	Promote immunity (T cell function); essential for immunotherapy	Autologous monocyte-derived dendritic cells (DCs) electroporated with synthetic messenger RNA (mRNA) encoding a CD40 ligand, a constitutively active Toll-like receptor 4 and CD70, together with mRNA encoding fusion proteins of a human leukocyte antigen (HLA)-class II targeting signal (DC-LAMP) and a melanoma-associated antigen (MAA); either MAGE-A3, MAGE-C2, tyrosinase or gp100) (TriMixDC-MEL) are superiorly immunogenic.
23904461	Melanoma	TYR	Promote immunity (T cell function); essential for immunotherapy	Autologous monocyte-derived dendritic cells (DCs) electroporated with synthetic messenger RNA (mRNA) encoding a CD40 ligand, a constitutively active Toll-like receptor 4 and CD70, together with mRNA encoding fusion proteins of a human leukocyte antigen (HLA)-class II targeting signal (DC-LAMP) and a melanoma-associated antigen (MAA); either MAGE-A3, MAGE-C2, tyrosinase or gp100) (TriMixDC-MEL) are superiorly immunogenic.
23904461	Melanoma	PMEL	Promote immunity (T cell function); essential for immunotherapy	Autologous monocyte-derived dendritic cells (DCs) electroporated with synthetic messenger RNA (mRNA) encoding a CD40 ligand, a constitutively active Toll-like receptor 4 and CD70, together with mRNA encoding fusion proteins of a human leukocyte antigen (HLA)-class II targeting signal (DC-LAMP) and a melanoma-associated antigen (MAA); either MAGE-A3, MAGE-C2, tyrosinase or gp100) (TriMixDC-MEL) are superiorly immunogenic.
23904171	Melanoma	TGFB1	Inhibit immunity (T cell function)	Blockage of endogenous TGF-β with either a TGF-β-blocking Ab or a small molecule inhibitor of TGF-βRI enhances the generation of CD62L(high)/CD44(high) central memory CD8(+) T cells accompanied with a robust recall response.
23897981	Melanoma	CTLA4	Inhibit immunity (T cell function)	Although subject to debate, current models favor a mechanism of activity involving blockade of the inhibitory activity of CTLA-4 on both effector (T eff) and regulatory (T reg) T cells, resulting in enhanced antitumor effector T cell activity capable of inducing tumor regression.
23891972	Pancreatic Ductal Adenocarcinoma	CXCL12	Promote immunity (T cell function)	In vitro migration assays showed that CD8(+) T cells, from patients with PDAC, had increased chemotaxis toward activated PSCs, which secrete CXCL12, compared with quiescent PSCs or tumor cells. These effects could be reversed by knockdown of CXCL12 or treatment of PSCs with ATRA.
23873689	Ovarian Cancinoma	IL18	Promote immunity (T cell function)	Interleukin (IL)-18 is an immune-enhancing cytokine, which induces IFN-γ production, T-helper 1 responses, and antitumor effects. Analysis of gene expression profiles revealed that IL18BP mRNA is increased in EOC tumors compared with normal ovary cells.
23873689	Ovarian Cancinoma	IL18BP	Inhibit immunity	In turn, IFN-γ stimulates IL-18-binding protein production, which blocks IL-18 activity. Together, these data indicate that IL-18BP, which is produced in EOC in response to microenvironmental factors, may inhibit endogenous or exogenous IL-18 activity.
23873689	Ovarian Cancinoma	IL27	Promote immunity	In vitro experiments and immunochemistry indicated that IL-27 is also involved in IL-18BP upregulation in EOC cell lines and primary cells through STAT1 activation.
23873689	Ovarian Cancinoma	STAT1	Inhibit immunity	In vitro experiments and immunochemistry indicated that IL-27 is also involved in IL-18BP upregulation in EOC cell lines and primary cells through STAT1 activation.
23873689	Ovarian Cancinoma	IFNG	Inhibit immunity	In turn, IFN-γ stimulates IL-18-binding protein production, which blocks IL-18 activity. However, its release is inducible both by IFN-γ stimulation in vitro and by xenotransplantation of EOC cells in immune-deficient mice, suggesting a role for the microenvironment.
23871358	Acute Myeloid Leukemia	IL2	Promote immunity	We envisage future treatment protocols, in which systemic immune activators, such as vaccines, dendritic cell-based therapies, engineered variants of IL-2, or IL-15, are combined with agents that counter immunosuppression mediated by, e.g., the PD/PDL interaction, CTLA-4, CD200, reactive oxygen species, IDO expression, CXCR4, or the KIR/class I interaction, based on characteristics of the prevailing malignant clone.
23871358	Acute Myeloid Leukemia	IL15	Promote immunity	We envisage future treatment protocols, in which systemic immune activators, such as vaccines, dendritic cell-based therapies, engineered variants of IL-2, or IL-15, are combined with agents that counter immunosuppression mediated by, e.g., the PD/PDL interaction, CTLA-4, CD200, reactive oxygen species, IDO expression, CXCR4, or the KIR/class I interaction, based on characteristics of the prevailing malignant clone.
23871358	Acute Myeloid Leukemia	CTLA4	Inhibit immunity	We envisage future treatment protocols, in which systemic immune activators, such as vaccines, dendritic cell-based therapies, engineered variants of IL-2, or IL-15, are combined with agents that counter immunosuppression mediated by, e.g., the PD/PDL interaction, CTLA-4, CD200, reactive oxygen species, IDO expression, CXCR4, or the KIR/class I interaction, based on characteristics of the prevailing malignant clone.
23871358	Acute Myeloid Leukemia	CD200	Inhibit immunity	We envisage future treatment protocols, in which systemic immune activators, such as vaccines, dendritic cell-based therapies, engineered variants of IL-2, or IL-15, are combined with agents that counter immunosuppression mediated by, e.g., the PD/PDL interaction, CTLA-4, CD200, reactive oxygen species, IDO expression, CXCR4, or the KIR/class I interaction, based on characteristics of the prevailing malignant clone.
23871358	Acute Myeloid Leukemia	IDO1	Inhibit immunity	We envisage future treatment protocols, in which systemic immune activators, such as vaccines, dendritic cell-based therapies, engineered variants of IL-2, or IL-15, are combined with agents that counter immunosuppression mediated by, e.g., the PD/PDL interaction, CTLA-4, CD200, reactive oxygen species, IDO expression, CXCR4, or the KIR/class I interaction, based on characteristics of the prevailing malignant clone.
23871358	Acute Myeloid Leukemia	CXCR4	Inhibit immunity	We envisage future treatment protocols, in which systemic immune activators, such as vaccines, dendritic cell-based therapies, engineered variants of IL-2, or IL-15, are combined with agents that counter immunosuppression mediated by, e.g., the PD/PDL interaction, CTLA-4, CD200, reactive oxygen species, IDO expression, CXCR4, or the KIR/class I interaction, based on characteristics of the prevailing malignant clone.
23871358	Acute Myeloid Leukemia	KIR3DL1	Inhibit immunity	We envisage future treatment protocols, in which systemic immune activators, such as vaccines, dendritic cell-based therapies, engineered variants of IL-2, or IL-15, are combined with agents that counter immunosuppression mediated by, e.g., the PD/PDL interaction, CTLA-4, CD200, reactive oxygen species, IDO expression, CXCR4, or the KIR/class I interaction, based on characteristics of the prevailing malignant clone.
23870385	Melanoma	CTLA4	Inhibit immunity (T cell function)	The first major advance was the development of selective mitogen-activated protein (MAP) kinase inhibitors (BRAF and MEK inhibitors) and immune checkpoint blockade with a CTLA4 antibody (ipilimumab).
23870385	Melanoma	PDCD1	Inhibit immunity (T cell function)	The second major advance is the development of other immune checkpoint blocking agents, including PD-1 and PD-L1 antibodies, and the use of BRAF and MEK inhibitors in combination, with a higher proportion of durable responses coupled with less toxicity
23870385	Melanoma	CD274	Inhibit immunity (T cell function)	The second major advance is the development of other immune checkpoint blocking agents, including PD-1 and PD-L1 antibodies, and the use of BRAF and MEK inhibitors in combination, with a higher proportion of durable responses coupled with less toxicity
23861541	Nasopharyngeal Carcinoma	CEBPD	Inhibit immunity	We showed that immunosuppressive prostaglandin E? (PGE?) led to the production and activity of the transcription factor CCAAT/enhancer binding protein δ (C/EBPδ) by stimulating the nucleocytoplasmic shuttling of the RNA binding protein Hu antigen R (HuR), which bound to and stabilized CEBPD mRNA in macrophages. An increase in C/EBPδ abundance in macrophages in response to PGE? resulted in enhanced production of the immunosuppressive cytokine interleukin-10 (IL-10) and of pentraxin 3 (PTX3), which suppresses the ability of macrophages to phagocytose tumor cells.
23861541	Nasopharyngeal Carcinoma	ELAVL1	Inhibit immunity	We showed that immunosuppressive prostaglandin E? (PGE?) led to the production and activity of the transcription factor CCAAT/enhancer binding protein δ (C/EBPδ) by stimulating the nucleocytoplasmic shuttling of the RNA binding protein Hu antigen R (HuR), which bound to and stabilized CEBPD mRNA in macrophages. Immunohistochemical analysis demonstrated that the amount of cytosolic HuR protein correlated with increased C/EBPδ abundance in TAMs in malignant nasopharyngeal carcinoma.
23861541	Nasopharyngeal Carcinoma	IL10	Inhibit immunity	An increase in C/EBPδ abundance in macrophages in response to PGE? resulted in enhanced production of the immunosuppressive cytokine interleukin-10 (IL-10) and of pentraxin 3 (PTX3), which suppresses the ability of macrophages to phagocytose tumor cells.
23861541	Nasopharyngeal Carcinoma	PTX3	Inhibit immunity	An increase in C/EBPδ abundance in macrophages in response to PGE? resulted in enhanced production of the immunosuppressive cytokine interleukin-10 (IL-10) and of pentraxin 3 (PTX3), which suppresses the ability of macrophages to phagocytose tumor cells.
23860186	B16 Malignant Melanoma	CD1D	Promote immunity (NK cell function)	Alpha-galactosylceramide (αGC), a lipid antigen present on CD1d molecules, is predicted to have clinical applications as a new class of adjuvant, because αGC strongly activates natural killer T (NKT) cells which produce large amounts of IFN-γ.
23851682	Lung Adenocarcinoma; Non-Small Cell Lung Carcinoma	IL2RA	Inhibit immunity (infiltration)	Because mice bearing early NSCLC treated with anti-CD25 mAb exhibited increased tumor cell death associated with infiltration by CD8(+) T cells expressing elevated levels of granzyme A, granzyme B, perforin, and IFN-γ, we therefore evaluated carboplatin combination therapy resulting in a significantly extended survival beyond that observed with chemotherapy alone, indicating that Treg depletion in combination with cytotoxic therapy may be beneficial as a treatment strategy for advanced NSCLC.
23851682	Lung Adenocarcinoma; Non-Small Cell Lung Carcinoma	GZMA	Promote immunity (infiltration)	Because mice bearing early NSCLC treated with anti-CD25 mAb exhibited increased tumor cell death associated with infiltration by CD8(+) T cells expressing elevated levels of granzyme A, granzyme B, perforin, and IFN-γ, we therefore evaluated carboplatin combination therapy resulting in a significantly extended survival beyond that observed with chemotherapy alone, indicating that Treg depletion in combination with cytotoxic therapy may be beneficial as a treatment strategy for advanced NSCLC.
23851682	Lung Adenocarcinoma; Non-Small Cell Lung Carcinoma	GZMB	Promote immunity (infiltration)	Because mice bearing early NSCLC treated with anti-CD25 mAb exhibited increased tumor cell death associated with infiltration by CD8(+) T cells expressing elevated levels of granzyme A, granzyme B, perforin, and IFN-γ, we therefore evaluated carboplatin combination therapy resulting in a significantly extended survival beyond that observed with chemotherapy alone, indicating that Treg depletion in combination with cytotoxic therapy may be beneficial as a treatment strategy for advanced NSCLC.
23851682	Lung Adenocarcinoma; Non-Small Cell Lung Carcinoma	IFNG	Promote immunity (infiltration)	Because mice bearing early NSCLC treated with anti-CD25 mAb exhibited increased tumor cell death associated with infiltration by CD8(+) T cells expressing elevated levels of granzyme A, granzyme B, perforin, and IFN-γ, we therefore evaluated carboplatin combination therapy resulting in a significantly extended survival beyond that observed with chemotherapy alone, indicating that Treg depletion in combination with cytotoxic therapy may be beneficial as a treatment strategy for advanced NSCLC.
23851682	Lung Adenocarcinoma; Non-Small Cell Lung Carcinoma	PRF1	Promote immunity (infiltration)	Because mice bearing early NSCLC treated with anti-CD25 mAb exhibited increased tumor cell death associated with infiltration by CD8(+) T cells expressing elevated levels of granzyme A, granzyme B, perforin, and IFN-γ, we therefore evaluated carboplatin combination therapy resulting in a significantly extended survival beyond that observed with chemotherapy alone, indicating that Treg depletion in combination with cytotoxic therapy may be beneficial as a treatment strategy for advanced NSCLC.
23843024	Breast Carcinoma	IFNG	Promote immunity (infiltration)	Using MMTV-neu mice as an animal model for HER2-positive breast cancer, we observed enhanced tumor infiltration by IFN-γ-secreting T cells after treatment with doxorubicin and/or lapatinib. Antibody depletion experiments revealed a contribution of CD8? but not CD4? T cells to the antitumor effect of these drugs.
23843024	Breast Carcinoma	STAT1	Promote immunity (T cell function); essential for immunotherapy	In contrast, Stat1-deficient mice were resistant to tumor growth inhibition by lapatinib and/or doxorubicin and exhibited impaired T-cell activation and reduced T-cell infiltration of the tumor in response to drug treatment. Furthermore, Stat1-deficiency resulted in reduced expression of the T-cell chemotactic factors CXCL9, CXCL10, and CXCL11 in the tumor epithelium. Taken together, the results point to an important contribution toward enhancing T-cell and IFN-γ-based immunity by lapatinib as well as doxorubicin and emphasize the role of Stat1 in building an effective antitumor immune response.
23843024	Breast Carcinoma	CXCL9	Promote immunity (infiltration)	Furthermore, Stat1-deficiency resulted in reduced expression of the T-cell chemotactic factors CXCL9, CXCL10, and CXCL11 in the tumor epithelium.
23843024	Breast Carcinoma	CXCL10	Promote immunity (infiltration)	Furthermore, Stat1-deficiency resulted in reduced expression of the T-cell chemotactic factors CXCL9, CXCL10, and CXCL11 in the tumor epithelium.
23843024	Breast Carcinoma	CXCL11	Promote immunity (T cell function)	Furthermore, Stat1-deficiency resulted in reduced expression of the T-cell chemotactic factors CXCL9, CXCL10, and CXCL11 in the tumor epithelium.
21540550	Lymphoma	CD28	Promote immunity (T cell function)	CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. CAR+ T cells containing the CD28 endodomain showed strikingly enhanced expansion and persistence compared with CAR+ T cells lacking this endodomain.
21540460	Chronic Lymphocytic Leukemia	BCR	Promote immunity (T cell function)	Donor-derived mature dendritic cells generated in vitro from CD14(+) monocytes were loaded with human leukocyte Ag-restricted peptides derived from PR1, WT1, and/or B-cell receptor-ABL and used to repetitively stimulate donor CD8(+) T cells in the presence of IL-2 and IL-7.
21540460	Chronic Lymphocytic Leukemia	PRH1	Promote immunity (T cell function)	Donor-derived mature dendritic cells generated in vitro from CD14(+) monocytes were loaded with human leukocyte Ag-restricted peptides derived from PR1, WT1, and/or B-cell receptor-ABL and used to repetitively stimulate donor CD8(+) T cells in the presence of IL-2 and IL-7.
21540460	Chronic Lymphocytic Leukemia	WT1	Promote immunity (T cell function)	Donor-derived mature dendritic cells generated in vitro from CD14(+) monocytes were loaded with human leukocyte Ag-restricted peptides derived from PR1, WT1, and/or B-cell receptor-ABL and used to repetitively stimulate donor CD8(+) T cells in the presence of IL-2 and IL-7.
21540460	Chronic Lymphocytic Leukemia	IL2	Promote immunity (T cell function)	Donor-derived mature dendritic cells generated in vitro from CD14(+) monocytes were loaded with human leukocyte Ag-restricted peptides derived from PR1, WT1, and/or B-cell receptor-ABL and used to repetitively stimulate donor CD8(+) T cells in the presence of IL-2 and IL-7.
21540460	Chronic Lymphocytic Leukemia	IL7	Promote immunity (T cell function)	Donor-derived mature dendritic cells generated in vitro from CD14(+) monocytes were loaded with human leukocyte Ag-restricted peptides derived from PR1, WT1, and/or B-cell receptor-ABL and used to repetitively stimulate donor CD8(+) T cells in the presence of IL-2 and IL-7.
21540305	Pleural Malignant Mesothelioma	MUC1	Inhibit immunity (T/NK cell function); immunotherapy target	Mucin (MUC)1, which is expressed and recognised by cytotoxic T-cells in numerous cancer types, has not been investigated as a potential immune target in MPM. Thus, MUC1 expression and antigen presentation by MPM cells may represent an attractive target for immunotherapeutic treatment of MPM despite its hyperglycosylated profile.
21540239	B-Cell Non-Hodgkin Lymphoma	CD274	Inhibit immunity (T cell function)	Programmed death ligand 1 is expressed by non-hodgkin lymphomas and inhibits the activity of tumor-associated T cells. In autologous cultures of primary ALCL and DLBCL, PD-L1 blockade enhanced secretion of inflammatory cytokines IFN-γ, granulocyte macrophage colony-stimulating factor, interleukin (IL)-1, IL-6, IL-8, IL-13, TNF-α, and macrophage inflammatory protein-1α. In establishing cell lines from an aggressive PD-L1(+) mature B-cell lymphoma, we also noted that PD-L1 expression could be lost under certain in vitro culture conditions.
21540239	B-Cell Non-Hodgkin Lymphoma	IFNG	Promote immunity (T cell function)	T-cell proliferation and IFN-γ secretion served as measures of T-cell activation.
21540234	Renal Cell Carcinoma	MTOR	Inhibit immunity (T cell function); resistant to immunotherapy	mTOR kinase inhibitor AZD8055 enhances the immunotherapeutic activity of an agonist CD40 antibody in cancer treatment. On this basis, we had explored the hypothesis that mTOR inhibition can enhance cancer immunotherapy. Here, we report that a combination of αCD40 agonistic antibody and the ATP-competitive mTOR kinase inhibitory drug AZD8055 elicited synergistic antitumor responses in a model of metastatic renal cell carcinoma. Levels of Th1 cytokines, including interleukin 12, IFN-γ, TNFα, and the Th1-associated chemokines RANTES, MIG, and IP-10 were each elevated significantly in the livers of mice treated with the combinatorial therapy versus individual treatments.
21540234	Renal Cell Carcinoma	IFNG	Promote immunity (T cell function); essential for immunotherapy	Notably, the AZD8055/αCD40-induced antitumor response was abolished in IFN-γ(-/-) and CD40(-/-) mice, establishing the reliance of the combination therapy on host IFN-γ and CD40 expression.
21540234	Renal Cell Carcinoma	CD40	Promote immunity (T cell function); essential for immunotherapy	Notably, the AZD8055/αCD40-induced antitumor response was abolished in IFN-γ(-/-) and CD40(-/-) mice, establishing the reliance of the combination therapy on host IFN-γ and CD40 expression.
21540234	Renal Cell Carcinoma	TNF	Promote immunity	We found that the combination treatment also increased macrophage production of TNFα, which played an indispensable role in activation of the observed antitumor immune response.
21536144	Plasma Cell Myeloma	CD274	Inhibit immunity (T cell function)	Immunosuppressive effects of multiple myeloma are overcome by PD-L1 blockade. These data demonstrate a role for PD-L1 in suppressing immune responses to myeloma and suggest that blockade of this pathway may enhance immunotherapy for this disease.
21531812	Non-Small Cell Lung Carcinoma; Neuroblastma	IL2	Promote immunity	The goal of the study was to engineer a form of interleukin 2 (IL-2) that, when delivered as a tumor-specific antibody fusion protein, retains the ability to stimulate an antitumor immune response via interaction with the high-affinity IL-2 receptor but has lower toxicity because of the reduced activation of the intermediate-affinity IL-2 receptor.
21527935	Acute Lymphoblastic Leukemia	IL4	Promote immunity (T cell function)	The combination of CpG, IL-4 and CD40L was identified as most effective to enhance expression of immunogenic molecules on BCP-ALL cells, resulting in an increased capacity to induce both allogeneic and autologous cytotoxic T lymphocytes (CTL).
21527935	Acute Lymphoblastic Leukemia	CD40LG	Promote immunity (T cell function)	The combination of CpG, IL-4 and CD40L was identified as most effective to enhance expression of immunogenic molecules on BCP-ALL cells, resulting in an increased capacity to induce both allogeneic and autologous cytotoxic T lymphocytes (CTL).
21527558	Melanoma	STAT3	Inhibit immunity (T cell function)	Vaccine efficacy could be rescued if tumor-bearing mice were treated initially with Salmonella encoding a short hairpin RNA (shRNA) targeting the tolerogenic molecule STAT3 (YS1646-shSTAT3). In vaccinated mice, silencing STAT3 increased the proliferation and granzyme B levels of intratumoral CD4(+) and CD8(+) T cells. The combined strategy also increased apoptosis in tumors of treated mice, enhancing tumor-specific killing of tumor targets.
21527558	Melanoma	GZMB	Promote immunity (T cell function)	In vaccinated mice, silencing STAT3 increased the proliferation and granzyme B levels of intratumoral CD4(+) and CD8(+) T cells. The combined strategy also increased apoptosis in tumors of treated mice, enhancing tumor-specific killing of tumor targets.
21523763	Pleural Malignant Mesothelioma	CD163	Inhibit immunity	Within MPM tumors, macrophages comprised 27% ± 9% of the tumor area and demonstrated an immunosuppressive phenotype with high expression of CD163, CD206, and interleukin-4 receptor α.
21523763	Pleural Malignant Mesothelioma	MRC1	Inhibit immunity	Within MPM tumors, macrophages comprised 27% ± 9% of the tumor area and demonstrated an immunosuppressive phenotype with high expression of CD163, CD206, and interleukin-4 receptor α.
21523763	Pleural Malignant Mesothelioma	IL4R	Inhibit immunity	Within MPM tumors, macrophages comprised 27% ± 9% of the tumor area and demonstrated an immunosuppressive phenotype with high expression of CD163, CD206, and interleukin-4 receptor α.
21521526	Basal-Like Breast Carcinoma	CXCR4	Inhibit immunity (infiltration)	We hypothesised that immune suppression in this subtype may be due to T regulatory cells (Treg) recruitment driven by hypoxia-induced up-regulation of CXCR4 in Treg. Up-regulation of CXCR4 in Treg correlated with the basal-like phenotype (P = 0.029) and tumour hypoxia, as indicated by CA9 expression (P = 0.049). Our data show that in the setting of hypoxia and CXCR4 up-regulation in Treg, CXCL12 expression may have the negative consequence of enhancing Treg recruitment and suppressing the anti-tumour immune response.
21521526	Basal-Like Breast Carcinoma	CXCL12	Inhibit immunity (infiltration)	High Treg infiltration correlated with tumour CXCL12 positivity (OR 1.89, 95% CI 1.22 to 2.94, P = 0.004) and basal phenotype (OR 3.14, 95% CI 1.08 to 9.17, P = 0.004) in univariate and multivariate analyses. CXCL12 positivity correlated with improved survival (P = 0.005), whereas high Treg correlated with shorter survival for all breast cancers (P = 0.001), luminal cancers (P < 0.001) and basal-like cancers (P = 0.040) that were confirmed in a multivariate analysis (OR 1.61, 95% CI 1.02 to 2.53, P = 0.042). Our data show that in the setting of hypoxia and CXCR4 up-regulation in Treg, CXCL12 expression may have the negative consequence of enhancing Treg recruitment and suppressing the anti-tumour immune response.
21518728	B16 Malignant Melanoma	IL2	Promote immunity (T cell function)	Furthermore, we showed that H1/pIL-2 stimulated the activation and proliferation of CD8+, CD4+ T cell, and natural killer cells in peripheral blood and increased the infiltration of CD8+, CD4+ Tcells, and natural killer cells into the tumor environment.
21515097	Colorectal Cancinoma	IL10	Inhibit immunity	In addition, Cy + AdIL-12 modified Tregs functionality by inhibiting the in vitro secretion of IL-10 and TGF-β and their ability to inhibit dendritic cells activation. Combined treatment decreased the number of myeloid-derived suppressor cells (MDSCs) in comparison to non-treated mice and, interestingly, administration of Tregs restored splenic MDSCs population.
21515097	Colorectal Cancinoma	TGFB1	Inhibit immunity	In addition, Cy + AdIL-12 modified Tregs functionality by inhibiting the in vitro secretion of IL-10 and TGF-β and their ability to inhibit dendritic cells activation. Combined treatment decreased the number of myeloid-derived suppressor cells (MDSCs) in comparison to non-treated mice and, interestingly, administration of Tregs restored splenic MDSCs population.
21515097	Colorectal Cancinoma; Pancreatic Carcinoma	IL12A	Promote immunity	We previously demonstrated that sub-therapeutic doses of an adenovirus expressing IL-12 genes (AdIL-12) mediated a potent antitumour effect against subcutaneous (s.c.) colorectal carcinomas (CRC) in mice pre-treated with low doses of cyclophosphamide (Cy). In addition, Cy + AdIL-12 modified Tregs functionality by inhibiting the in vitro secretion of IL-10 and TGF-β and their ability to inhibit dendritic cells activation. Combined treatment decreased the number of myeloid-derived suppressor cells (MDSCs) in comparison to non-treated mice and, interestingly, administration of Tregs restored splenic MDSCs population.
21515097	Colorectal Cancinoma	IFNG	Promote immunity	Furthermore, combined therapy potently generated specific cytotoxic IFN-γ-secreting CD4+ T cells able to eradicate established CRC tumours after adoptive transfer.
21514665	B16 Malignant Melanoma	CD40	Promote immunity	Immunostimulatory therapies that activate immune response pathways are of great interest for overcoming the immunosuppression present in advanced tumors. Agonistic anti-CD40 antibodies and CpG oligonucleotides have previously demonstrated potent, synergistic anti-tumor effects, but their clinical use even as monotherapies is hampered by dose-limiting inflammatory toxicity provoked upon systemic exposure.
21505426	Glioblastoma	FLT3LG	Promote immunity	In a model of GBM recurrence, we demonstrate that Flt3L/TK mediated immunological memory is capable of recognizing brain tumor neoantigens absent from the original treated tumor. These data demonstrate that the Flt3L/TK gene therapeutic approach can induce systemic immunological memory capable of recognizing a brain tumor neoantigen in a model of recurrent GBM.
21483002	Breast Carcinoma (ERBB-(+))	ESR1	Inhibit immunity (infiltration)	The total number of CD8(+) cells was positively correlated with tumor grade (r(s) = 0.20; P < .001) and inversely correlated with patient's age at diagnosis, estrogen receptor-alpha (ER-α), and progesterone receptor (PgR) expression (Mann-Whitney U test, P < .001).
21483002	Breast Carcinoma (ERBB-(+))	PGR	Inhibit immunity (infiltration)	The total number of CD8(+) cells was positively correlated with tumor grade (r(s) = 0.20; P < .001) and inversely correlated with patient's age at diagnosis, estrogen receptor-alpha (ER-α), and progesterone receptor (PgR) expression (Mann-Whitney U test, P < .001).
21482773	Breast Carcinoma (ERBB-(+))	PDCD1	Inhibit immunity (T cell function)	Finally, we investigated whether immunostimulatory approaches with antibodies against programmed death-1 (PD-1) or 41BB (CD137) could be used to capitalize on the immune-mediated effects of trastuzumab. We demonstrate that anti-PD-1 or anti-CD137 mAb can significantly improve the therapeutic activity of anti-ErbB-2 mAb in immunocompetent mice.
21482773	Breast Carcinoma (ERBB-(+))	TNFRSF9	Inhibit immunity (T/NK cell function); immunotherapy target	Finally, we investigated whether immunostimulatory approaches with antibodies against programmed death-1 (PD-1) or 41BB (CD137) could be used to capitalize on the immune-mediated effects of trastuzumab. We demonstrate that anti-PD-1 or anti-CD137 mAb can significantly improve the therapeutic activity of anti-ErbB-2 mAb in immunocompetent mice.
21482773	Breast Carcinoma (ERBB-(+))	IFNA1	Promote immunity (T cell function); essential for immunotherapy	We report here that anti-ErbB-2 mAb therapy is dependent on the release of type I and type II IFNs but is independent of perforin or FasL.
21482773	Breast Carcinoma (ERBB-(+))	IFNB1	Promote immunity (T cell function); essential for immunotherapy	We report here that anti-ErbB-2 mAb therapy is dependent on the release of type I and type II IFNs but is independent of perforin or FasL.
21482773	Breast Carcinoma (ERBB-(+))	IFNG	Promote immunity (T cell function); essential for immunotherapy	We report here that anti-ErbB-2 mAb therapy is dependent on the release of type I and type II IFNs but is independent of perforin or FasL.
21480325	Hepatocellular Carcinoma	PPIB	Inhibit immunity (T/NK cell function); immunotherapy target	The TAAs consisting of cyclophilin B, squamous cell carcinoma antigen recognized by T cells (SART) 2, SART3, p53, multidrug resistance-associated protein (MRP) 3, alpha-fetoprotein (AFP) and human telomerase reverse transcriptase (hTERT) were frequently recognized by T cells and these TAA-derived peptides were capable of generating peptide-specific CTLs in HCC patients, which suggested that these TAAs are immunogenic. Cyclophilin B, SART2, SART3, p53, MRP3, AFP, and hTERT were immunogenic targets for HCC immunotherapy.
21480325	Hepatocellular Carcinoma	DSE	Promote immunity	The TAAs consisting of cyclophilin B, squamous cell carcinoma antigen recognized by T cells (SART) 2, SART3, p53, multidrug resistance-associated protein (MRP) 3, alpha-fetoprotein (AFP) and human telomerase reverse transcriptase (hTERT) were frequently recognized by T cells and these TAA-derived peptides were capable of generating peptide-specific CTLs in HCC patients, which suggested that these TAAs are immunogenic. Cyclophilin B, SART2, SART3, p53, MRP3, AFP, and hTERT were immunogenic targets for HCC immunotherapy.
21480325	Hepatocellular Carcinoma	SART3	Inhibit immunity (T/NK cell function); immunotherapy target	The TAAs consisting of cyclophilin B, squamous cell carcinoma antigen recognized by T cells (SART) 2, SART3, p53, multidrug resistance-associated protein (MRP) 3, alpha-fetoprotein (AFP) and human telomerase reverse transcriptase (hTERT) were frequently recognized by T cells and these TAA-derived peptides were capable of generating peptide-specific CTLs in HCC patients, which suggested that these TAAs are immunogenic. Cyclophilin B, SART2, SART3, p53, MRP3, AFP, and hTERT were immunogenic targets for HCC immunotherapy.
21480325	Hepatocellular Carcinoma	TP53	Inhibit immunity (T/NK cell function); immunotherapy target	The TAAs consisting of cyclophilin B, squamous cell carcinoma antigen recognized by T cells (SART) 2, SART3, p53, multidrug resistance-associated protein (MRP) 3, alpha-fetoprotein (AFP) and human telomerase reverse transcriptase (hTERT) were frequently recognized by T cells and these TAA-derived peptides were capable of generating peptide-specific CTLs in HCC patients, which suggested that these TAAs are immunogenic. Cyclophilin B, SART2, SART3, p53, MRP3, AFP, and hTERT were immunogenic targets for HCC immunotherapy.
21480325	Hepatocellular Carcinoma	TERT	Promote immunity	The TAAs consisting of cyclophilin B, squamous cell carcinoma antigen recognized by T cells (SART) 2, SART3, p53, multidrug resistance-associated protein (MRP) 3, alpha-fetoprotein (AFP) and human telomerase reverse transcriptase (hTERT) were frequently recognized by T cells and these TAA-derived peptides were capable of generating peptide-specific CTLs in HCC patients, which suggested that these TAAs are immunogenic. Cyclophilin B, SART2, SART3, p53, MRP3, AFP, and hTERT were immunogenic targets for HCC immunotherapy.
21480325	Hepatocellular Carcinoma	CTLA4	Inhibit immunity (T cell function)	Blocking cytotoxic T-lymphocyte antigen-4 (CTLA-4) resulted in unmasking of TAA-specific immune responses by changing cytokine and chemokine profiles of peripheral blood mononuclear cells stimulated by TAA-derived peptides. TAA-specific immunotherapy combined with HCC treatments and anti-CTLA-4 antibody has the possibility to produce stronger tumor-specific immune responses.
21480223	Bladder Carcinoma	FUT4	Inhibit immunity	Our results demonstrate that PBMC from bladder cancer patients contain two major CD11b myeloid cell subsets: granulocyte-type CD15(high) CD33(low) cells and monocyte-type CD15(low) CD33(high) cells. Granulocytic myeloid cells were able to inhibit in vitro T cell proliferation through induction of CD4(+) Foxp3(+) T regulatory cells.
21480223	Bladder Carcinoma	CCL2	Inhibit immunity	Both myeloid cell subsets from cancer patients were highly activated and produced substantial amounts of proinflammatory chemokines/cytokines including CCL2, CCL3, CCL4, G-CSF, IL-8 and IL-6. Both myeloid cell subsets from cancer patients were highly activated and produced substantial amounts of proinflammatory chemokines/cytokines including CCL2, CCL3, CCL4, G-CSF, IL-8 and IL-6.
21480223	Bladder Carcinoma	CCL3	Inhibit immunity	Both myeloid cell subsets from cancer patients were highly activated and produced substantial amounts of proinflammatory chemokines/cytokines including CCL2, CCL3, CCL4, G-CSF, IL-8 and IL-6. We demonstrate that these highly activated inflammatory myeloid cells represent a source of multiple chemokines/cytokines and may contribute to inflammation and immune dysfunction in bladder cancer.
21480223	Bladder Carcinoma	CCL4	Inhibit immunity	Both myeloid cell subsets from cancer patients were highly activated and produced substantial amounts of proinflammatory chemokines/cytokines including CCL2, CCL3, CCL4, G-CSF, IL-8 and IL-6. We demonstrate that these highly activated inflammatory myeloid cells represent a source of multiple chemokines/cytokines and may contribute to inflammation and immune dysfunction in bladder cancer.
21480223	Bladder Carcinoma	CSF3	Inhibit immunity	Both myeloid cell subsets from cancer patients were highly activated and produced substantial amounts of proinflammatory chemokines/cytokines including CCL2, CCL3, CCL4, G-CSF, IL-8 and IL-6. We demonstrate that these highly activated inflammatory myeloid cells represent a source of multiple chemokines/cytokines and may contribute to inflammation and immune dysfunction in bladder cancer.
21480223	Bladder Carcinoma	CXCL8	Inhibit immunity	Both myeloid cell subsets from cancer patients were highly activated and produced substantial amounts of proinflammatory chemokines/cytokines including CCL2, CCL3, CCL4, G-CSF, IL-8 and IL-6. We demonstrate that these highly activated inflammatory myeloid cells represent a source of multiple chemokines/cytokines and may contribute to inflammation and immune dysfunction in bladder cancer.
21480223	Bladder Carcinoma	IL6	Inhibit immunity	Both myeloid cell subsets from cancer patients were highly activated and produced substantial amounts of proinflammatory chemokines/cytokines including CCL2, CCL3, CCL4, G-CSF, IL-8 and IL-6. We demonstrate that these highly activated inflammatory myeloid cells represent a source of multiple chemokines/cytokines and may contribute to inflammation and immune dysfunction in bladder cancer.
21467163	Melanoma	CD28	Promote immunity (T cell function); essential for immunotherapy	Cancer immunotherapy relies on the ability of the immune system to target tumor-specific antigens to generate an immune response. This initial response requires both binding of the MHC/antigen peptide to T-cell receptor complex, along with a second costimulatory signal created by the binding of CD28 on the T cell, with B7 located on the antigen-presenting cell.
21467163	Melanoma	CTLA4	Inhibit immunity (T cell function)	Regulatory checkpoints, such as cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), serve to attenuate this signal, thereby preventing autoimmunity. Its key role in regulating the immune system has made CTLA-4 an attractive therapeutic target for cancer, with the development of fully human monoclonal antibodies that have successfully targeted CTLA-4 in clinical trials.
21455984	Other Mammary Carcinoma of Mouse	TLR4	Promote immunity	Cell mediated immune responses through TLR4 prevents DMBA-induced mammary carcinogenesis in mice. T cells of TLR4 deficient mice produced elevated levels of IL-17 and lower levels of IFN-γ relative to WT mice. IL-12 secreted by CD11c(+) cells was higher in WT mice, whereas greater amounts of IL-23 were produced by CD11c(+) cells from TLR4 deficient mice. The results of this study indicate that TLR4 plays an important role in the prevention of DMBA induced mouse mammary tumorigenesis and efforts to divert the cell-mediated immune response may, therefore, prove to be beneficial in the prevention of mammary tumors.
21455984	Other Mammary Carcinoma of Mouse	IL17A	Inhibit immunity	TLR4 deficient mice developed more tumors relative to the WT mice. T cells of TLR4 deficient mice produced elevated levels of IL-17 and lower levels of IFN-γ relative to WT mice. IL-12 secreted by CD11c(+) cells was higher in WT mice, whereas greater amounts of IL-23 were produced by CD11c(+) cells from TLR4 deficient mice.
21455984	Other Mammary Carcinoma of Mouse	IFNG	Promote immunity	TLR4 deficient mice developed more tumors relative to the WT mice. T cells of TLR4 deficient mice produced elevated levels of IL-17 and lower levels of IFN-γ relative to WT mice. IL-12 secreted by CD11c(+) cells was higher in WT mice, whereas greater amounts of IL-23 were produced by CD11c(+) cells from TLR4 deficient mice.
21453957	Ovarian Cancinoma	TACSTD2	Inhibit immunity (T/NK cell function); immunotherapy target	High-grade, chemotherapy-resistant primary ovarian carcinoma cell lines overexpress human trophoblast cell-surface marker (Trop-2) and are highly sensitive to immunotherapy with hRS7, a humanized monoclonal anti-Trop-2 antibody. All primary ovarian cancer cell lines expressing Trop-2 were highly sensitive to hRS7-mediated ADCC in vitro (range of killing: 19.3% to 40.8%) (p<0.001).
21453957	Ovarian Cancinoma	IL2	Promote immunity	Human serum did not significantly inhibit hRS7-mediated cytotoxicity while incubation with IL-2 in addition to hRS7 further increased the cytotoxic activity (p=0.04).
21447719	Renal Cell Carcinoma; Melanoma	IL12A	Promote immunity	AS1409 is a fusion protein comprising a humanized antibody BC1 linked to interleukin-12 (IL-12). IFN-γ and interferon-inducible protein-10 (IP-10) were elevated in all patients, indicating activation of cell-mediated immune response; this was attenuated at subsequent cycles.
21447719	Renal Cell Carcinoma; Melanoma	IFNG	Promote immunity	IFN-γ and interferon-inducible protein-10 (IP-10) were elevated in all patients, indicating activation of cell-mediated immune response; this was attenuated at subsequent cycles.
21441454	Melanoma	LAG3	Inhibit immunity	The lymphocyte activation gene-3 (LAG-3) is a natural ligand for MHC II that is substantially expressed on melanoma-infiltrating T cells including those endowed with potent immune-suppressive activity. In this study, we demonstrate that both soluble LAG-3 and LAG-3-transfected cells can protect MHC II-positive melanoma cells, but not MHC II-negative cells, from FAS-mediated and drug-induced apoptosis. Interaction of LAG-3 with MHC II expressed on melanoma cells upregulates both MAPK/Erk and PI3K/Akt pathways, albeit with different kinetics. Altogether, our data suggest that the LAG-3-MHC II interaction could be viewed as a bidirectional immune escape pathway in melanoma, with direct consequences shared by both melanoma and immune cells.
21441454	Melanoma	MAPK1	Inhibit immunity	Interaction of LAG-3 with MHC II expressed on melanoma cells upregulates both MAPK/Erk and PI3K/Akt pathways, albeit with different kinetics. Inhibition studies using specific inhibitors of both pathways provided evidence of their involvement in the LAG-3-induced protection from apoptosis.
21441454	Melanoma	AKT1	Inhibit immunity	Interaction of LAG-3 with MHC II expressed on melanoma cells upregulates both MAPK/Erk and PI3K/Akt pathways, albeit with different kinetics. Inhibition studies using specific inhibitors of both pathways provided evidence of their involvement in the LAG-3-induced protection from apoptosis.
21441454	Melanoma	PIK3CD	Inhibit immunity	Interaction of LAG-3 with MHC II expressed on melanoma cells upregulates both MAPK/Erk and PI3K/Akt pathways, albeit with different kinetics. Inhibition studies using specific inhibitors of both pathways provided evidence of their involvement in the LAG-3-induced protection from apoptosis.
21436454	Pancreatic Ductal Adenocarcinoma; Pancreatic Carcinoma	CD40	Promote immunity (T cell function & infiltration); essential for immunotherapy	Because CD40 activation can reverse immune suppression and drive antitumor T cell responses, we tested the combination of an agonist CD40 antibody with gemcitabine chemotherapy in a small cohort of patients with surgically incurable PDA and observed tumor regressions in some patients. CD40-activated macrophages rapidly infiltrated tumors, became tumoricidal, and facilitated the depletion of tumor stroma.
21430221	Melanoma	IL12A	Promote immunity (T cell function)	In vitro priming of mouse tumor-specific CD8(+) T cells in the presence of IL-12 induced a diverse and rapid antitumor effector activity while still promoting the generation of memory cells.
21430221	Melanoma	IL2RA	Promote immunity (T cell function)	Control of tumor growth by CD8(+) T cells was dependent on IL-12-mediated upregulation of the high-affinity IL-2R (CD25) and a subsequent increase in the sensitivity to IL-2 stimulation.
21427357	Breast Carcinoma	TLR5	Promote immunity	Activation of Toll-like receptor 5 on breast cancer cells by flagellin suppresses cell proliferation and tumor growth. These findings indicate that TLR5 activation by flagellin mediates innate immune response to elicit potent antitumor activity in breast cancer cells themselves, which may serve as a novel therapeutic target for human breast cancer therapy.
21421234	Bladder Carcinoma	TLR2	Promote immunity (T cell function & infiltration); essential for immunotherapy	Treatment with toll-like receptor 2 and 3 agonists showed the strongest inflammatory response in 2 primary cultures of normal urothelial cells and 3 bladder cancer cell lines. In cultured urothelial cells agonist inducible toll-like receptor 2 or constitutively expressed toll-like receptor 3 is functional. These data suggest the potential use of toll-like receptor agonists for antitumor immunotherapy of nonmuscle invasive tumors.
21421234	Bladder Carcinoma	TLR3	Promote immunity (T cell function & infiltration); essential for immunotherapy	Treatment with toll-like receptor 2 and 3 agonists showed the strongest inflammatory response in 2 primary cultures of normal urothelial cells and 3 bladder cancer cell lines. In cultured urothelial cells agonist inducible toll-like receptor 2 or constitutively expressed toll-like receptor 3 is functional. These data suggest the potential use of toll-like receptor agonists for antitumor immunotherapy of nonmuscle invasive tumors.
21413013	Esophageal Carcinoma; Prostate carcinoma	CTAG1B	Promote immunity (T cell function)	In a recent phase I clinical trial, we vaccinated 13 patients bearing NY-ESO-1-expressing tumors with a complex of cholesterol-bearing hydrophobized pullulan (CHP) and NY-ESO-1 protein (CHP-NY-ESO-1) and showed efficient induction of NY-ESO-1 antibody, and CD4 and CD8 T cell responses using peripheral blood from the patients.
21406718	Chronic Lymphocytic Leukemia	FCER2	Promote immunity	Moreover, CLL-derived CD23.CAR(+) T cells released inflammatory cytokines (1445-fold more TNF-β, 20-fold more TNF-α, and 4-fold more IFN-γ). IL-2 was also produced (average release 2681 pg/mL) and sustained the antigen-dependent proliferation of CD23.CAR(+) T cells. Redirected T cells were also effective in vivo in a CLL Rag2(-/-)γ(c)(-/-) xenograft mouse model. These data suggest that CD23.CAR(+) T cells represent a selective immunotherapy for the elimination of CD23(+) leukemic cells in patients with CLL.
21406718	Chronic Lymphocytic Leukemia	IL2	Promote immunity	IL-2 was also produced (average release 2681 pg/mL) and sustained the antigen-dependent proliferation of CD23.CAR(+) T cells.
21394097	Acute Myeloid Leukemia	CD52	Inhibit immunity	CD52 as a molecular target for immunotherapy to treat acute myeloid leukemia with high EVI1 expression. In this study, we determined that CD52, which is mainly expressed on lymphocytes, is highly expressed in most cases of AML with a high EVI1 expression (EVI1(High)). CAMPATH-1H significantly inhibited cell growth and induced apoptosis in CD52-positive EVI1(High) leukemia cells. Furthermore, CAMPATH-1H induced complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity against CD52-positive EVI1(High) leukemia cells.
21385853	Acute Myeloid Leukemia	HAVCR2	Inhibit immunity (T cell function)	Coexpression of Tim-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia. PD-1(+)Tim-3(+) CD8(+) T cells were deficient in their ability to produce IFN-γ, TNF-α, and IL-2 in response to PD-1 ligand (PDL1) and Tim-3 ligand (galectin-9) expressing AML cells. PD-1 knockout (KO), which were partially resistant to AML challenge, up-regulated Tim-3 during AML progression and such Tim-3(+)PD-1- KO CD8(+) T cells had reduced cytokine production. Therefore, combined PD-1/PDL1 and Tim-3/galectin-9 blockade may be beneficial in preventing CD8(+) T-cell exhaustion in patients with hematologic malignancies such as advanced AML.
21385853	Acute Myeloid Leukemia	PDCD1	Inhibit immunity (T cell function)	Coexpression of Tim-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia. PD-1(+)Tim-3(+) CD8(+) T cells were deficient in their ability to produce IFN-γ, TNF-α, and IL-2 in response to PD-1 ligand (PDL1) and Tim-3 ligand (galectin-9) expressing AML cells. PD-1 knockout (KO), which were partially resistant to AML challenge, up-regulated Tim-3 during AML progression and such Tim-3(+)PD-1- KO CD8(+) T cells had reduced cytokine production. Therefore, combined PD-1/PDL1 and Tim-3/galectin-9 blockade may be beneficial in preventing CD8(+) T-cell exhaustion in patients with hematologic malignancies such as advanced AML.
21385853	Acute Myeloid Leukemia	LGALS9	Inhibit immunity	Galectin-9 KO mice were more resistant to AML, which was associated with reduced T-regulatory cell accumulation and a modest induction of PD-1 and Tim-3 expression on CD8(+) T cells. Therefore, combined PD-1/PDL1 and Tim-3/galectin-9 blockade may be beneficial in preventing CD8(+) T-cell exhaustion in patients with hematologic malignancies such as advanced AML.
21385853	Acute Myeloid Leukemia	CD274	Inhibit immunity	Coexpression of Tim-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia. PD-1(+)Tim-3(+) CD8(+) T cells were deficient in their ability to produce IFN-γ, TNF-α, and IL-2 in response to PD-1 ligand (PDL1) and Tim-3 ligand (galectin-9) expressing AML cells. PD-1 knockout (KO), which were partially resistant to AML challenge, up-regulated Tim-3 during AML progression and such Tim-3(+)PD-1- KO CD8(+) T cells had reduced cytokine production. Therefore, combined PD-1/PDL1 and Tim-3/galectin-9 blockade may be beneficial in preventing CD8(+) T-cell exhaustion in patients with hematologic malignancies such as advanced AML.
21383767	Pancreatic Carcinoma	MSR1	Inhibit immunity	Absence of scavenger receptor A promotes dendritic cell-mediated cross-presentation of cell-associated antigen and antitumor immune response. Selective downregulation or blockade of this immunoregulatory molecule may lead to enhanced potency of DC-based vaccines capable of breaking immune tolerance against cancer.
21378275	Lung Adenocarcinoma	MMP12	Inhibit immunity	Both in vitro and in vivo studies showed an immunosuppressive function on T-cell proliferation and function by CD11b(+)/Gr-1(+) immature cells from MMP12-overexpressing bitransgenic mice. MMP12 directly stimulated lineage-negative (Lin?) progenitor cells to differentiate into CD11b(+)/Gr-1(+) immature cells that showed immunosuppression on T-cell proliferation and function in vitro. Regulatory T cells (Tregs) were increased. In the lung, the concentration of IL-6 was increased, which aberrantly activated oncogenic Stat3 and increased expression of Stat3 downstream genes in epithelial tumor progenitor cells. Spontaneous emphysema and lung adenocarcinoma were sequentially developed after MMP12 overexpression. BM chimeras confirmed that the MMP12-induced myeloid cell autonomous defect led to abnormal myelopoiesis, immune suppression, and lung adenocarcinoma.
21378130	Melanoma	VTCN1	Inhibit immunity (T cell function)	The numbers of CD68(+) macrophages were significantly lower in patients with low B7-H4 expression, whereas CD8(+) T-cell infiltrates were independent of expression levels. Overexpression of B7-H4 on melanoma cells did not alter the cytotoxicity of different CD8(+) effector cells, but drastically inhibited cytokine production. Our study provides for the first time evidence of B7-H4 expression on melanoma cells as a mechanism controlling tumor immunity which is associated with patients' survival.
21357681	Lung Carcinoma; Mesothelioma	IL13RA2	Promote immunity	This augmented expression of IL-13Rα2 resulted in growth inhibition of the mesothelioma cells when cocultured with anti-IL-13Rα2 and effector cells, such as splenocytes and peritoneal exudate cells. These observations indicate a promising role for IL-13Rα2 as a target for antibody treatment in malignant mesothelioma, and, in combination with epigenetic regulation by a DNA methylation inhibitor, suggest the potential for a novel strategy to enhance therapeutic potency.
21355077	Melanoma	IL15	Promote immunity (T cell function)	We compared the efficacy of human Langerhans cells (LC) as tumor immunogens in vivo with monocyte-derived dendritic cells (moDC) and investigated how interleukin 15 (IL15) supports optimal DC-stimulated antitumor immunity. IL15 promotes T-cell expression of the antiapoptotic bcl-2 and inhibits candidate regulatory T-cell (Treg) expansion after DC stimulation, countering two effects of IL2 that do not foster tumor immunity.
21355077	Melanoma	IL2	Promote immunity (T cell function)	IL2 and IL15 can be synergistic in moDC stimulation of cytolytic T cells.
21325070	Melanoma	IL2	Increase the efficacy of immunotherapy	A number of nonrandomized clinical trials using TIL combined with high-dose interleukin-2 (IL-2) have consistently found clinical response rates of 50% or more in metastatic melanoma patients accompanied by long progression-free survival.
21324923	Glioma	PTGS2	Inhibit immunity	Because PGE? induces expansion of myeloid-derived suppressor cells (MDSC), we hypothesized that COX-2 blockade would suppress gliomagenesis by inhibiting MDSC development and accumulation in the tumor microenvironment (TME). Taken together, our findings show that the COX-2 pathway promotes gliomagenesis by directly supporting systemic development of MDSCs and their accumulation in the TME, where they limit CTL infiltration.
21324923	Glioma	CCL2	Inhibit immunity	ASA treatment also reduced the MDSC-attracting chemokine CCL2 (C-C motif ligand 2) in the TME along with numbers of CD11b(+)Ly6G(hi)Ly6C(lo) granulocytic MDSCs in both the bone marrow and the TME.
21324923	Glioma	CXCL10	Promote immunity (infiltration)	Conversely, these mice or ASA-treated wild-type mice displayed enhanced expression of CXCL10 (C-X-C motif chemokine 10) and infiltration of cytotoxic T lymphocytes (CTL) in the TME, consistent with a relief of MDSC-mediated immunosuppression. Antibody-mediated depletion of MDSCs delayed glioma growth in association with an increase in CXCL10 and CTLs in the TME, underscoring a critical role for MDSCs in glioma development. Finally, Cxcl10-deficient mice exhibited reduced CTL infiltration of tumors, establishing that CXCL10 limited this pathway of immunosuppression.
21321117	Chronic myelogenous leukemia	IL32	Promote immunity (NK cell function); increase the efficacy of immunotherapy	Overexpression of IL-32alpha increases natural killer cell-mediated killing through up-regulation of Fas and UL16-binding protein 2 (ULBP2) expression in human chronic myeloid leukemia cells. Taken together, these data show that IL-32α stimulates Fas and ULBP2 expression via activation of p38 MAPK, which increases NK susceptibility of CML cells. Enhanced NK cell susceptibility of CML cells by IL-32α overexpression may improve the efficiency of NK cell-based immunotherapy.
21321117	Chronic myelogenous leukemia	FAS	Promote immunity (NK cell function)	Overexpression of IL-32alpha increases natural killer cell-mediated killing through up-regulation of Fas and UL16-binding protein 2 (ULBP2) expression in human chronic myeloid leukemia cells. Taken together, these data show that IL-32α stimulates Fas and ULBP2 expression via activation of p38 MAPK, which increases NK susceptibility of CML cells. Enhanced NK cell susceptibility of CML cells by IL-32α overexpression may improve the efficiency of NK cell-based immunotherapy.
21321117	Chronic myelogenous leukemia	ULBP2	Promote immunity (NK cell function)	Overexpression of IL-32alpha increases natural killer cell-mediated killing through up-regulation of Fas and UL16-binding protein 2 (ULBP2) expression in human chronic myeloid leukemia cells. Taken together, these data show that IL-32α stimulates Fas and ULBP2 expression via activation of p38 MAPK, which increases NK susceptibility of CML cells. Enhanced NK cell susceptibility of CML cells by IL-32α overexpression may improve the efficiency of NK cell-based immunotherapy.
21321117	Chronic myelogenous leukemia	MAPK14	Promote immunity (NK cell function)	Overexpression of IL-32alpha increases natural killer cell-mediated killing through up-regulation of Fas and UL16-binding protein 2 (ULBP2) expression in human chronic myeloid leukemia cells. T IL-32α-induced Fas and ULBP2 expression are regulated p38 MAPK.
21317394	Lung Neoplasm	IL15	Promote immunity (NK cell function)	Taken altogether, our data suggest that NK cell adoptive transfer can trigger adaptive antitumor T cell responses, and regulatory T cell depletion by Ontak is mandatory for enabling HC/IL-15-activated NK cells to promote long-lasting adaptive antitumor immunity.
21310826	Colorectal Cancinoma	STAT3	Inhibit immunity	STAT3 is a transcription factor that is constitutively activated in some cancers. It seems to play crucial roles in cell proliferation and survival, angiogenesis, tumor-promoting inflammation, and suppression of antitumor host immune response in the tumor microenvironment. p-STAT3 overexpression was associated with significantly higher colorectal cancer-specific mortality [log-rank P = 0.0020; univariate HR (p-STAT3-high vs. p-STAT3-negative): 1.85, 95% CI: 1.30-2.63, P(trend) = 0.0005; multivariate HR: 1.61, 95% CI: 1.11-2.34, P(trend) = 0.015]. p-STAT3 expression was positively associated with peritumoral lymphocytic reaction (multivariate OR: 3.23; 95% CI: 1.89-5.53, P < 0.0001).
21310823	Leukemia	HLA-DRB1	Promote immunity (T cell function)	Increased HLA-DR and IFN-γ expression was observed for CD4(+) T cells stimulated with CLIP(-) leukemic blasts, in contrast to CLIP(+) leukemic blasts, which indicated an activation and polarization of the CD4(+) T cells toward T-helper 1 cells. In addition, CLIP(-) leukemic blasts induced greater outgrowth of effector memory CD4(+) T cells (with HLA-DR-restricted T-cell receptor Vβ repertoires) that were associated with better leukemia-specific reactivity than with CLIP(+) leukemic blasts.
21310823	Leukemia	IFNG	Promote immunity (T cell function)	Increased HLA-DR and IFN-γ expression was observed for CD4(+) T cells stimulated with CLIP(-) leukemic blasts, in contrast to CLIP(+) leukemic blasts, which indicated an activation and polarization of the CD4(+) T cells toward T-helper 1 cells. In addition, CLIP(-) leukemic blasts induced greater outgrowth of effector memory CD4(+) T cells (with HLA-DR-restricted T-cell receptor Vβ repertoires) that were associated with better leukemia-specific reactivity than with CLIP(+) leukemic blasts.
21300825	Metastatic Malignant Neoplasm in the Lung	IL1A	Promote immunity (T cell function)	The absence of IL-1 signaling or its excess in the lung microenvironment (in IL-1β and IL-1R antagonist knockout [KO] mice, respectively) resulted in a poor prognosis and reduced T cell activity, compared with WT mice. In IL-1β KO mice, enhanced T regulatory cell development/function, due to a favorable in situ cytokine network and impairment in APC maturation, resulted in suppressed antitumor immunity, whereas in IL-1R antagonist KO mice, enhanced accumulation and activity of myeloid-derived suppressor cells were found. In the microenvironment of lung tumors, IL-1 induces IL-17 through recruitment of γ/δ T cells and their activation for IL-17 production, with no involvement of Th17 cells.
21300825	Metastatic Malignant Neoplasm in the Lung	IL17A	Promote immunity (T cell function)	Reduced tumor progression along with improved T cell function was found in IL-17 KO mice, compared with WT mice.
21298574	Ovarian Cancinoma	VEGFA	Inhibit immunity	We will discuss the role of angiogenesis and the tumor endothelium on regulation of the antitumor immune response with a special emphasis on the role of vascular endothelial growth factor (VEGF) in the suppression of immunological processes, which control tumor progression and its unique crosstalk with endothelin systems, and how their interactions may shape the antitumor immune response.
20160057	Adult T-Cell Leukemia/Lymphoma	CCR4	Inhibit immunity	We have developed the humanized defucosylated anti-CC chemokine receptor 4 (CCR4) monoclonal antibody KW-0761 as a next generation immunotherapeutic agent. The degree of KW-0761 ADCC against primary ATLL cells in an autologous setting was mainly determined by the amount of effector natural killer cells present, but not the amount of the target molecule CCR4 on the ATLL cell surface. KW-0761 should be sufficiently active for therapeutic clinical application for ATLL.
20160037	Malignant Pancreatic Insulinoma	F11R	Inhibit immunity (infiltration)	Inactivation of junctional adhesion molecule-A enhances antitumoral immune response by promoting dendritic cell and T lymphocyte infiltration. In the absence of JAM-A, tumors showed a small but significant reduction in angiogenesis and a marked increase in the immune reaction with enhanced infiltration of DCs (CD11c+ and MHC-II+) and CD4+ and CD8+ lymphocytes. These findings support the idea that, in the Rip1Tag2 tumor model, abrogation of JAM-A reduces cancer development by increasing antitumor immune response.
20156971	Melanoma	CTLA4	Inhibit immunity (T cell function)	Furthermore, blockade of the coinhibitory receptor CTL-associated antigen 4 (CTLA-4) on the transferred CD4(+) T cells resulted in greater expansion of effector T cells, diminished accumulation of tumor-reactive regulatory T cells, and superior antitumor activity capable of inducing regression of spontaneous mouse melanoma. These findings suggest a novel potential therapeutic role for cytotoxic CD4(+) T cells and CTLA-4 blockade in cancer immunotherapy.
20154208	B16 Malignant Melanoma; Lymphoma	VCAM1	Promote immunity (infiltration)	Small-molecule inhibitors of vascular adhesion protein-1 reduce the accumulation of myeloid cells into tumors and attenuate tumor growth in mice. We found that both anti-VAP-1 Abs and VAP-1 inhibitors reduced the number of leukocytes in the tumors, but they targeted partially different leukocyte subpopulations. Anti-VAP-1 Abs selectively inhibited infiltration of CD8-positive lymphocytes into tumors and had no effect on accumulation of myeloid cells into tumors. In contrast, the VAP-1 inhibitors significantly reduced only the number of proangiogenic Gr-1(+)CD11b(+) myeloid cells in melanomas and lymphomas. Blocking of VAP-1 by either means left tumor homing of regulatory T cells and type 2 immune-suppressing monocytes/macrophages intact. The VAP-1 inhibitors also reduced the binding of Gr-1(+) myeloid cells to the tumor vasculature. We conclude that tumors use the catalytic activity of VAP-1 to recruit myeloid cells into tumors and to support tumor progression.
20150362	Glioblastoma	KLRK1	Promote immunity (NK and T cell function)	The activating receptor NKG2D, expressed by natural killer (NK) cells and CD8(+) T cells, has a role in the specific killing of transformed cells. Expression of NKG2D on lymphocytes significantly increased following tumor resection and correlated with an increased ability to kill NKG2D ligand-positive tumor targets.
20150362	Glioblastoma	TGFB1	Inhibit immunity (T/NK cell function)	TGF-beta downregulates the activating receptor NKG2D on NK cells and CD8+ T cells in glioma patients. Despite the presence of soluble NKG2D ligands in the sera of glioblastoma patients, NKG2D downregulation was primarily caused by tumor-derived tumor growth factor-beta, suggesting that blocking of this cytokine may have therapeutic benefit.
20145137	Breast Carcinoma	TGFB1	Inhibit immunity	To evaluate the potential role of tumor-derived, antiestrogen-induced TGFbeta as an immune suppressor, we established in vitro mixed lymphocyte tumor reactions (MLTR) using MCF-7 cells and peripheral blood mononuclear cells (PBMC), as well as tumor tissue and autologous tumor infiltrating lymphocytes (TIL) obtained from primary breast cancer biopsies.
20145137	Breast Carcinoma	GZMB	Promote immunity (T cell function)	In allogeneic MLTR, antiestrogen-treated MCF-7 cells caused downregulation of the effector molecules granzyme B, perforin, and Fas ligand in CD8(+) T cells, and suppressed the generation of cytotoxic effector cells in a TGFbeta-dependent manner.
20145137	Breast Carcinoma	PRF1	Promote immunity (T cell function)	In allogeneic MLTR, antiestrogen-treated MCF-7 cells caused downregulation of the effector molecules granzyme B, perforin, and Fas ligand in CD8(+) T cells, and suppressed the generation of cytotoxic effector cells in a TGFbeta-dependent manner.
20145137	Breast Carcinoma	FASLG	Promote immunity (T cell function)	In allogeneic MLTR, antiestrogen-treated MCF-7 cells caused downregulation of the effector molecules granzyme B, perforin, and Fas ligand in CD8(+) T cells, and suppressed the generation of cytotoxic effector cells in a TGFbeta-dependent manner.
20145137	Breast Carcinoma	FOXP3	Inhibit immunity (T cell function)	Furthermore, we documented induction of regulatory T cells in CD4(+) T cells, based on Foxp3 expression and T-cell activation in cocultures. In autologous MLTR, antiestrogen treatment gave rise to enhanced Foxp3 expression of TIL/PBMC and decreased the number of apoptotic tumor cells.
20144842	Ovarian Cancinoma	IL10	Inhibit immunity	Besides the immune-activating tumor infiltrating lymphocytes (TILs), immune-suppressive regulatory T-cells (Tregs), tolerance-inducing plasmacytoid dendritic cells (pDCs), B7-H4+ macrophages, immune-suppressive cytokines such as IL10 and TGF-beta are also found in the tumor environment.
20144842	Ovarian Cancinoma	TGFB1	Inhibit immunity	Besides the immune-activating tumor infiltrating lymphocytes (TILs), immune-suppressive regulatory T-cells (Tregs), tolerance-inducing plasmacytoid dendritic cells (pDCs), B7-H4+ macrophages, immune-suppressive cytokines such as IL10 and TGF-beta are also found in the tumor environment.
20144842	Ovarian Cancinoma	VEGFA	Inhibit immunity	Furthermore, vascular endothelial growth factor (VEGF) is also known to have an immune-suppressing role besides its angiogenic role.
20133697	Hodgkin Lymphoma	CT45A1	Inhibit immunity	Despite frequent CT45 expression, only 1 of 67 Hodgkin lymphoma patients had detectable anti-CT45 antibodies in the serum, suggesting that the immune response to CT45 may be suppressed.
20130242	B16 Malignant Melanoma; HLA-A2.1 Melanoma	TERT	Promote immunity	Targeting human telomerase reverse transcriptase with recombinant lentivector is highly effective to stimulate antitumor CD8 T-cell immunity in vivo. Compared with peptide-based vaccinations, the lv-hTERT vector triggers better and more sustained CD8(+) T-cell response against self/TERT epitope in vivo. Both primary and long-lasting self/TERT-specific CD8(+) T-cell responses induced with Iv-hTERT vector required the presence of CD4 T cells in vivo. This lv-hTERT-based active immunotherapy efficiently inhibits the growth of telomerase expressing tumors (B16/HLA-A2.1 murine melanoma) in HHD mice. These data show that targeting hTERT with lentivector is highly effective in stimulating a broad range of CD8 T-cell immunity that can be exploited for cancer immunotherapy.
20124451	Colon Carcinoma; Pancreatic Carcinoma	IDO1	Inhibit immunity	Expression of indoleamine-2,3-dioxygenase (IDO; IDO1), a rate-limiting enzyme in the catabolism of tryptophan into kynurenine, contributes to this immune evasion. Substantiating the fundamental role of tumor cell-derived IDO expression, hydroxyamidines control the growth of IDO-expressing tumors in Ido1-deficient mice. These activities can be attributed, at least partially, to the increased immunoreactivity of lymphocytes found in tumors and their draining lymph nodes and to the reduction in tumor-associated regulatory T cells.
20110422	B Acute Lymphoblastic Leukemia	CD19	Promote immunity	We have now generated CTL lines from peripheral blood (PB) or CB units that recognize multiple common viruses and provide antileukemic activity by transgenic expression of a chimeric antigen receptor (CAR) targeting CD19 expressed on B-ALL.
20101024	Leukemia; Lymphoma	KLRK1	Promote immunity	Consistent with this, blockade of NKG2D, the receptor for ULBP1 expressed on all Vgamma9(+) T cells, significantly inhibits lymphoma cell killing.
20100959	Intermediate Atypical Prostate Carcinoma	CD80	Promote immunity	PROSTVAC-VF comprises two recombinant viral vectors, each encoding transgenes for PSA, and three immune costimulatory molecules (B7.1, ICAM-1, and LFA-3).
20100959	Intermediate Atypical Prostate Carcinoma	ICAM1	Promote immunity	PROSTVAC-VF comprises two recombinant viral vectors, each encoding transgenes for PSA, and three immune costimulatory molecules (B7.1, ICAM-1, and LFA-3).
20100959	Intermediate Atypical Prostate Carcinoma	CD58	Promote immunity	PROSTVAC-VF comprises two recombinant viral vectors, each encoding transgenes for PSA, and three immune costimulatory molecules (B7.1, ICAM-1, and LFA-3).
20100959	Intermediate Atypical Prostate Carcinoma	KLK3	Promote immunity	Overall survival analysis of a phase II randomized controlled trial of a Poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer. Therapeutic prostate-specific antigen (PSA) -targeted poxviral vaccines for prostate cancer have been well tolerated.
20099279	Melanoma	IL1B	Inhibit immunity (T cell function)	Interleukins 1alpha and 1beta secreted by some melanoma cell lines strongly reduce expression of MITF-M and melanocyte differentiation antigens. Accordingly, treating some melanoma cells with IL-1beta reduced by 40-100% their ability to activate such antimelanoma cytolytic T lymphocytes. These results indicate that the repression of melanocyte-differentiation genes by IL-1 produced by stromal cells or by tumor cells themselves may represent an additional mechanism of melanoma immune escape.
20099279	Melanoma	MITF	Promote immunity	MITF-M regulates the expression of melanocyte differentiation genes such as MLANA, tyrosinase and gp100, which encode antigens recognized on melanoma cells by autologous cytolytic T lymphocytes.
20099279	Melanoma	IL1A	Inhibit immunity (T cell function)	Interleukins 1alpha and 1beta secreted by some melanoma cell lines strongly reduce expression of MITF-M and melanocyte differentiation antigens. These results indicate that the repression of melanocyte-differentiation genes by IL-1 produced by stromal cells or by tumor cells themselves may represent an additional mechanism of melanoma immune escape.
20087354	Hepatocellular Carcinoma	AFP	Promote immunity	Alpha-Fetoprotein (AFP) is a tumour-associated antigen in hepatocellular carcinoma (HCC) and is a target for immunotherapy.
20083664	Acute Myeloid Leukemia; Myeloma	HMMR	Promote immunity	These patients showed an increase of CD8(+)RHAMM-R3_tetramer(+)/CD45RA(+)/CCR7(-)/CD27(-)/CD28(-) effector T cells and an increase of R3-specific CD8+ T cells. Two of these patients showed a significant decrease of regulatory T cells (Tregs). High-dose RHAMM-R3 peptide vaccination induced immunological responses and positive clinical effects. Therefore, RHAMM constitutes a promising structure for further targeted immunotherapies in patients with different hematologic malignancies.
20080644	Breast Carcinoma	NT5E	Inhibit immunity	Anti-CD73 antibody therapy inhibits breast tumor growth and metastasis.In addition to its immunosuppressive effect, CD73 enhanced tumor-cell chemotaxis, suggesting a role for CD73-derived adenosine in tumor metastasis. In conclusion, our study identified tumor-derived CD73 as a mechanism of tumor immune escape and tumor metastasis.
20072155	B-cell Chronic Lymphocytic Leukemia	CD40LG	Promote immunity	We examined the fate of these cells in six of these individuals who received autologous human CD40 ligand and interleukin-2 (hCD40L/IL-2) gene-modified tumor cells as part of a tumor vaccine study. Vaccinated patients showed an increase in B-CLL-reactive T cells followed by a corresponding decline in circulating CD5(+)CD19(+) SP cells.
20072155	B-cell Chronic Lymphocytic Leukemia	IL2	Promote immunity	We examined the fate of these cells in six of these individuals who received autologous human CD40 ligand and interleukin-2 (hCD40L/IL-2) gene-modified tumor cells as part of a tumor vaccine study. Vaccinated patients showed an increase in B-CLL-reactive T cells followed by a corresponding decline in circulating CD5(+)CD19(+) SP cells.
20065291	Skin Basal Cell Carcinoma	TLR7	Promote immunity (T cell function); essential for immunotherapy	Toll-like receptor (TLR) agonists are prime candidates to fulfill this role because they induce innate immune activation and promote adaptive immune responses. The successful application of the TLR7 agonist R837 for treatment of basal cell carcinoma shows the potential for exploiting this pathway in tumor immunotherapy. Imidazoquinolines like R837 and stimulatory ssRNA oligonucleotides both trigger TLR7-mediated immune activation, but little is known about their comparative ability to promote immunity induction.
20065291	Skin Basal Cell Carcinoma	IFNA1	Increase the efficacy of immunotherapy	Plasmacytoid dendritic cell-derived type I interferon is crucial for the adjuvant activity of Toll-like receptor 7 agonists. Notably, exogenous IFN-alpha augmented the adjuvant activity of R848, whereas depletion of PDC abrogated the adjuvanticity of polyUs21. This study, therefore, identifies sufficient IFN-alpha production by PDC as an important determinant of vaccine efficacy.
20063317	Gastric Carcinoma; Pancreatic Carcinoma; Colorectal Carcinoma	SPARC	Inhibit immunity	Identification of SPARC as a candidate target antigen for immunotherapy of various cancers. A genome-wide cDNA microarray analysis identified that secreted protein acidic and rich in cysteine (SPARC) gene is overexpressed in the gastric, pancreatic and colorectal cancer tissues but not in their noncancerous counterparts. The SPARC-A24-1(143-151) (DYIGPCKYI) and SPARC-A24-4(225-234) (MYIFPVHWQF) peptides-reactive CTLs were successfully induced from peripheral blood mononuclear cells by in vitro stimulation with these two peptides in HLA-A24 (A*2402) positive healthy donors and cancer patients, and these CTLs exhibited cytotoxicity specific to cancer cells expressing both SPARC and HLA-A24 (A*2402).
20053772	Glioblastoma	STAT3	Inhibit immunity	Recent studies have found that the activated form of signal transducer and activator of transcription 3 (STAT3) is a key mediator in GBM immunosuppression. The STAT3 pathway is constitutively active in these clones and the immunosuppressive properties were markedly diminished when the STAT3 pathway was blocked in the cancer-initiating cells. These findings indicate that cancer-initiating cells contribute to the immune evasion of GBM and that blockade of the STAT3 pathway has therapeutic potential.
20053761	Endometrial Serous Adenocarcinoma	EPCAM	Immunotherapy target	Overexpression of EpCAM in uterine serous papillary carcinoma: implications for EpCAM-specific immunotherapy with human monoclonal antibody adecatumumab (MT201). EpCAM-positive cell lines were found highly sensitive to MT201-mediated antibody-dependent cellular cytotoxicity in vitro, whereas primary USPC cell lines were resistant to natural killer cell-dependent cytotoxicity.
20042467	Metastatic Malignant Neoplasm in the Liver	ITGAM	Inhibit immunity (T cell function)	Liver CD11b(+)Gr1(+) cells are highly suppressive of T cell activation, proliferation, and cytotoxicity and induce the development of Tregs.
20039320	Stage 4 Neuroblastoma	IL21	Promote immunity (T cell function); essential for immunotherapy	Transient depletion of CD4(+) T cells augments IL-21-based immunotherapy of disseminated neuroblastoma in syngeneic mice. Neuro2a/IL-21 vaccination showed increased expression of IFN-alpha2, -beta1 and -gamma mRNA. In conclusion, anti-CD4 mAb potentiated IL-21-based IT by removing Treg cells and/or their precursors and other potentially immune-suppressive CD4+ cell subsets, thus allowing the development of an IL-21-driven CD8+ T cell response, which mediates NB rejection.
20038811	Melanoma	BTLA	Inhibit immunity (T cell function)	BTLA mediates inhibition of human tumor-specific CD8+ T cells that can be partially reversed by vaccination. Thus, BTLA activation inhibits the function of human CD8+ cancer-specific T cells, and appropriate immunotherapy may partially overcome this inhibition.
20028856	Non-Small Cell Lung Carcinoma; Mesothelioma	CCL2	Inhibit immunity (T cell function)	CCL2 blockade augments cancer immunotherapy. CCL2 seems to be a key proximal cytokine mediating immunosuppression in tumors. Its blockade augments CD8+ T-cell immune response to tumors elicited by vaccines via multifactorial mechanisms.
20028741	Renal Cell Carcinoma	TGFB1	Inhibit immunity (T cell function); resistant to immunotherapy	Transforming growth factor-beta (TGF-beta) is a potent immunosuppressor that has been associated with tumor evasion from the host immune surveillance and, thus, tumor progression. Adoptive transfer of autologous TGF-beta-insensitive CD8(+) T cells into tumor-bearing Hu-PBMC-SCID mice induced robust tumor-specific CTL responses in vitro, were associated with tumor apoptosis, suppressed lung metastasis, and prolonged survival times in vivo.
20027629	Colorectal Cancinoma	NPM1	Inhibit immunity	Overexpression of Npm by tumors of various histological types, recognition of the antigen by T cells derived from different CRC patients and association of the antigen with poor prognostic outcome make it a promising target for immunotherapeutic intervention in cancer patients.
20013807	Gastrointestinal Stromal Tumor	IL10	Inhibit immunity	However, imatinib and sunitinib did induce secretion of anti-inflammatory IL-10 in macrophage cultures, indicating that treatment with these inhibitors might contribute to an immune suppressive microenvironment in GIST.
20013806	Colorectal Cancinoma	RFX5	Promote immunity	We conclude that somatic mutations of the RFX5 gene represent a novel mechanism of loss of HLA class II antigen expression in tumor cells, potentially contributing to immune evasion in MSI-H CRCs.
20008791	Acute Myeloid Leukemia	TNFSF9	Inhibit immunity (NK cell function)	Bidirectional signaling following CD137-CD137L interaction induced the release of the immunomodulatory cytokines interleukin-10 and TNF by AML cells and directly diminished granule mobilization, cytotoxicity, and interferon-gamma production of human NK cells, which was restored by blocking CD137. Our data underline the necessity to study the function of seemingly analog immunoregulatory molecules in mice compared with men and demonstrate that CD137-CD137L interaction enables immune evasion of AML cells by impairing NK-cell tumor surveillance in humans.
20008791	Acute Myeloid Leukemia	IL10	Inhibit immunity	Bidirectional signaling following CD137-CD137L interaction induced the release of the immunomodulatory cytokines interleukin-10 and TNF by AML cells and directly diminished granule mobilization, cytotoxicity, and interferon-gamma production of human NK cells, which was restored by blocking CD137.
20008791	Acute Myeloid Leukemia	IFNG	Promote immunity	Bidirectional signaling following CD137-CD137L interaction induced the release of the immunomodulatory cytokines interleukin-10 and TNF by AML cells and directly diminished granule mobilization, cytotoxicity, and interferon-gamma production of human NK cells, which was restored by blocking CD137.
20007574	Mesothelioma	CD274	Inhibit immunity (T cell function)	One of these is expression of T cell inhibitory ligands such as programmed death-ligand 1 (PD-L1; B7-H1). In this study, we show that PD-L1 is highly expressed on mesothelioma tumor cells and within the tumor stroma. Thus, PD-L1 blockade activates antitumor CD8 T cell most potently in the absence of CD4 T cells.
19966210	Plasma Cell Myeloma	IL7	Inhibit immunity	The increases in IL-7 and IL-15 levels were inversely correlated to the absolute lymphocyte count, unlike monocyte or myeloid counts. Furthermore, we have shown that CD3 T cells present in the ASC graft are activated, die rapidly when they are cultured without cytokine in vitro, and that addition of IL-7 or IL-15 could induce their survival and proliferation.
19949105	Melanoma	IL15	Promote immunity	An analysis of different supportive cytokine mixtures during the REP found that a combination of IL-15 and IL-21 facilitated comparable expansion of CD8(+) TILs as IL-2, but prevented the loss of CD28 expression with improved responsiveness to antigenic restimulation post-REP. A REP protocol using IL-15 and IL-21 may greatly increase the number of CD28(+) TILs capable of long-term persistence.
19949105	Melanoma	IL21	Promote immunity	An analysis of different supportive cytokine mixtures during the REP found that a combination of IL-15 and IL-21 facilitated comparable expansion of CD8(+) TILs as IL-2, but prevented the loss of CD28 expression with improved responsiveness to antigenic restimulation post-REP. A REP protocol using IL-15 and IL-21 may greatly increase the number of CD28(+) TILs capable of long-term persistence.
19961944	T-cell Non-Hodgkin Lymphoma	TP53	Promote immunity (T cell function)	In this report we show that, in response to TCR stimulation, T cells from na?ve p53-deficient mice exhibited higher proliferation and drastically reduced apoptosis than WT T cells. CD28 costimulation enhanced the proliferation of TCR-stimulated WT and p53(-/-) T cells, suggesting that p53 uncouples CD28-mediated antiapoptotic and proliferative signals. Unlike WT mice, p53(-/-) mice exhibited a robust tumor-resistant phenotype and developed cytotoxic T-cell responses against OVA. Collectively, these data support the hypothesis that p53 is an essential factor in negative regulation of T-cell responses and have implication for immunomodulation during treatment of cancers and other inflammatory conditions.
19949105	Melanoma	IL15	Promote immunity	An analysis of different supportive cytokine mixtures during the REP found that a combination of IL-15 and IL-21 facilitated comparable expansion of CD8(+) TILs as IL-2, but prevented the loss of CD28 expression with improved responsiveness to antigenic restimulation post-REP. A REP protocol using IL-15 and IL-21 may greatly increase the number of CD28(+) TILs capable of long-term persistence.
19949105	Melanoma	IL21	Promote immunity	An analysis of different supportive cytokine mixtures during the REP found that a combination of IL-15 and IL-21 facilitated comparable expansion of CD8(+) TILs as IL-2, but prevented the loss of CD28 expression with improved responsiveness to antigenic restimulation post-REP. A REP protocol using IL-15 and IL-21 may greatly increase the number of CD28(+) TILs capable of long-term persistence.
19949105	Melanoma	IL2	Promote immunity	An analysis of different supportive cytokine mixtures during the REP found that a combination of IL-15 and IL-21 facilitated comparable expansion of CD8(+) TILs as IL-2, but prevented the loss of CD28 expression with improved responsiveness to antigenic restimulation post-REP. These results suggest that current expansion protocols using IL-2 for melanoma adoptive T cell therapy yields largely CD8(+) T cells unable to persist and divide in vivo following Ag contact.
19934056	Melanoma	NCR2	Promote immunity (NK cell function)	Thus, both the IL-2-induced up-regulation of the surface expression of NKp44, NKp30, and DNAM-1 triggering receptors and the acquisition of cytolytic granules were inhibited in NK cells. This resulted in an impairment of the NK cell-mediated killing of melanoma target cells.
19934056	Melanoma	NCR3	Promote immunity (NK cell function)	Thus, both the IL-2-induced up-regulation of the surface expression of NKp44, NKp30, and DNAM-1 triggering receptors and the acquisition of cytolytic granules were inhibited in NK cells. This resulted in an impairment of the NK cell-mediated killing of melanoma target cells.
19934056	Melanoma	CD226	Promote immunity (NK cell function)	Thus, both the IL-2-induced up-regulation of the surface expression of NKp44, NKp30, and DNAM-1 triggering receptors and the acquisition of cytolytic granules were inhibited in NK cells. This resulted in an impairment of the NK cell-mediated killing of melanoma target cells.
19934056	Melanoma	IL2	Promote immunity (NK cell function)	Thus, both the IL-2-induced up-regulation of the surface expression of NKp44, NKp30, and DNAM-1 triggering receptors and the acquisition of cytolytic granules were inhibited in NK cells. This resulted in an impairment of the NK cell-mediated killing of melanoma target cells.
29362448	Prostate Adenocarcinoma	EBAG9	Inhibit immunity (infiltration)	Extracellular vesicle-mediated EBAG9 transfer from cancer cells to tumor microenvironment promotes immune escape and tumor progression. EBAG9 in cancer cells suppresses T-cell infiltration into tumor in vivo, whereas that in host immune cells functions as a limiter for T-cell cytotoxicity. We identified TM9SF1 as a collaborative EBAG9 interactor, which regulates epithelial-mesenchymal transition (EMT) in cancer cells. Notably, extracellular vesicles (EVs) from EBAG9-overexpressing prostate cancer cells have a potential to facilitate immune escape of tumors by inhibiting T-cell cytotoxicity and modulating immune-related gene expression in T cells. In addition to its autocrine functions in cancer cells, EBAG9 could behave as a new class of immune checkpoint that suppresses tumor immunity in a secretory manner.
29362448	Prostate Adenocarcinoma	TM9SF1	Inhibit immunity (infiltration)	Extracellular vesicle-mediated EBAG9 transfer from cancer cells to tumor microenvironment promotes immune escape and tumor progression.We identified TM9SF1 as a collaborative EBAG9 interactor, which regulates epithelial-mesenchymal transition (EMT) in cancer cells.
29361059	Renal Cell Carcinoma	CD274	Inhibit immunity	PD-1, PD-L2, CTLA4 and FOXP3, all of which are implicated in the evasion of an anti-tumor immune response, had a significantly higher expression for samples representing co-detection of productive TcR-α and -β recombination reads.
29361059	Renal Cell Carcinoma	PDCD1LG2	Inhibit immunity	PD-1, PD-L2, CTLA4 and FOXP3, all of which are implicated in the evasion of an anti-tumor immune response, had a significantly higher expression for samples representing co-detection of productive TcR-α and -β recombination reads.
29361059	Renal Cell Carcinoma	CTLA4	Inhibit immunity	PD-1, PD-L2, CTLA4 and FOXP3, all of which are implicated in the evasion of an anti-tumor immune response, had a significantly higher expression for samples representing co-detection of productive TcR-α and -β recombination reads.
29361059	Renal Cell Carcinoma	FOXP3	Inhibit immunity	PD-1, PD-L2, CTLA4 and FOXP3, all of which are implicated in the evasion of an anti-tumor immune response, had a significantly higher expression for samples representing co-detection of productive TcR-α and -β recombination reads.
29360722	Melanoma	CTLA4	Inhibit immunity (T cell function)	Part of these advances emerged through the identification of the importance of factors that regulate the immune system, including proteins that negatively modulate T cell-mediated responses termed "immune checkpoints." Indeed, blockade of the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) immune checkpoint served as a proof of principle that the manipulation of these molecules could induce robust anticancer effects, yet limited to a small percentage of patients.
29360722	Melanoma	PDCD1	Inhibit immunity (T cell function)	Targeting a distinct checkpoint, the PD-1 yielded improved outcomes and reduced toxicity compared with CTLA-4 blockade and, in separate studies, chemotherapy.
29353075	Diffuse Large B-Cell Lymphoma	BTLA	Inhibit immunity (T cell function); resistant to immunotherapy	BTLA marks a less cytotoxic T-cell subset in diffuse large B-cell lymphoma with high expression of checkpoints. Our results suggest that BTLA+ T cells highly express other checkpoint molecules, including PD-1, TIM-3, LIGHT, and LAG-3. Taken together, our data provide the first evidence that increased BTLA predicts poor prognosis in patients with DLBCL, and blockade of BTLA with other checkpoints may potentially represent a new strategy for immunotherapy of DLBCL.
29345842	Gastric Carcinoma	CD274	Inhibit immunity	In particular, programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) are widely known as important immune checkpoint molecules associated with the mechanisms of immune escape by malignant tumor cells.
29339209	Esophageal Adenocarcinoma	PDCD1	Immunotherapy target	Importantly, PD-1-expressing T cells are significantly lower in EAC tumor post neoadjuvant chemoradiotherapy, suggesting that combination with specific conventional treatments may severely impair the efficacy of anti-PD-1 immunotherapy.
29336814	Pancreatic Carcinoma	IL10	Inhibit immunity	Inhibition of Interleukin-10 in the tumor microenvironment can restore mesothelin chimeric antigen receptor T cell activity in pancreatic cancer in vitro. Pancreatic cancer cells are known to shield themselves from immunosurveillance by secreting immune inhibitory cytokines such as Interleukin-10. Substantial reversal of tumor-derived immunosuppression may be achieved by blocking Interleukin-10 in the local microenvironment, allowing for more effective cytotoxicity of mesothelin-engrafted chimeric antigen receptor T cells and enhancing the potential for clinical application.
29336814	Pancreatic Carcinoma	IFNG	Promote immunity	Coculture supernatants of conditioned medium displayed significant inhibition of interferon γ and granzyme B secretion, both of which are crucial for induction of target cell cytotoxicity.
29336814	Pancreatic Carcinoma	GZMB	Promote immunity	Coculture supernatants of conditioned medium displayed significant inhibition of interferon γ and granzyme B secretion, both of which are crucial for induction of target cell cytotoxicity.
29334771	Ovarian Cancinoma	CD19	Promote immunity	CD19-targeted chimeric antigen receptor (CAR) engineered T/natural killer (NK)-cell therapies can result in durable clinical responses in B-cell malignancies.
29327244	Myeloma	TNF	Promote immunity	Antibody-based delivery of tumor necrosis factor (L19-TNFα) and interleukin-2 (L19-IL2) to tumor-associated blood vessels has potent immunological and anticancer activity in the syngeneic J558L BALB/c myeloma model. IL2, TNFα, or IL2 plus TNFα (final 20 h) increased the proportion of CD4- CD25low effector lymphocytes possibly indicating immune activation.
29327244	Myeloma	IL2	Promote immunity	Antibody-based delivery of tumor necrosis factor (L19-TNFα) and interleukin-2 (L19-IL2) to tumor-associated blood vessels has potent immunological and anticancer activity in the syngeneic J558L BALB/c myeloma model. IL2, TNFα, or IL2 plus TNFα (final 20 h) increased the proportion of CD4- CD25low effector lymphocytes possibly indicating immune activation.
29327110	Neuroblastoma	IL2	Promote immunity	Various strategies have been employed in the clinic to improve antibody-dependent cell-mediated cytotoxicity (ADCC), such as the addition of interleukin (IL)-2 to enhance natural killer (NK) cell function, adoptive transfer of allogeneic NK cells to exploit immune surveillance, and retinoid-induced differentiation therapy. In conclusion, IL-2 is an important component of immunotherapy because it can improve the cytolytic function of NK cells against neuroblastoma cells and could lower the antibody dose required for efficacy, thereby reducing toxicity.
29326088	Melanoma	CTLA4	Immunotherapy target	We used a mouse model of transplantable, orthotopic B16 melanoma to test age effects of treatments with anti-CTLA-4, anti-PD-1 and anti-PD-L1 antibodies.
29326088	Melanoma	PDCD1	Immunotherapy target	We used a mouse model of transplantable, orthotopic B16 melanoma to test age effects of treatments with anti-CTLA-4, anti-PD-1 and anti-PD-L1 antibodies.
29326088	Melanoma	CD274	Immunotherapy target	We used a mouse model of transplantable, orthotopic B16 melanoma to test age effects of treatments with anti-CTLA-4, anti-PD-1 and anti-PD-L1 antibodies.
29316944	Acute Myeloid Leukemia	CLEC12A	Promote immunity	CAR-T cells targeting CLL-1 as an approach to treat acute myeloid leukemia. CLL-1 CAR-T represents a promising immunotherapy for the treatment of AML.
29308322	Melanoma	MICA	Promote immunity (NK cell function)	We demonstrate that BRAFV600E mutant melanoma cells cultured in the presence of vemurafenib, strongly decreased surface expression of ligands for NK activating receptors including the NKG2D-ligand, MICA, and the DNAM-1 ligand, CD155, and became significantly less susceptible to NK cell attack.
29308322	Melanoma	PVR	Promote immunity (NK cell function)	We demonstrate that BRAFV600E mutant melanoma cells cultured in the presence of vemurafenib, strongly decreased surface expression of ligands for NK activating receptors including the NKG2D-ligand, MICA, and the DNAM-1 ligand, CD155, and became significantly less susceptible to NK cell attack.
29308322	Melanoma	CD226	Promote immunity (NK cell function)	We demonstrate that BRAFV600E mutant melanoma cells cultured in the presence of vemurafenib, strongly decreased surface expression of ligands for NK activating receptors including the NKG2D-ligand, MICA, and the DNAM-1 ligand, CD155, and became significantly less susceptible to NK cell attack.
29308322	Melanoma	KLRK1	Promote immunity (NK cell function)	We demonstrate that BRAFV600E mutant melanoma cells cultured in the presence of vemurafenib, strongly decreased surface expression of ligands for NK activating receptors including the NKG2D-ligand, MICA, and the DNAM-1 ligand, CD155, and became significantly less susceptible to NK cell attack.
29308321	Glioma	CD47	Inhibit immunity	We next examined the effects of anti-CD47 antibody on glioma cells/GSCs in an immune competent mouse glioma model, revealing significant inhibition of tumor growth and prolonged survival times. In summary, we have shown that CD47 is a potentially safe and effective therapeutic target for glioma.
29308319	Pancreatic Carcinoma; Lung Carcinoma	ENO1	Promote immunity	Citrullinated α-enolase is an effective target for anti-cancer immunity.
29308317	Colorectal Carcinoma (MMR-deficient)	B2M	Promote immunity	Increasing PDCD1 (PD-1)-positive T-cell infiltration was significantly related to an increased likelihood of B2M mutations (OR = 1.81). HLA class II antigen expression status was significantly associated with enhanced overall T-cell infiltration, but not related to PDCD1 (PD-1)-positive T-cells. These results suggest that immune evasion mediated by B2M mutation-induced loss of HLA class I antigen expression predominantly occurs in an environment of activated PDCD1 (PD-1)-positive T cell infiltration.
29308316	Pancreatic Ductal Adenocarcinoma	IL6	Immunotherapy target	Targeting of mesenchymal pancreatic tumors in vivo with anti-IL-6RmAb (RoActemra) successfully decreased tumor growth in immunodeficient mice, inhibited the inflammatory stroma and NF-kB-p65 and STAT3 phosphorylation in cancer cells.
29308312	Metastatic Melanoma	IFNG	Promote immunity	The enhanced tumor destruction was accompanied with significantly increased tumor infiltration of CD4+ and CD8+ T cells as well as elevated IFN-γ in the tumor sites.
29308300	Prostate Carcinoma	PSCA	Promote immunity	Prostate cancer may be amenable to T cell-based immunotherapy since several tumor antigens, including prostate stem-cell antigen (PSCA), are widely over-expressed in metastatic disease. A 4-1BB intracellular co-stimulatory signaling domain in PSCA-CARs confers improved selectivity for higher tumor antigen density, reduced T cell exhaustion phenotype, and equivalent tumor killing ability compared to PSCA-CARs containing the CD28 co-stimulatory signaling domain. PSCA-CARs exhibit robust in vivo anti-tumor activity in patient-derived bone-metastatic prostate cancer xenograft models, and 4-1BB-containing CARs show superior T cell persistence and control of disease compared with CD28-containing CARs.
29308299	Metastatic Non-Squamous Non-Small Cell Lung Carcinoma	ADAM10	Inhibit immunity (NK cell function)	Platelet-mediated shedding of NKG2D ligands impairs NK cell immune-surveillance of tumor cells. Similar results were obtained upon exposure of tumor cells to platelet-releasate and can be attributed to the sheddases ADAM10 and ADAM17 that are detectable on the platelet surface and in releasate following activation and at higher levels on platelets of patients with metastasized lung cancer compared with healthy controls.
29308299	Metastatic Non-Squamous Non-Small Cell Lung Carcinoma	ADAM17	Inhibit immunity (NK cell function)	Platelet-mediated shedding of NKG2D ligands impairs NK cell immune-surveillance of tumor cells. Similar results were obtained upon exposure of tumor cells to platelet-releasate and can be attributed to the sheddases ADAM10 and ADAM17 that are detectable on the platelet surface and in releasate following activation and at higher levels on platelets of patients with metastasized lung cancer compared with healthy controls.
29308299	Metastatic Non-Squamous Non-Small Cell Lung Carcinoma	MICA	Promote immunity (NK cell function)	Here we report that platelet-coating reduces surface expression of NKG2D ligands, in particular MICA and MICB, on tumor cells, which was mirrored by enhanced release of their soluble ectodomains.
29308299	Metastatic Non-Squamous Non-Small Cell Lung Carcinoma	MICB	Promote immunity (NK cell function)	Here we report that platelet-coating reduces surface expression of NKG2D ligands, in particular MICA and MICB, on tumor cells, which was mirrored by enhanced release of their soluble ectodomains.
29307625	Vulvar Melanoma	FOXP3	Promote immunity	In conclusion, our study shows that, independent from tumor thickness, an increased density of peritumoral FoxP3+ lymphocytes may positively impact survival in a subset of vulvar melanomas.
29307625	Vulvar Melanoma	CD274	Inhibit immunity (T cell function)	PDL1 expression >5% and peritumoral CD8+, peritumoral FoxP3+, and tumoral FoxP3+ lymphocytes correlated with better overall survival. Tumoral PDL1 expression correlated with tumoral as well as peritumoral CD8+ and FoxP3+ lymphocytes, supportive of an adaptive immune response. Although the frequency of PDL1 expression is low in vulvar melanoma, its expression may identify a subset of vulvar melanoma that might respond to immunotherapy.
29301960	Renal Cell Carcinoma	PBRM1	Decrease the efficacy of immunotherapy	We found that clinical benefit was associated with loss-of-function mutations in the PBRM1 gene (P = 0.012), which encodes a subunit of the PBAF switch-sucrose nonfermentable (SWI/SNF) chromatin remodeling complex. PBRM1 loss in ccRCC may alter global tumor-cell expression profiles to influence responsiveness to immune checkpoint therapy.
29301578	B16 Malignant Melanoma	NOTCH1	Inhibit immunity (infiltration)	Notch1 signaling in melanoma cells promoted tumor-induced immunosuppression via upregulation of TGF-β1. Notch1 expression in B16 melanoma cells inhibited the infiltration of CD8+ cytotoxic T lymphocytes and NK cells and reduced IFN-γ release in tumor tissue. It could also enhance B16 cell-mediated inhibition of T cell proliferation and activation, and upregulate PD-1 expression on CD4+ and CD8+ T cells. These findings suggested that Notch1 signaling in B16 melanoma cells might inhibit antitumor immunity by upregulation of TGF-β1.
29301578	B16 Malignant Melanoma	PDCD1	Inhibit immunity	It could also enhance B16 cell-mediated inhibition of T cell proliferation and activation, and upregulate PD-1 expression on CD4+ and CD8+ T cells.
29301578	B16 Malignant Melanoma	IFNG	Promote immunity	Notch1 expression in B16 melanoma cells inhibited the infiltration of CD8+ cytotoxic T lymphocytes and .NK cells and reduced IFN-γ release in tumor tissue
29301578	B16 Malignant Melanoma	TGFB1	Inhibit immunity (T cell function)	The percentage of CD4+CD25+FoxP3+ Tregs and Gr1+CD11b+MDSCs were significantly increased in tumor microenvironment, and all these were attributed to the upregulation of TGF-β1.
29293164	Colorectal Cancinoma	IL2	Promote immunity (NK cell function)	Resting NK cells were unable to display sizeable levels of cytotoxic activity against mCRC cells, whereas their cytotoxic activity was enhanced after overnight or 5-day incubation with IL-2 or IL-15.
29293164	Colorectal Cancinoma	IL15	Promote immunity (NK cell function)	Resting NK cells were unable to display sizeable levels of cytotoxic activity against mCRC cells, whereas their cytotoxic activity was enhanced after overnight or 5-day incubation with IL-2 or IL-15.
29293164	Colorectal Cancinoma	EGFR	Inhibit immunity (NK cell function); immunotherapy target	In Vitro Killing of Colorectal Carcinoma Cells by Autologous Activated NK Cells is Boosted by Anti-Epidermal Growth Factor Receptor-induced ADCC Regardless of RAS Mutation Status. These data open perspectives for combined NK-based immunotherapy with anti-epidermal growth factor receptor antibodies in a cohort of mCRC patients with a poor prognosis refractory to conventional therapies.
29270668	Rectal Carcinoma	HMGB1	Promote immunity	The better outcome is likely due to the release of HMGB1, which triggers the maturation of dendritic cells (DCs) via TLR4 activation, and the subsequent recruitment of PD-1+?tumor-infiltrating lymphocytes to the tumor site, where they participate in immune-scavenging.
29270668	Rectal Carcinoma	TLR4	Promote immunity	The better outcome is likely due to the release of HMGB1, which triggers the maturation of dendritic cells (DCs) via TLR4 activation, and the subsequent recruitment of PD-1+?tumor-infiltrating lymphocytes to the tumor site, where they participate in immune-scavenging.
29251665	Lung Adenocarcinoma	CD274	Inhibit immunity (T cell function)	Therapies with antibodies that block the interaction of PD-L1 with PD-1 and thereby liberate an antitumor immune response have introduced a new era in cancer therapy with impressive therapeutic benefits.
29251665	Lung Adenocarcinoma	PDCD1	Inhibit immunity (T cell function)	Therapies with antibodies that block the interaction of PD-L1 with PD-1 and thereby liberate an antitumor immune response have introduced a new era in cancer therapy with impressive therapeutic benefits.
29239915	Ovarian Cancinoma	TPBG	Promote immunity	These results demonstrate proof of principle that 5T4 is an attractive target for immune intervention in ovarian cancer and that patient T cells engineered to express a 5T4-specific CAR can recognize and respond physiologically to autologous tumor cells.
29224228	B16 Malignant Melanoma	IL15	Promote immunity (T cell function); essential for immunotherapy	The cytotoxicity assay showed that murine melanoma cells modified with LX/IL(15+7) could significantly enhance the antitumor immune response in vitro. Interleukin 15 (IL15) and IL7 are two cytokines essential for T cell development and homeostasis. Taken together, our data strongly indicated that tumor vaccine modified with NDV strain LX/IL(15+7) is a promising agent for cancer immunotherapy.
29215754	Head and Neck Squamous Cell Carcinoma	JAK2	Inhibit immunity	Inhibition of JAK2/STAT3 reduces tumor-induced angiogenesis and myeloid-derived suppressor cells in head and neck cancer. Moreover, in HNSCC transgenic mouse model, inhibiting JAK2/STAT3 not only suppressed angiogenesis but also reduced MDSCs in the tumor microenvironment through suppressing VEGFA and CK2. Our findings demonstrated the close relationship between angiogenesis and MDSCs in HNSCC, and inhibition of JAK2/STAT3 could reduce tumor-induced angiogenesis and decrease MDSCs.
29215754	Head and Neck Squamous Cell Carcinoma	STAT3	Inhibit immunity	Inhibition of JAK2/STAT3 reduces tumor-induced angiogenesis and myeloid-derived suppressor cells in head and neck cancer. Moreover, in HNSCC transgenic mouse model, inhibiting JAK2/STAT3 not only suppressed angiogenesis but also reduced MDSCs in the tumor microenvironment through suppressing VEGFA and CK2. Our findings demonstrated the close relationship between angiogenesis and MDSCs in HNSCC, and inhibition of JAK2/STAT3 could reduce tumor-induced angiogenesis and decrease MDSCs.
29215754	Head and Neck Squamous Cell Carcinoma	VEGFA	Inhibit immunity	Moreover, in HNSCC transgenic mouse model, inhibiting JAK2/STAT3 not only suppressed angiogenesis but also reduced MDSCs in the tumor microenvironment through suppressing VEGFA and CK2.
29210217	Hepatocellular Carcinoma	BSG	Inhibit immunity	The efficacy of I131 -metuximab (I131 -mab), a newly developed agent that targets CD147, as a radio-immunotherapy for local HCC, has been validated in clinical practice.
29173750	Head and Neck Squamous Cell Carcinoma	PDCD1	Immunotherapy target	The application of anti-PD-1 therapies for recurrent or metastatic HNSCC has found promising results. Other ongoing trials are evaluating the use of anti-PD-1 and anti-PD-L1 therapies in the upfront setting for newly diagnosed high-risk, locally advanced HNSCC, in an effort to improve disease control.
29173750	Head and Neck Squamous Cell Carcinoma	CD274	Immunotherapy target	Other ongoing trials are evaluating the use of anti-PD-1 and anti-PD-L1 therapies in the upfront setting for newly diagnosed high-risk, locally advanced HNSCC, in an effort to improve disease control.
29157965	Skin Carcinoma	TLR7	Promote immunity	Small-molecule agonists for the Toll-like receptors (TLR) 7 and 8 are effective for the immunotherapy of skin cancer when used as topical agents. Thus, polymer-based nanoparticles represent a promising delivery system that allows lymph node targeting for small-molecule TLR7 agonists in the context of systemic cancer immunotherapy.
29153898	Non-Small Cell Lung Carcinoma	CD274	Immunotherapy target	Immunotherapy targeting programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) has recently been shown to improve the survival in advanced NSCLC.
29153898	Non-Small Cell Lung Carcinoma	PDCD1	Immunotherapy target	Immunotherapy targeting programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) has recently been shown to improve the survival in advanced NSCLC.
29132013	Non-Small Cell Lung Carcinoma	EPHA2	Inhibit immunity	Chimeric Antigen Receptor-Modified T Cells Redirected to EphA2 for the Immunotherapy of Non-Small Cell Lung Cancer. These EphA2-specifc T cells can cause tumor cell lysis by producing the cytokines IFN-γ when cocultured with EphA2-positive targets, and the cytotoxicity effects was specific in vitro. Thus, EphA2-specific T-cell immunotherapy may be a promising approach for the treatment of EphA2-positive NSCLC.
29127039	B16 Malignant Melanoma	TMEM173	Promote immunity	Cyclic dinucleotides (CDNs), a potent Stimulator of Interferon Receptor (STING) agonist, are currently in phase I trials. Here we utilized biodegradable, poly(beta-amino ester) (PBAE) nanoparticles to deliver CDNs to the cytosol leading to robust immune response at >100-fold lower extracellular CDN concentrations in vitro.
29124314	Melanoma	NOS2	Inhibit immunity	Furthermore, Foxp3 vaccination resulted in a significant reduction of arginase-1(Arg-1)-induced nitric oxide synthase (iNOS), reactive oxygen species (ROS) and suppressed MDSC activity. Moreover, this concurrent depletion restored production of inflammatory cytokine IFN-γ and enhanced tumor-specific CTL response, which subsequently resulted in the reduction of tumor growth and the improved survival rate of vaccinated mice.
29124314	Melanoma	ARG1	Inhibit immunity	Furthermore, Foxp3 vaccination resulted in a significant reduction of arginase-1(Arg-1)-induced nitric oxide synthase (iNOS), reactive oxygen species (ROS) and suppressed MDSC activity.
29124314	Melanoma	IFNG	Promote immunity	Moreover, this concurrent depletion restored production of inflammatory cytokine IFN-γ and enhanced tumor-specific CTL response, which subsequently resulted in the reduction of tumor growth and the improved survival rate of vaccinated mice.
29124314	Melanoma	FOXP3	Promote immunity	In conclusion, our results revealed that Foxp3 vaccine promotes an immune response against tumor by targeting both Treg and MDSC, which could be exploited as a potential immunotherapy approach.
29104081	Colon Cacinoma	GSK3B	Inhibit immunity (T cell function)	In this study, we sought to evaluate whether the activation of the wnt/β-catenin pathway through inhibition of glycogen synthase kinase-3β (GSK-3β) using 4,6-disubstituted pyrrolopyrimidine (TWS119) could be an efficient strategy to improve the proliferation, differentiation and cytolytic activity of γδT cells against colon cancer cells. Remarkably, we found that TWS119 significantly enhanced the proliferation and survival of γδT cells via activation of the mammalian target of rapamycin (mTOR) pathway, upregulation of the expression of the anti-apoptotic protein Bcl-2 and inhibition of cleaved caspase-3 in addition to the Wnt pathway.
29104081	Colon Cacinoma	GZMB	Promote immunity (T cell function)	Our results also showed that enhancement of the cytolytic activity of γδT cells against human colon cancer cells by TWS119 was chiefly associated with upregulation of the expression of perforin and granzyme B in vitro and in vivo.
29104081	Colon Cacinoma	CTNNB1	Promote immunity	Our results also showed that enhancement of the cytolytic activity of γδT cells against human colon cancer cells by TWS119 was chiefly associated with upregulation of the expression of perforin and granzyme B in vitro and in vivo.
29104081	Colon Cacinoma	SELL	Promote immunity	Additionally, TWS119 can induce the expression of CD62L or CCR5 to generate a population of CD62L+γδT or CCR5+γδT cells in a dose-dependent manner.
29104081	Colon Cacinoma	CCR5	Promote immunity	Additionally, TWS119 can induce the expression of CD62L or CCR5 to generate a population of CD62L+γδT or CCR5+γδT cells in a dose-dependent manner.
18687687	Leukemia	ZAP70	Promote immunity	The zeta chain-associated 70-kDa protein (ZAP-70) of tyrosine kinase plays a critical role in T cell receptor-mediated signal transduction and the immune response. A high level of ZAP-70 expression is observed in leukemia, which suggests ZAP-70 as a logical target for immunomodulatory therapies. Overall, these results strongly indicated that ZAP-70 activity was inhibited specifically by EGCG, which contributed to suppressing the CD3-mediated T cell-induced pathways in leukemia cells.
18684866	Hodgkin Lymphoma	IL21	Inhibit immunity (T cell function)	Aberrant expression of the Th2 cytokine IL-21 in Hodgkin lymphoma cells regulates STAT3 signaling and attracts Treg cells via regulation of MIP-3alpha. We demonstrate that IL-21 activates STAT3 in HRS cells, up-regulates STAT3 target genes, and protects HRS cells from CD95 death receptor-induced apoptosis. Furthermore, IL-21 is involved in up-regulation of the CC chemokine macrophage-inflammatory protein-3alpha (MIP-3alpha) in HRS cells.
18684866	Hodgkin Lymphoma	CCL20	Inhibit immunity (T cell function)	Furthermore, IL-21 is involved in up-regulation of the CC chemokine macrophage-inflammatory protein-3alpha (MIP-3alpha) in HRS cells. MIP-3alpha in turn attracts CCR6(+)CD4(+)CD25(+)FoxP3(+)CD127(lo) regulatory T cells toward HRS cells, which might favor their immune escape.
18676860	Leukemia	WT1	Promote immunity	The Wilms' tumor antigen is a novel target for human CD4+ regulatory T cells: implications for immunotherapy. The Wilms' tumor antigen (WT1) is overexpressed in several human leukemias and thus considered as promising target for development of leukemia vaccine. Furthermore, priming of T cells with the WT1-126 HLA-A0201-restricted peptide in the presence of T(regs) strongly inhibited the induction of anti-WT1-126 CD8(+) CTL responses as evidenced by both very low cytotoxic activity and IFN-gamma production.
18676826	Renal Cell Carcinoma	VTCN1	Inhibit immunity	B7x is the newest member of the B7-CD28 family and is thought to dampen immune responses via negative costimulation. Tumor expression of B7x was recently described in renal cell carcinoma (RCC) and was associated with poor outcome.
18676771	Breast Carcinoma	TGFB1	Inhibit immunity	Overexpression of transforming growth factor (TGF)-beta has been implicated in promoting immune suppression, tumor angiogenesis, tumor cell migration, and invasion in many cancers, including carcinoma of the breast.
18676762	Colorectal Cancinoma; Prostate Carcinoma	BIRC5	Promote immunity	The level of CD8(+) T cells capable of binding tetramers for the tumor-associated antigen survivin, which is overexpressed in both cancer types, was enumerated in HLA-A*0201 patient samples.
18676751	Infiltrating Bladder Urothelial Carcinoma	PDCD1	Inhibit immunity (T cell function)	Aberrant expression of T-cell coregulatory molecules has been investigated as a mechanism by which certain cancers may evade host immune surveillance. We evaluated expression of the T-cell coregulators B7-H1, B7-H3, and PD-1 in urothelial cell carcinoma (UCC) of the bladder.
18676737	Glioblastoma	STAT3	Inhibit immunity	Aberrant activation of STAT proteins, particularly STAT-3, is implicated in the pathogenesis of many cancers, including GBM, by promoting cell cycle progression, stimulating angiogenesis, and impairing tumor immune surveillance. Conversely, PIAS3 overexpression inhibited STAT-3 transcriptional activity, expression of STAT-3-regulated genes, and cell proliferation.
18676737	Glioblastoma	PIAS3	Promote immunity	Inhibition of PIAS3 resulted in enhanced glioblastoma cellular proliferation. Conversely, PIAS3 overexpression inhibited STAT-3 transcriptional activity, expression of STAT-3-regulated genes, and cell proliferation. We propose that the loss of PIAS3 in GBM contributes to enhanced STAT-3 transcriptional activity and subsequent cell proliferation.
18661524	Ovarian Cancinoma	MUC1	Immunotherapy target	Immunotherapy against MUC1 could be effective in the treatment of epithelial ovarian cancer.
18648368	Colon Cacinoma	PTGS2	Inhibit immunity	Despite studies strongly implicating tumour-expressed FasL as a major inhibitor of the anti-tumour immune response, little is known about the mechanisms that regulate FasL expression in tumours. In this study, we show that the cyclooxygenase (COX) signalling pathway, and in particular prostaglandin E(2) (PGE(2)), plays a role in the upregulation of FasL expression in colon cancer.
18648368	Colon Cacinoma	PTGS1	Inhibit immunity	Despite studies strongly implicating tumour-expressed FasL as a major inhibitor of the anti-tumour immune response, little is known about the mechanisms that regulate FasL expression in tumours. In this study, we show that the cyclooxygenase (COX) signalling pathway, and in particular prostaglandin E(2) (PGE(2)), plays a role in the upregulation of FasL expression in colon cancer. Suppression of either COX-2 or COX-1 by RNA interference in HCA-7 and HT29 colon tumour cells reduced FasL expression at both the mRNA and protein level.
18648368	Colon Cacinoma	PTGS2	Inhibit immunity	Despite studies strongly implicating tumour-expressed FasL as a major inhibitor of the anti-tumour immune response, little is known about the mechanisms that regulate FasL expression in tumours. In this study, we show that the cyclooxygenase (COX) signalling pathway, and in particular prostaglandin E(2) (PGE(2)), plays a role in the upregulation of FasL expression in colon cancer. Suppression of either COX-2 or COX-1 by RNA interference in HCA-7 and HT29 colon tumour cells reduced FasL expression at both the mRNA and protein level.
18645037	Hepatoma	CCR1	Promote immunity (infiltration)	Tumor-infiltrating DCs expressed chemokine receptors CCR1 and CCR5, and T cells and macrophages expressed CCL3, a ligand for CCR1 and CCR5. Thus, we provide definitive evidence indicating that CCR1 and CCR5 and their ligand CCL3 play a crucial role in the regulation of intratumoral DC accumulation and the subsequent establishment of tumor immunity following induction of tumor apoptosis by suicide genes.
18645037	Hepatoma	CCR5	Promote immunity (infiltration)	Tumor-infiltrating DCs expressed chemokine receptors CCR1 and CCR5, and T cells and macrophages expressed CCL3, a ligand for CCR1 and CCR5. Thus, we provide definitive evidence indicating that CCR1 and CCR5 and their ligand CCL3 play a crucial role in the regulation of intratumoral DC accumulation and the subsequent establishment of tumor immunity following induction of tumor apoptosis by suicide genes.
18645037	Hepatoma	CCL3	Promote immunity	Tumor-infiltrating DCs expressed chemokine receptors CCR1 and CCR5, and T cells and macrophages expressed CCL3, a ligand for CCR1 and CCR5. Thus, we provide definitive evidence indicating that CCR1 and CCR5 and their ligand CCL3 play a crucial role in the regulation of intratumoral DC accumulation and the subsequent establishment of tumor immunity following induction of tumor apoptosis by suicide genes.
18641325	Neuroblastoma	MIF	Inhibit immunity (T cell function)	Expression of macrophage migration inhibitory factor by neuroblastoma leads to the inhibition of antitumor T cell reactivity in vivo. We found that MIF expression in neuroblastoma inhibits T cell proliferation in vitro, raising the possibility that MIF promotes tumorigenesis, in part, by suppressing antitumor immunity.
18624349	Colorectal Cancinoma	CEACAM5	Promote immunity	Efficient antitumor immunity in a murine colorectal cancer model induced by CEA RNA-electroporated B cells. In this study, we compared B cells and DC, after electroporation with carcinoembryonic antigen (CEA) RNA, for their capacity to generate cytotoxic T lymphocytes and antitumor immunity.
18619700	Hepatocellular Carcinoma	ABCC3	Promote immunity	Our study demonstrates that MRP3 is a potential candidate for tumor antigen with strong immunogenicity in HCC immunotherapy.
18612161	Melanoma	CTLA4	Inhibit immunity (T cell function)	Blockade of CTLA4 prevents inhibitory signals that downregulate T-cell activation.
18612161	Melanoma	TLR9	Promote immunity	TLR9 agonists stimulate dendritic cell maturation and ultimately induce a more effective immune response.
18594005	Squamous Cell Carcinoma	NCAM1	Promote immunity (T cell function)	Isopentenyl pyrophosphate-activated CD56+ {gamma}{delta} T lymphocytes display potent antitumor activity toward human squamous cell carcinoma. Our data indicate that CD56(+) gammadelta T cells are potent antitumor effectors capable of killing squamous cell carcinoma and may play an important therapeutic role in patients with head and neck cancer and other malignancies.
18593929	Non-Hodgkin Lymphoma	MS4A1	Promote immunity	Improved therapeutic results by pretargeted radioimmunotherapy of non-Hodgkin's lymphoma with a new recombinant, trivalent, anti-CD20, bispecific antibody.
18593896	Colon Cacinoma; Head and Neck Carcinoma	EGFR	Inhibit immunity	Therapeutic monoclonal antibodies against the epidermal growth factor receptor (EGFR) have advanced the treatment of colon and head and neck cancer, and show great promise for the development of treatments for other solid cancers.
18591381	Chronic Myeloid Leukemia	PRAME	Immunotherapy target	Cytotoxic T lymphocytes directed to the preferentially expressed antigen of melanoma (PRAME) target chronic myeloid leukemia.
18587008	B16 Malignant Melanoma	TLR2	Promote immunity (T cell function); increase the efficacy of immunotherapy	Recent studies by several groups, including ours, have shown that TLRs can function as costimulatory receptors for antigen-specific T cells, resulting in enhanced T-cell survival and increased expression of effector molecules. These findings emphasize the physiological significance of TLR2 engagement on CTLs and could make possible new approaches for the development of effective immunotherapies by manipulating TLR signaling within CTLs.
18568025	Plasma Cell Myeloma	IRF4	Promote immunity	The transcription factor IRF4 (interferon regulatory factor 4) is required during an immune response for lymphocyte activation and the generation of immunoglobulin-secreting plasma cells.
18566400	Renal Cell Carcinoma	FLT1	Inhibit immunity	Oxidative stress regulates expression of VEGFR1 in myeloid cells: link to tumor-induced immune suppression in renal cell carcinoma. Data suggest that tumor-induced oxidative stress may promote both VEGFR1 up-regulation and immunosuppressive function in bone marrow-derived myeloid cells.
18561323	Bladder Carcinoma	MUC1	Immunotherapy target	Upregulated expression of complement inhibitory proteins on bladder cancer cells and anti-MUC1 antibody immune selection.
18559587	Head and Neck Squamous Cell Carcinoma	TGFB1	Inhibit immunity (T cell function)	Tr1 cells suppressed proliferation of autologous responders via IL-10 and TGF-beta1 secretion. In HNSCC, Tr1 cell generation is promoted at the tumor site. Tr1 cells use TGF-beta and IL-10 to mediate suppression.
18559587	Head and Neck Squamous Cell Carcinoma	IL10	Inhibit immunity (T cell function)	Tr1 cells suppressed proliferation of autologous responders via IL-10 and TGF-beta1 secretion. In HNSCC, Tr1 cell generation is promoted at the tumor site. Tr1 cells use TGF-beta and IL-10 to mediate suppression.
18559528	Breast Carcinoma	IL12B	Promote immunity	We also showed that the anticancer effect exerted by the IL-12 MSCs is immune mediated because it is absent in immunodeficient mice, is not due to systemic IL-12 delivery, and also occurs in a B16 melanoma model.
18559521	Prostate Carcinoma	KLRK1	Promote immunity	The MHC class I chain-related (MIC) molecules play important roles in tumor immune surveillance through their interaction with the NKG2D receptor on natural killer and cytotoxic T cells. Thus, shedding of the MIC molecules from the tumor cell membrane represents a potential mechanism of escape from NKG2D-mediated immune surveillance.
18539480	Malignant Glioma	EGFR	Inhibit immunity	Tumor-specific immunotherapy targeting the EGFRvIII mutation in patients with malignant glioma.
18537185	Hepatocellular Carcinoma	CD40LG	Promote immunity	CD40/CD40L interaction is essential for DC activation and induction of antigen-specific T-cells. Ad-CD40L transduction exerted CD40/CD40L interactions between DCs, increasing DC immunostimulation with up-regulation of CD80/CD86- and interleukin-12 (IL-12) expression. Transduction of DCs with Ad-CD40L increases significantly the stimulatory capacity of DCs.
18537185	Hepatocellular Carcinoma	CD40	Promote immunity	CD40/CD40L interaction is essential for DC activation and induction of antigen-specific T-cells. Ad-CD40L transduction exerted CD40/CD40L interactions between DCs, increasing DC immunostimulation with up-regulation of CD80/CD86- and interleukin-12 (IL-12) expression.
18537185	Hepatocellular Carcinoma	IL12A	Promote immunity	Ad-CD40L transduction exerted CD40/CD40L interactions between DCs, increasing DC immunostimulation with up-regulation of CD80/CD86- and interleukin-12 (IL-12) expression.
18537185	Hepatocellular Carcinoma	CD80	Promote immunity	Ad-CD40L transduction exerted CD40/CD40L interactions between DCs, increasing DC immunostimulation with up-regulation of CD80/CD86- and interleukin-12 (IL-12) expression.
18537185	Hepatocellular Carcinoma	CD86	Promote immunity	Ad-CD40L transduction exerted CD40/CD40L interactions between DCs, increasing DC immunostimulation with up-regulation of CD80/CD86- and interleukin-12 (IL-12) expression.
18533240	Endometrial Adenocarcinoma	FOXP3	Inhibit immunity (infiltration)	CD4(+)CD25(+) regulatory T-cells (Tregs), that express the transcription factor FOXP3, suppress effector T-cell populations and can enable tumour cells to evade the host immune response. In tumors, 55/79 (69.6%) cases showed little FOXP3(+) lymphocytic infiltration (0-2 per x100 optical field).
18523263	Melanoma	EOMES	Promote immunity	Antitumor responses depend on type 1 immunity, which is severely impaired in mice deficient for the T-box expressed in T cells (T-bet) transcription factor. Both T-bet-deficient (T-bet(-/-)) NK and CTL show defective function, which can be overcome by strong stimuli due to the expression of eomesodermin, another member of the T-box family.
18522536	Melanoma	CSF2	Promote immunity (T cell function); essential for immunotherapy	LAG-3Ig combined with a GM-CSF-secreting tumor cell immunotherapy stimulated both cellular and humoral antitumor immune responses that correlated with prolonged survival in tumor-bearing animals.
18519766	Ovarian Cancinoma	TAP1	Promote immunity (infiltration)	The majority of APM component expression examined was significantly associated with both intratumoral and peritumoral T-cell infiltration (P < 0.05). The expression of APM components and the presence of intratumoral T-cell infiltrates were significantly associated with improved survival (all P < or = 0.01);
18519766	Ovarian Cancinoma	TAP2	Promote immunity (infiltration)	The majority of APM component expression examined was significantly associated with both intratumoral and peritumoral T-cell infiltration (P < 0.05). The expression of APM components and the presence of intratumoral T-cell infiltrates were significantly associated with improved survival (all P < or = 0.01);
18519755	Non-Small Cell Lung Carcinoma	DPPA2	Promote immunity	The restricted expression in normal tissues, expression in tumors with coexpression of CTAs, and spontaneous immunogenicity indicate that ECSA/DPPA2 is a promising target for antigen-specific immunotherapy in NSCLC.
18502835	Leukemia	WT1	Promote immunity	The Wilms tumor antigen, WT1, is associated with several human cancers, including leukemia. We evaluated WT1 as an immunotherapeutic target using our proven DNA fusion vaccine design, p.DOM-peptide, encoding a minimal tumor-derived major histocompatibility complex (MHC) class I-binding epitope downstream of a foreign sequence of tetanus toxin.
18490770	Glioblastoma	NCAM1	Promote immunity (infiltration)	Interestingly, nearly half of all T cells infiltrating GBM specimens were CD56(+) T cells, while much smaller percentages of similar cells were identified within metastatic lung tumors and meningiomas.
18490770	Glioblastoma	IL4	Promote immunity	In addition, direct ex vivo analysis of cytokine expression by TIL from GBM demonstrated significant numbers of IL-4/IL-13 positive cells, cytokines that are integral in the cell-mediated repression of tumor immunity in experimental models.
18490770	Glioblastoma	IL13	Inhibit immunity	In addition, direct ex vivo analysis of cytokine expression by TIL from GBM demonstrated significant numbers of IL-4/IL-13 positive cells, cytokines that are integral in the cell-mediated repression of tumor immunity in experimental models.
18490733	Ovarian Carcinoma	MIF	Inhibit immunity (NK cell function)	The proinflammatory cytokine macrophage migration inhibitory factor (MIF) stimulates tumor cell proliferation, migration, and metastasis; promotes tumor angiogenesis; suppresses p53-mediated apoptosis; and inhibits antitumor immunity by largely unknown mechanisms. Functionally, we find that MIF may contribute to the immune escape of ovarian carcinoma by transcriptionally down-regulating NKG2D in vitro and in vivo which impairs NK cell cytotoxicity toward tumor cells.
18490733	Ovarian Carcinoma	KLRK1	Promote immunity (NK cell function)	Functionally, we find that MIF may contribute to the immune escape of ovarian carcinoma by transcriptionally down-regulating NKG2D in vitro and in vivo which impairs NK cell cytotoxicity toward tumor cells.
18485901	Hepatocellular Carcinoma	CD14	Inhibit immunity (T cell function)	CD14(+) HLA-DR(-/low) cells were unable to stimulate an allogeneic T-cell response, suppressed autologous T-cell proliferation, and had high arginase activity, a hallmark characteristic of MDSC. Most important, CD14(+)HLA-DR(-/low) cells from HCC patients induced a CD4(+)CD25(+)Foxp3(+) regulatory T-cell population when cocultured with autologous T cells.
18483384	B16 Malignant Melanoma	IL2RA	Inhibit immunity	Our results indicate that combined CD25 depletion and homeostatic proliferation support a potent antitumor immune response--an approach with potential for clinical translation.
18483284	Skin Carcinoma	PTAFR	Inhibit immunity	Early steps in the cascade of events leading to immune suppression are the binding of UV-induced platelet-activating factor (PAF) to its receptor and the binding of cis-urocanic acid, a photoreceptor for UVB radiation, to the serotonin (5-HT(2A)) receptor. These data indicate that treating UV-irradiated mice with PAF and 5-HT(2A) receptor antagonists blocks skin cancer induction in vivo, in part by reversing UV-induced damage to the skin and by preventing the induction of immune suppression.
18483277	Colon Cacinoma; Breast Carcinoma	TGFB1	Inhibit immunity	Transforming growth factor beta subverts the immune system into directly promoting tumor growth through interleukin-17. Overexpression of the immunosuppressive cytokine transforming growth factor beta (TGF-beta) is one strategy that tumors have developed to evade effective immunesurveillance. Thus, in addition to suppressing immune surveillance, tumor-induced TGF-beta may actively subvert the CD8+ arm of the immune system into directly promoting tumor growth by an IL-17-dependent mechanism.
18483268	Breast Carcinoma	TGFB1	Inhibit immunity (T cell function); immunotherapy target	We showed that efficacy of the anti-TGF-beta antibody 1D11 in suppressing metastasis was dependent on a synergistic combination of effects on both the tumor parenchyma and microenvironment. The main outcome was a highly significant enhancement of the CD8+ T-cell-mediated antitumor immune response, but effects on the innate immune response and on angiogenesis also contributed to efficacy.
18478568	Melanoma	IL12A	Promote immunity	Therefore the p44/42 MAPK is a target for tumour-mediated immune suppression of DC resulting in transcriptional down-regulation of IL-12 p35 and p40 genes, reduced IL-12 secretion and suppressed Th1-responses.
16106251	Hepatocellular Carcinoma	TSPY1	Immunotherapy target	A serological survey revealed that 6.6% (seven of 106) HCC patients had anti-TSPY antibody response, demonstrating the immunogenicity of TSPY in humans. In conclusion, these data suggest that TSPY is a novel cancer/testis (CT) antigen and may be a potential candidate in vaccine strategy for immunotherapy in HCC patients.
16103105	Plasma Cell Myeloma	MICA	Promote immunity	MICA expressed by multiple myeloma and monoclonal gammopathy of undetermined significance plasma cells Costimulates pamidronate-activated gammadelta lymphocytes. Our results indicate that MICA expressed by monoclonal plasma cells is functional and correlates with disease stages, suggesting a role for the molecule in the immune surveillance against multiple myeloma.
16103104	B-Cell Non-Hodgkin Lymphoma	CD40	Promote immunity	Certain novel immunomodulatory mAbs such as anti-CD40 have shown significant activity in preclinical models. We therefore assessed the efficacy of combining anti-CD40 mAb, known to elicit CTL responses against murine lymphoma models with the commonly used cytotoxic drug, cyclophosphamide.
16094420	Chronic Lymphocytic Leukemia	CTLA4	Inhibit immunity (T cell function)	Patients with chronic lymphocytic leukemia (CLL) have defects in both cellular and humoral immunity. Since CD152 (CTLA-4) plays a critical role in downregulating T-cell responses, we studied the expression of surface and cytoplasmic CD152 (sCD152 and cCD152, respectively) in freshly isolated T cells from treatment-na?ve patients with CLL.
16081794	Melanoma	IL21	Promote immunity	We demonstrate that exposure to IL-21 increased the total number of MART-1-specific CD8+ T cells that could be elicited by >20-fold and, at the clonal level, enriched for a population of high-affinity CD8+ T cells with a peptide dose requirement more than 1 log(10)-fold less than their untreated counterparts. Our studies demonstrate a significant role for IL-21 in the primary Ag-specific human CTL response and support the use of IL-21 in the ex vivo generation of potent Ag-specific CTLs for adoptive therapy or as an adjuvant cytokine during in vivo immunization against tumor Ags.
16081783	Breast Carcinoma; Lung Carcinoma; Prostate Carcinoma	IL21	Promote immunity	IL-21 is a cytokine that can promote the anti-tumor responses of the innate and adaptive immune system. Collectively, these findings suggest that IL-21 therapy may work optimally against tumors that can elicit a NKG2D-mediated immune response.
16081691	Chronic Lymphocytic Leukemia	CD80	Promote immunity (T cell function)	We have investigated the ability of in vitro manipulated CLL cells, via hyperexpression of a triad of costimulatory molecules (B7-1, intercellular adhesion molecule 1 [ICAM-1], and leukocyte-function-associated antigen 3 [LFA-3], designated TRICOM), to stimulate effective antitumor T-cell responses.
16081691	Chronic Lymphocytic Leukemia	ICAM1	Promote immunity (T cell function)	We have investigated the ability of in vitro manipulated CLL cells, via hyperexpression of a triad of costimulatory molecules (B7-1, intercellular adhesion molecule 1 [ICAM-1], and leukocyte-function-associated antigen 3 [LFA-3], designated TRICOM), to stimulate effective antitumor T-cell responses.
16081691	Chronic Lymphocytic Leukemia	CD58	Promote immunity (T cell function)	We have investigated the ability of in vitro manipulated CLL cells, via hyperexpression of a triad of costimulatory molecules (B7-1, intercellular adhesion molecule 1 [ICAM-1], and leukocyte-function-associated antigen 3 [LFA-3], designated TRICOM), to stimulate effective antitumor T-cell responses.
16061910	Colorectal Carcinoma	CSF2	Promote immunity	Chemo-immunotherapy of metastatic colorectal carcinoma with gemcitabine plus FOLFOX 4 followed by subcutaneous granulocyte macrophage colony-stimulating factor and interleukin-2 induces strong immunologic and antitumor activity in metastatic colon cancer patients.
16061910	Colorectal Carcinoma	IL2	Promote immunity	Chemo-immunotherapy of metastatic colorectal carcinoma with gemcitabine plus FOLFOX 4 followed by subcutaneous granulocyte macrophage colony-stimulating factor and interleukin-2 induces strong immunologic and antitumor activity in metastatic colon cancer patients.
16061683	Melanoma	IL2	Promote immunity	Human high molecular weight melanoma-associated antigen mimicry by mouse anti-idiotypic monoclonal antibody MK2-23: enhancement of immunogenicity of anti-idiotypic monoclonal antibody MK2-23 by fusion with interleukin 2. Conjugation of human interleukin 2 (IL-2) to mAb MK2-23 variable regions covalently linked to human immunoglobulin constant regions enhanced mAb MK2-23 immunogenicity in BALB/c mice to an extent similar to that induced by mAb MK2-23 conjugated to KLH and given with Freund's adjuvant.
16056250	Ovarian Dysgerminoma	KIT	Inhibit immunity	Although the prognosis of patients with dysgerminoma is generally good, this receptor could potentially serve as a target for site-specific immunotherapy as an alternative and/or complement to conventional treatment options.
16052233	Lung Adenocarcinoma	E2F1	Promote immunity	Importantly, we also provide evidence that E2F1 sensitizes tumor as well as primary cells to apoptosis mediated by FAS ligand or tumor necrosis factor-related apoptosis-inducing ligand, and enhances the cytotoxic effect of T lymphocytes against tumor cells.Overall, our data identify E2F1 as a critical determinant of the cellular response to death-receptor-mediated apoptosis, and suggest that its downregulation contributes to the immune escape of lung adenocarcinoma tumor cells.
16049975	Gastric Carcinoma	IL18	Inhibit immunity	Exploitation of interleukin-18 by gastric cancers for their growth and evasion of host immunity. Interleukin-18 (IL-18) is a pleiotropic cytokine that enhances Th1 or Th2 immune response. Our results indicate that gastric cancers exploit IL-18 to grow/invade and evade immunosurveillance in the hosts.
16061687	B16 Malignant Melanoma	DCT	Promote immunity	To exploit these properties for immunization purposes, we conjugated the melanoma antigen tyrosinase-related protein (TRP)-2 to alphaDEC-205 antibodies and immunized mice with these conjugates together with dendritic cell-activating oligonucleotides (CpG). Thus, these data show that targeting of dendritic cells in situ by the means of antibody-antigen conjugates may be a novel way to induce long-lasting antitumor immunity.
16061687	B16 Malignant Melanoma	PMEL	Promote immunity	Approximately 70% of the animals were cured from existing tumors by treatment with alphaDEC conjugates carrying two different melanoma antigens (TRP-2 and gp100). Thus, these data show that targeting of dendritic cells in situ by the means of antibody-antigen conjugates may be a novel way to induce long-lasting antitumor immunity.
16045815	Melanoma	HLA-G	Inhibit immunity (T/NK cell function)	The non-classical HLA class I antigen HLA-G is an immune modulator which inhibits the functions of T cells, NK cells, and the Dendritic cells (DC). As a result, HLA-G expression in malignant cells may provide them with a mechanism to escape the immune surveillance. Our data strongly suggest that HLA-G is silenced as a result of CpG hypermethylation within a 5' regulatory region encompassing 220 bp upstream of the start codon.
16034143	Melanoma	TLR7	Promote immunity (T cell function)	Activation of innate immune cells through TLR triggers immunomodulating events that enhance cell-mediated immunity, raising the possibility that ligands to these receptors might act as adjuvants in conjunction with T cell activating vaccines. In this report, topical imiquimod, a synthetic TLR7 agonist, significantly enhanced the protective antitumor effects of a live, recombinant listeria vaccine against murine melanoma.
16034085	Lung Carcinoma	FOXP3	Inhibit immunity (T cell function)	PGE2 exposure induced the T reg cell-specific transcription factor forkhead/winged helix transcription factor gene (FOXP3) in CD4+CD25- T cells and significantly up-regulated its expression in CD4+CD25+ T reg cells.
16034082	B16 Malignant Melanoma	CTLA4	Inhibit immunity	The combination of peptide vaccination and treatment with an Ab directed against the inhibitory receptor CTLA-4 enhanced the immune response against TRP-2 peptide, inducing autoimmune depigmentation and further decreasing lung tumor nodules. Furthermore, addition of CTLA-4 blockade increased the frequency of TRP-2-specific, IFN-secreting T cells in spleen and lymph nodes.
16034082	B16 Malignant Melanoma	CSF2	Promote immunity	Provision of granulocyte-macrophage colony-stimulating factor converts an autoimmune response to a self-antigen into an antitumor response. Subsequent studies revealed that provision of GM-CSF increased dendritic cell numbers in lymph nodes and spleen.
16024634	Hepatocellular Carcinoma	MICA	Promote immunity (NK cell function)	The induction of MIC molecules increased lysis of hepatocellular carcinoma cells by NK cells which was abolished by addition of a blocking NKG2D antibody.
16024634	Hepatocellular Carcinoma	MICB	Promote immunity (NK cell function)	The induction of MIC molecules increased lysis of hepatocellular carcinoma cells by NK cells which was abolished by addition of a blocking NKG2D antibody.
15986140	Melanoma	STAT3	Inhibit immunity	STAT3 participates in the regulation of tumor immune evasion by inhibiting expression of proinflammatory mediators while promoting expression of immune-suppressing factors, which in turn activates STAT3 signaling in dendritic cells leading to immune tolerance.
15986139	Melanoma	NFKB1	Inhibit immunity	Nuclear Factor-kappa B (NF-kappa B) is an inducible transcription factor that regulates the expression of many genes involved in the immune response.
15981208	Renal Cell Carcinoma	CD80	Promote immunity	In contrast, in a HLA Class I-matched situation, B7-2 is more effective in the induction of IFN-gamma and GM-CSF secretion than B7-1, but both B7 molecules induce T cell proliferation equally efficient.
15981208	Renal Cell Carcinoma	CD86	Promote immunity	In contrast, in a HLA Class I-matched situation, B7-2 is more effective in the induction of IFN-gamma and GM-CSF secretion than B7-1, but both B7 molecules induce T cell proliferation equally efficient.
15981207	Cervical Carcinoma	FAS	Promote immunity (T cell function)	Our results demonstrated that chimeric CRT/E7 DNA vaccine resulted in control of tumors with downregulated Fas expression, highlighting the importance of the Fas-FasL pathway in the potent antitumor effect of antigen-specific CD8+ cytotoxic T lymphocytes and the role of Fas as part of in vivo tumor evasion.
15981207	Cervical Carcinoma	FASLG	Promote immunity (T cell function)	Our results demonstrated that chimeric CRT/E7 DNA vaccine resulted in control of tumors with downregulated Fas expression, highlighting the importance of the Fas-FasL pathway in the potent antitumor effect of antigen-specific CD8+ cytotoxic T lymphocytes and the role of Fas as part of in vivo tumor evasion.
15958592	Glioblastoma	CD70	Inhibit immunity	Here we report that glioblastoma multiforme (GBM) mediates immunosuppression by promoting T-cell death via tumor-associated CD70 and gangliosides that act through receptor-dependent and receptor-independent pathways, respectively. Our results indicate that CD70 and gangliosides are both products synthesized by GBMs that may be key mediators of T-cell apoptosis and likely contribute to the T-cell dysfunction observed within the tumor microenvironment.
15958592	Glioblastoma	UGCG	Promote immunity	Gangliosides were found to participate in the induction of T-cell apoptosis, because the glucosylceramide synthase inhibitor (PPPP) significantly reduced the abilities of all four apoptogenic lines to kill the lymphocytes.
15958566	Non-Small Cell Lung Carcinoma	PTGS2	Inhibit immunity	Cyclooxygenase (COX)-2 and its product prostaglandin (PG) E2 underlie an immunosuppressive network that is important in the pathogenesis of non-small cell lung cancer. We conclude that inhibition of COX-2/PGE2 suppresses Treg cell activity and enhances antitumor responses.
15958566	Non-Small Cell Lung Carcinoma	FOXP3	Inhibit immunity	Tumor-derived COX-2/PGE2 induced expression of the Treg cell-specific transcription factor, Foxp3, and increased Treg cell activity.
15958556	Melanoma	SPARC	Inhibit immunity	In the present study, we show that SPARC produced by melanoma cells modulates the antitumor activity of polymorphonuclear leukocytes (PMN). In addition, SPARC-sup cells stimulated the in vitro migration and triggered the antimelanoma cytotoxic capacity of human PMN, an effect that was reverted in the presence of SPARC purified from melanoma cells or by reexpressing SPARC in SPARC-sup cells.
15951291	Acute Lymphoblastic Leukemia	IL2	Promote immunity (NK cell function)	In addition, incubating these effectors for 24 hours with IL-2 + IL-15 significantly increased this cytotoxic function.
15951291	Acute Lymphoblastic Leukemia	IL15	Promote immunity (NK cell function)	Expansion of natural killer cells with lytic activity against autologous blasts from adult and pediatric acute lymphoid leukemia patients in complete hematologic remission. In addition, incubating these effectors for 24 hours with IL-2 + IL-15 significantly increased this cytotoxic function.
15947685	Bladder Carcinoma	PTGS2	Inhibit immunity	The inhibition of PGE2 synthesis by COX inhibition favored the production of IL-12 by BCG activated DC. This potentially will result in the generation of a T-helper type 1, polarized T-cell response that may improve the efficacy of BCG therapy.
15947685	Bladder Carcinoma	IL12A	Promote immunity	The inhibition of PGE2 synthesis by COX inhibition favored the production of IL-12 by BCG activated DC. This potentially will result in the generation of a T-helper type 1, polarized T-cell response that may improve the efficacy of BCG therapy.
15944250	B16 Malignant Melanoma	PTPRC	Promote immunity	Immune activation in tumor-draining lymph nodes correlated with an increase in the number of CD45(+) cells infiltrating single dose irradiated tumors compared with nonirradiated mice.
15943986	Cervical Carcinoma	EBAG9	Inhibit immunity	The number of cells with positive expression of RCAS1, but not of FasL or TNF-alpha, was significantly correlated with the number of apoptotic lymphocytes in uterine cervix and metastatic lymph nodes (P < 0.0001 for both). RCAS1 expression may be related to tumor cell evasion of immune surveillance via induction of lymphocyte apoptosis in primary lesions and metastatic lymph nodes in uterine cervical cancer.
15940614	Colorectal Cancinoma	FASLG	Inhibit immunity (T cell function)	These data show that colorectal cancer induces T-cell apoptosis through the release of Fas ligand-bearing and tumor necrosis factor-related apoptosis-inducing ligand-bearing microvesicles both in vitro and in vivo.
15940614	Colorectal Cancinoma	TNF	Inhibit immunity (T cell function)	These data show that colorectal cancer induces T-cell apoptosis through the release of Fas ligand-bearing and tumor necrosis factor-related apoptosis-inducing ligand-bearing microvesicles both in vitro and in vivo.
15937544	Melanoma	CD80	Promote immunity (T cell function)	The melanoma microenvironment may lead to local T cell tolerance in part through downregulation of costimulatory molecules, such as B7.1 (CD80).
15905531	Lung Carcinoma	CD5	Inhibit immunity (T cell function)	Although these clones elicited identical functional avidity and similar cytolytic potential, only T cell clones derived from TIL efficiently lysed autologous tumor cells. Interestingly, all of these clones expressed the same T cell surface markers except for the TCR inhibitory molecule CD5, which was expressed at much lower levels in TIL than in PBL. Significantly, analysis of a panel of circulating clones indicated that antitumor cytolytic activity was inversely proportional to CD5 expression levels.
15894359	Cervical Carcinoma	CTSB	Inhibit immunity	Immunosuppressive activity of proteases in cervical carcinoma. We found that purified enzymes such as trypsin, cathepsin B, uPA and type IV collagenase suppressed the proliferative response in a dose-dependent fashion.
29530936	Non-Small Cell Lung Carcinoma	CD276	Inhibit immunity (T cell function)	B7-H3 negatively modulates CTL-mediated cancer immunity. B7-H3 expressed on tumor cells potentially circumvents CD8+-T-cell-mediated immune surveillance.
29523597	Prostate Carcinoma	CD40LG	Inhibit immunity (T cell function)	Thus mast cells have an immunoregulatory effect on PMN-MDSCs activity through CD40L-CD40 interaction, favoring immunosuppression and tumor onset.
29510987	Colorectal Carcinoma	CTNNB1	Inhibit immunity (infiltration)	WNT/β-catenin signaling genes were significantly mutated in all CRC subtypes, and activated WNT/β-catenin signaling was correlated with the absence of T-cell infiltration.
29496759	Melanoma	MEX3B	resistant to immunotherapy	The RNA-binding protein MEX3B mediates resistance to cancer immunotherapy by downregulating HLA-A expression. In addition, significantly decreased levels of IFNγ were secreted from TILs incubated with MEX3B-overexpressing tumor cells. MEX3B mediates resistance to cancer immunotherapy by binding to the 3' UTR ofHLA-Ato destabilize theHLA-AmRNA and thus downregulate HLA-A expression on the surface of tumor cells, thereby making the tumor cells unable to be recognized and killed by T cells.
29496759	Melanoma	HLA-A	Promote immunity	In addition, significantly decreased levels of IFNγ were secreted from TILs incubated with MEX3B-overexpressing tumor cells. Interestingly, this phenotype was rescued upon overexpression of exogenous HLA-A2.
29490991	Prostate Carcinoma; Melanoma	TNF	Promote immunity (infiltration); Essential for immunotherapy	Targeting the tumor vasculature with low-dose TNF in association with ACT may represent a novel strategy for enhancing T-cell infiltration in tumors and overcoming resistance to immune checkpoint blockers. NGR The combination of ACT, NGR-TNF and ICB was the most effective in delaying disease progression, and in improving overall survival of mice bearing ICB-resistant prostate cancer or melanoma.
29489427	Urothelial Carcinoma	DDR1	Resistant to immunotherapy	We examined the relationship between DDR alterations and response to PD-1/PD-L1 blockade. A higher response rate was observed in patients whose tumors harbored known or likely deleterious DDR alterations (80%) compared with DDR alterations of unknown significance (54%) and in those whose tumors were wild-type for DDR genes (19%; P < .001). DDR alterations are independently associated with response to PD-1/PD-L1 blockade in patients with metastatic urothelial carcinoma.
29487385	Melanoma	HDAC6	Inhibit immunity; immunotherapy target	Histone deacetylase (HDAC) inhibitor ACY241 enhances anti-tumor activities of antigen-specific central memory cytotoxic T lymphocytes against multiple myeloma and solid tumors. Here we show ACY241 significantly reduces the frequency of CD138+MM cells, CD4+CD25+FoxP3+regulatory T cells, and HLA-DRLow/-CD11b+CD33+myeloid-derived suppressor cells; and decreases expression of PD1/PD-L1 on CD8+T cells and of immune checkpoints in bone marrow cells from myeloma patients. ACY241 increased B7 (CD80, CD86) and MHC (Class I, Class II) expression on tumor and dendritic cells. ACY241 induces co-stimulatory (CD28, 41BB, CD40L, OX40) and activation (CD38) molecule expression in a dose- and time-dependent manner, and anti-tumor activities, evidenced by increased perforin/CD107a expression, IFN-γ/IL-2/TNF-α production, and antigen-specific central memory CTL.
29487200	Prostate Carcinoma	IL27	Inhibit immunity; candidate for immunotherapy target	Interleukin-30/IL-27p28 shapes prostate cancer stem-like cell behavior and is critical for tumor onset and metastasization. PCSLC-derived IL-30 supported PCSLC viability, self-renewal and tumorigenicity, expression of inflammatory mediators and growth factors, tumor immune evasion and regulated chemokine and chemokine receptor genes, primarily via STAT1/STAT3 signaling. Furthermore, it promoted PCSLC dissemination to lymph nodes and bone marrow by upregulating the CXCR5/CXCL13 axis, and drove metastasis to lungs through the CXCR4/CXCL12 axis.
29483645	Melanoma	MAPK7	Inhibit immunity; immunotherapy target	ERK5 is activated by oncogenic BRAF and promotes melanoma growth. Genetic silencing and pharmacological inhibition of ERK5 pathway drastically reduce the growth of melanoma cells and xenografts harboring wild-type (wt) or mutated BRAF (V600E).
29483645	Melanoma	BRAF	Resistant to immunotherapy	We also found that oncogenic BRAF positively regulates expression, phosphorylation, and nuclear localization of ERK5.
29467301	Myeloproliferative Neoplasm	JAK2	Inhibit immunity	We show that oncogenic JAK2 (Janus kinase 2) activity caused STAT3 (signal transducer and activator of transcription 3) and STAT5 phosphorylation, which enhanced PD-L1 promoter activity and PD-L1 protein expression in JAK2V617F-mutant cells, whereas blockade of JAK2 reduced PD-L1 expression in myeloid JAK2V617F-mutant cells. PD-L1 expression was higher on primary cells isolated from patients with JAK2V617F-myeloproliferative neoplasms (MPNs) compared to healthy individuals and declined upon JAK2 inhibition.
29467128	Gastrointestinal Stromal Tumor	CD40	Promote immunity	Here, we showed that ligation of CD40 using an agonistic antibody (anti-CD40) activated tumor-associated macrophages (TAMs) in vivo in a knock-in mouse model of GIST harboring a germline mutation in Kit exon 11. CD40 ligation did not have a direct inhibitory effect on human GIST cells. Our findings provide the rationale for combining anti-CD40 and tyrosine kinase inhibition to treat human GIST.
29463595	Prostate Carcinoma	UBE3A	Inhibit immunity	Genetic manipulations of E6AP in prostate cancer cells expose a role of E6AP in promoting growth and survival of prostate cancer cells in vitro and in vivo. Concomitant knockdown of E6AP and clusterin supported the contribution of clusterin to the phenotype induced by E6AP.
29463593	Colon Carcinoma	IL33	Promote immunity	The decrease of this IFNγ gene expression signature was associated with more aggressive disease in human colon cancer patients, suggesting that lack of IL33 signaling impaired the generation of a potent IFNγ-mediated antitumor immune response. Collectively, our data reveal that IL33 functions as a tumor suppressor in sporadic colon cancer.
29440144	Hepatocellular Carcinoma	SPON2	Promote immunity (infiltration)	Here we report that, in the tumor microenvironment of hepatocellular carcinoma (HCC), SPON2 not only promotes infiltration of M1-like macrophages but also inhibits tumor metastasis. SPON2-α4β1 integrin signalling activated RhoA and Rac1, increased F-actin reorganization, and promoted M1-like macrophage recruitment. Overall, our findings provide evidence that SPON2 is a critical factor in mediating the immune response against tumor cell growth and migration in HCC.
29438695	Triple-Negative Breast Carcinoma	EGF	Inhibit immunity	In the study of immune receptor glycosylation, we showed that EGF induces programmed death ligand 1 (PD-L1) and receptor programmed cell death protein 1 (PD-1) interaction, requiring β-1,3-N-acetylglucosaminyl transferase (B3GNT3) expression in triple-negative breast cancer.
29438695	Triple-Negative Breast Carcinoma	B3GNT3	Inhibit immunity	Downregulation of B3GNT3 enhances cytotoxic T cell-mediated anti-tumor immunity.
29438108	Lung Carcinoma; Breast Carcinoma	STAT3	Inhibit immunity (infiltration)	Furthermore, using knock-in transgenic mouse models for lung and breast cancers, we establish the host-specific tumor-extrinsic functions of STAT3-enhancing germline variants in impeding the tumor infiltration of CD8 T cells. Thus, STAT3-enhancing germline receptor variants contribute to immune evasion through their pleiotropic functions in immune cells.
29436395	Melanoma	CSF1R	Inhibit immunity; immunotherapy target	We demonstrate in an autochthonous, poorly immunogenic mouse model of melanoma that combination therapy with an agonistic anti-CD40 mAb and CSF-1R inhibitor potently suppressed tumor growth.
29431745	Colorectal Carcinoma; Melanoma	DKK2	Inhibit immunity; Resistant to immunotherapy	DKK2 secreted by tumor cells acts on cytotoxic lymphocytes, inhibiting STAT5 signaling by impeding STAT5 nuclear localization via LRP5, but independently of LRP6 and the Wnt-β-catenin pathway. Genetic or antibody-mediated ablation of DKK2 activates natural killer (NK) cells and CD8+T cells in tumors, impedes tumor progression, and enhances the effects of PD-1 blockade.
29429992	Cervical Carcinoma	SRSF10	Inhibit immunity	SRSF10-mediated IL1RAP alternative splicing regulates cervical cancer oncogenesis via mIL1RAP-NF-κB-CD47 axis. SRSF10-mediated mIL1RAP upregulates the expression of the "don't eat me" signal CD47 to inhibit macrophage phagocytosis by promoting nuclear factor-κB activation, which is pivotal in inflammatory, immune, and tumorigenesis processes.
29422611	Lung Carcinoma	IRF7	Inhibit immunity	Meanwhile, IRF7 enhanced constitutive PD-L1 expression, which was independent of IFN-γ though directly promote transcription of PD-L1, leading to abrogating cytotoxic T lymphocytes (CTLs) generation which could be restored by anti-PD-L1 antibody, or siRNA-IRF7.
29408314	Cholangiocarcinoma	MCL1	Inhibit immunity	Enforced expression of N terminus-truncated MCL1 targeted to the mitochondrial matrix, but not full-length MCL1 targeted to the outer mitochondrial membrane, rescued cell death and mitochondrial function. These observations support a heretofore unidentified, alternative MCL1 survival function, namely prevention of cell necrosis, and have implications for treatment of human CCA. Cellular depletion of MCL1 resulted in the death of the cancer cells by a process characterised by cell rupture.
29233972	Melanoma	IRF8	Promote immunity	In vivo, IRF8 is essential for the anti-tumour effects of Th9 cells in mouse melanoma models. Our results show that IRF8 complexes boost the Th9 program and repress Il4 expression to modulate Th9 cell differentiation. IRF8 functions through a transcription factor complex consisting of IRF8, IRF4, PU.1 and BATF, which binds to DNA and boosts Il9 transcription.
29233903	Head and Neck Carcinoma	CD274	Inhibit immunity	HNSCCs expressing elevated levels of PD-L1 have especially poor outcome. PD-L1 levels on exosomes, but not levels of sPD-L1, associated with disease progression in HNSCC patients. Circulating PD-L1+exosomes emerge as useful metrics of disease and immune activity in HNSCC patients.
29229854	Triple-Negative Breast Carcinoma	IFNB1	Promote immunity	Treatment with IFN-beta (IFN-β) led to a less aggressive epithelial/non-CSC-like state, with repressed expression of mesenchymal proteins (VIMENTIN, SLUG), reduced migration and tumor sphere formation, and reexpression of CD24 (a surface marker for non-CSCs), concomitant with an epithelium-like morphology. Here we report a positive translational role for IFN-β, as gene expression profiling of patient-derived TNBC tumors demonstrates that an IFN-β metagene signature correlates with improved patient survival, an immune response linked with tumor-infiltrating lymphocytes (TILs), and a repressed CSC metagene signature.
29229829	Prostate Carcinoma	FOLH1	Promote immunity	Prostate tumors invariably overexpress prostate surface membrane antigen (PSMA). PPD selectively delivered polyIC into PSMA-overexpressing PC cells, inducing apoptosis, cytokine secretion, and the recruitment of human peripheral blood mononuclear cells (PBMCs).
29226764	Diffuse Large B-Cell Lymphoma; Follicular Lymphoma	CD19	Promote immunity	We used autologous T cells that express a CD19-directed CAR (CTL019) to treat patients with diffuse large B-cell lymphoma or follicular lymphoma that had relapsed or was refractory to previous treatments. CTL019 cells can be effective in the treatment of relapsed or refractory diffuse large B-cell lymphoma and follicular lymphoma.
29217732	Lung Carcinoma	TPP1	Promote immunity	Using a T-cell activation assay and mixed lymphocyte reaction, TPP-1 was verified to interfere with the interaction of PD-1/PD-L1. The growth rate of tumor masses in TPP-1 or PD-L1 antibody-treated mice was 56% or 71% lower than that in control peptide-treated mice, respectively, indicating that TPP-1 inhibits, or at least retards, tumor growth. IHC of the tumors showed that IFNγ and granzyme B expression increased in the TPP-1 or PD-L1 antibody-treated groups, indicating that TPP-1 attenuates the inhibitory effect of PD-L1 on T cells and that T cells may get reactivated.
29217528	Follicular Lymphoma	TIGIT	Inhibit immunity	CD8 FL T cells demonstrated highly reduced TCR-induced phosphorylation (p) of ERK and reduced production of IFNγ, while TCR proximal signaling (p-CD3ζ, p-SLP76) was not affected. Dysfunctional TCR signaling correlated with TIGIT expression in FL CD8 T cells and could be fully restored upon in vitro culture.
29213079	Mesothelioma; Melanoma	DPP4	Promote immunity (T cell function)	Further analysis revealed that CD26high cells have a rich chemokine receptor profile (including CCR2 and CCR5), profound cytotoxicity (Granzyme B and CD107A), resistance to apoptosis (c-KIT and Bcl2), and enhanced stemness (β-catenin and Lef1). These properties license CD26high T cells with a natural capacity to traffic to, regress and survive in solid tumors.
29208683	Squamous Cell Carcinoma	PTK2	Inhibit immunity	Focal adhesion kinase (FAK) mediates tumor cell-intrinsic behaviors that promote tumor growth and metastasis. We previously showed that FAK also induces the expression of inflammatory genes that inhibit antitumor immunity in the microenvironment.
29208683	Squamous Cell Carcinoma	IL33	Inhibit immunity	IL-33 and ST2 mediate FAK-dependent antitumor immune evasion through transcriptional networks. IL-33 associated with FAK in the nucleus, and the FAK-IL-33 complex interacted with a network of chromatin modifiers and transcriptional regulators, including TAF9, WDR82, and BRD4, which promote the activity of nuclear factor κB (NF-κB) and its induction of genes encoding chemokines, including CCL5.
29198913	Lymphoma	CD27	Promote immunity	Antibody Tumor Targeting Is Enhanced by CD27 Agonists through Myeloid Recruitment. Only the anti-CD27/CD20 combination provided cures. Detailed mechanistic analysis using single-cell RNA sequencing demonstrated that anti-CD27 stimulated CD8+T and natural killer cells to release myeloid chemo-attractants and interferon gamma, to elicit myeloid infiltration and macrophage activation.
29196603	Soft Tissue Sarcoma	CSPG4	Inhibit immunity	Inhibiting NG2/CSPG4 expression in established murine and human STSs decreased tumor volume by almost two-thirds and cell proliferation rate by 50%. NG2/CSPG4 antibody immunotherapy in human sarcomas established as xenografts in mice similarly decreased tumor volume, and expression of a lentivirus blocking NG2/CSPG4 expression inhibited tumor cell proliferation and increased the latency of engraftment. Gene profiling showed that Ng2/Cspg4 deletion altered the expression of genes regulating cell proliferation and apoptosis. Surprisingly, Ng2/Cspg4 deletion at the time of tumor initiation resulted in larger tumors. Gene expression profiling indicated substantial down-regulation of insulin-like growth factor binding protein (Igfbp) genes when Ng2/Cspg4 is depleted at tumor initiation, but not when Ng2/Cspg4 is depleted after tumor initiation.
29187357	Lung Melanoma	IL2	Promote immunity	Consistent with this, mature mouse primary iNKT cells and iNKT hybridomas increased production of effector cytokines in the presence of IAP antagonists. In vivo administration of IAP antagonists and α-GalCer resulted in increased IFNγ and IL-2 production from iNKT cells and decreased tumor burden in a mouse model of melanoma lung metastasis.
29186113	Colorectal Carcinoma	MLH1	Inhibit immunity	Immune surveillance improved when cancer cells, in which MLH1 had been inactivated, accumulated neoantigens for several generations.
29181007	Breast Carcinoma	ERBB2	Inhibit immunity	Overexpression of the human epidermal growth factor receptor 2 (HER2) defines a subgroup of breast tumors with aggressive behavior. HER2-specific antibodies can trigger natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity and indirectly enhance the development of tumor-specific T cell immunity; both mechanisms contributing to their antitumor efficacy in preclinical models.
29180808	Ovarian Carcinoma; Colon Carcinoma	LILRB1	Inhibit immunity; candidate for immunotherapy target	Engagement of MHC class I by the inhibitory receptor LILRB1 suppresses macrophages and is a target of cancer immunotherapy. Our results demonstrated that expression of the common MHC class I component β2-microglobulin (β2M) by cancer cells directly protected them from phagocytosis. We further showed that this protection was mediated by the inhibitory receptor LILRB1, whose expression was upregulated on the surface of macrophages, including tumor-associated macrophages.
29180626	Melanoma	FAM73B	Inhibit immunity	Here we show that FAM73b, a mitochondrial outer membrane protein, has a pivotal function in Toll-like receptor-regulated mitochondrial morphology switching from fusion to fission. Switching to mitochondrial fission via ablation of Fam73b (also known as Miga2) promotes IL-12 production. In tumor-associated macrophages, this switch results in T-cell activation and enhances anti-tumor immunity.
29160310	Prostate Carcinoma	CDK4	Promote immunity	Here we show that PD-L1 protein abundance is regulated by cyclin D-CDK4 and the cullin 3-SPOP E3 ligase via proteasome-mediated degradation. Inhibition of CDK4 and CDK6 (hereafter CDK4/6) in vivo increases PD-L1 protein levels by impeding cyclin D-CDK4-mediated phosphorylation of speckle-type POZ protein (SPOP) and thereby promoting SPOP degradation by the anaphase-promoting complex activator FZR1. Loss-of-function mutations in SPOP compromise ubiquitination-mediated PD-L1 degradation, leading to increased PD-L1 levels and reduced numbers of tumour-infiltrating lymphocytes in mouse tumours and in primary human prostate cancer specimens.
29155426	B Acute Lymphoblastic Leukemia	CD22	Promote immunity	CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. CD22 is also expressed in most cases of B-ALL and is usually retained following CD19 loss. Relapses were associated with diminished CD22 site density that likely permitted CD22+cell escape from killing by CD22-CAR T cells. These results are the first to establish the clinical activity of a CD22-CAR in B-ALL, including leukemia resistant to anti-CD19 immunotherapy, demonstrating potency against B-ALL comparable to that of CD19-CAR at biologically active doses.
29150430	Melanoma	CTLA4	Inhibit immunity; immunotherapy target	CTLA4 is a cell surface receptor on T cells that functions as an immune checkpoint molecule to enforce tolerance to cognate antigens. Anti-CTLA4 immunotherapy is highly effective at reactivating T-cell responses against melanoma, which is postulated to be due to targeting CTLA4 on T cells.
29150430	Melanoma	IFNG	Inhibit immunity	Interferon-γ (IFNG) signaling activated the expression of the human CTLA4 gene in a melanocyte and melanoma cell-specific manner. Mechanistically, IFNG activated CTLA4 expression through JAK1/2-dependent phosphorylation of STAT1, which bound a specific gamma-activated sequence site on the CTLA4 promoter, thereby licensing CBP/p300-mediated histone acetylation and local chromatin opening.
29145561	Triple-Negative Breast Carcinoma	NT5E	Inhibit immunity	CD73 is an ecto-enzyme that promotes tumor immune escape through the production of immunosuppressive extracellular adenosine in the tumor microenvironment. Our results demonstrated that high levels of CD73 expression on epithelial tumor cells were significantly associated with reduced disease-free survival, overall survival and negatively correlated with tumor immune infiltration (Spearman's R= -0.50, p < 0.0001).
29136509	Melanoma	HIF1A	Promote immunity	Furthermore, loss of HIF-1α in CD8+ T cells reduced tumor infiltration and tumor cell killing, and altered tumor vascularization.
29136509	Breast Carcinoma	VEGFA	Inhibit immunity	Analyses of human breast cancer showed inverse correlations between VEGF-A expression and CD8+T cell infiltration, and a link between T cell infiltration and vascularization.
29129643	Non-Small Cell Lung Carcinoma	TGFB1	Inhibit immunity	Aberrant upregulation of TGFβ expression in the tumor microenvironment has also been implicated in promoting NSCLC progression and metastasis, as well as driving the development of resistance to cytotoxic, targeted, and immunomodulatory therapeutic interventions.
29123081	Melanoma	FAS	Inhibit immunity	Apoptosis of tumor-infiltrating lymphocytes can be prevented by interrupting the Fas/Fas-ligand axis, and is triggered by polymorphonuclear-myeloid-derived suppressor cells, which express high levels of Fas-ligand and are enriched in TiRP tumors. Blocking Fas-ligand increases the anti-tumor efficacy of adoptive T-cell therapy in TiRP tumors, and increases the efficacy of checkpoint blockade in transplanted tumors.
29118090	Lung Carcinoma	C3	Inhibit immunity	Notably, growth of primary tumors and metastases was both strongly inhibited in C3-deficient mice (C3-/-mice), with tumors undetectable in many subjects. Similarly, antagonists of the C3a or C5a receptors inhibited tumor growth.
29097606	Glioma	NRP1	Inhibit immunity	Mice that lack the transmembrane receptor neuropilin-1 (Nrp1), which modulates GAM immune polarization, exhibit a decrease in glioma volumes and neoangiogenesis and an increase in antitumorigenic GAM infiltrate. Mice with Nrp1-deficient microglia and wild-type peripheral macrophages showed resistance to glioma development and had higher microglial infiltrate than mice with wild-type GAMs.
28911087	Lung Carcinoma	TGFB2	Inhibit immunity	An antisense oligonucleotide targeting TGF-β2 inhibits lung metastasis and induces CD86 expression in tumor-associated macrophages. In addition, using an orthotopic xenograft model of a lung cancer cell line (CRL5807) that mainly expresses TGF-β2, we observed that ISTH0047 had an important effect on the lung microenvironment inhibiting the growth of lung lesions. ISTH0047 treatment re-educated macrophages in the lung parenchyma to express the tumor-suppressive factor, CD86.
28904226	Melanoma	VEGFC	Promote immunity	In human metastatic melanoma, gene expression of VEGF-C strongly correlated with CCL21 and T cell inflammation, and serum VEGF-C concentrations associated with both T cell activation and expansion after peptide vaccination and clinical response to checkpoint blockade. We propose that VEGF-C potentiates immunotherapy by attracting naïve T cells, which are locally activated upon immunotherapy-induced tumor cell killing, and that serum VEGF-C may serve as a predictive biomarker for immunotherapy response.
28904130	Skin Squamous Cell Carcinoma	CCR5	Inhibit immunity	Analysis of tumor lesions in wild-type (WT) and CCR5KO mice revealed that lack of CCR5 lead to significant reduction in frequency of Tregs and increased of CD4 T cells into the tumors. In this study, we also demonstrated that Treg migration to the tumor microenvironment is mediated by CCR5, and these cells are promoting tumor growth via inhibition of antitumor cells such as cytotoxic CD8+T cells.
28903971	Plasma Cell Myeloma	S100A9	Inhibit immunity; candidate for immunotherapy target	We showed that S100A9 acted as a chemoattractant for MM cells and induced MDSCs to express and secrete inflammatory and pro-myeloma cytokines, including TNFα, IL6, and IL10. Our data suggest that extracellular S100A9 promotes MM and that inhibition of S100A9 may have therapeutic benefit.
28899975	Choriocarcinoma	VEGFA	Inhibit immunity	We recently identified endocrine gland-derived vascular endothelial growth factor (EG-VEGF) as a novel key placental growth factor that controls trophoblast proliferation and invasion. Treatment of the animal model with EG-VEGF receptor's antagonists significantly reduced tumor development and progression and preserved pregnancy.
28898695	Neuroblastoma	GPC2	Inhibit immunity	We confirm GPC2 to be highly expressed on most neuroblastomas, but not detectable at appreciable levels in normal childhood tissues. In addition, we demonstrate that GPC2 is required for neuroblastoma proliferation.
28895560	Acute Myeloid Leukemia	TXK	Resistant to immunotherapy	Tyrosine kinase inhibition increases the cell surface localization of FLT3-ITD and enhances FLT3-directed immunotherapy of acute myeloid leukemia. TKI treatment increased the surface expression through upregulation of FLT3 and glycosylation of FLT3-ITD and FLT3-D835Y mutants.
28895560	Acute Myeloid Leukemia	FLT3	Promote immunity	The fms-related tyrosine kinase 3 (FLT3) receptor has been extensively studied over the past two decades with regard to oncogenic alterations that do not only serve as prognostic markers but also as therapeutic targets in acute myeloid leukemia (AML).
28894087	Hepatocellular Carcinoma	ENTPD2	Inhibit immunity	Mechanistically, we demonstrate that ENTPD2 converts extracellular ATP to 5'-AMP, which prevents the differentiation of MDSCs and therefore promotes the maintenance of MDSCs. We further find that ENTPD2 inhibition is able to mitigate cancer growth and enhance the efficiency and efficacy of immune checkpoint inhibitors.
28892778	Non-Small Cell Lung Carcinoma	CD274	Inhibit immunity (T cell function)	An increase in BAG-1 by PD-L1 confers resistance to tyrosine kinase inhibitor in non-small cell lung cancer via persistent activation of ERK signalling. Mechanistically, the PD-L1-induced BAG-1 expression reciprocally increased PD-L1 expression due to persistent activation of ERK signalling, and it consequently conferred TKI resistance in NSCLC cells.
28891811	Pancreatic Carcinoma	NFKB1	Inhibit immunity	NF-κB regulates GDF-15 to suppress macrophage surveillance during early tumor development. Mechanistically, we found that GDF-15 suppresses macrophage activity by inhibiting TGF-β-activated kinase (TAK1) signaling to NF-κB, thereby blocking synthesis of TNF and NO.
28891811	Pancreatic Carcinoma	GDF15	Inhibit immunity	In vitro, tumor-derived GDF-15 signals in macrophages to suppress their proapoptotic activity by inhibiting TNF and nitric oxide (NO) production. In vivo, depletion of GDF-15 in Ras-driven tumor xenografts and in an orthotopic model of pancreatic cancer delayed tumor development.
28886380	Melanoma	REL	Inhibit immunity; Resistant to immunotherapy	We show that NF-κB c-Rel ablation specifically impairs the generation and maintenance of the activated Treg (aTreg) subset, which is known to be enriched at sites of tumors. Moreover, chemical inhibition of c-Rel function delayed melanoma growth by impairing a Treg-mediated immunosuppression and potentiated the effects of anti-PD-1 immunotherapy.
28878352	Hodgkin Lymphoma	S1PR1	Inhibit immunity	S1PR1 drives a feedforward signalling loop to regulate BATF3 and the transcriptional programme of Hodgkin lymphoma cells. S1P activates phosphatidylinositide 3-kinase (PI3-K) in these cells that is mediated by the increased expression of S1PR1 and the decreased expression of S1PR2. Genes upregulated by the PI3-K pathway included the basic leucine zipper transcription factor, ATF-like 3 (BATF3), which is normally associated with the development of dendritic cells. Knockdown of BATF3 in HL cell lines revealed that BATF3 contributed to the transcriptional programme of primary HRS cells, including the upregulation of S1PR1.
28878208	Melanoma	HSP90AA1	Inhibit immunity	HSP90 inhibition enhances cancer immunotherapy by upregulating interferon response genes. We show that inhibition of HSP90 with ganetespib enhances T-cell-mediated killing of patient-derived human melanoma cells by their autologous T cells in vitro and potentiates responses to anti-CTLA4 and anti-PD1 therapy in vivo. Mechanistic studies reveal that HSP90 inhibition results in upregulation of interferon response genes, which are essential for the enhanced killing of ganetespib treated melanoma cells by T cells.
28874561	Melanoma	CD47	Inhibit immunity; Resistant to immunotherapy	CD47 is an antiphagocytic ligand broadly expressed on normal and malignant tissues that delivers an inhibitory signal through the receptor signal regulatory protein alpha (SIRPα). Inhibitors of the CD47-SIRPα interaction improve antitumor antibody responses by enhancing antibody-dependent cellular phagocytosis (ADCP) in xenograft models. Generation of a B16F10 cell line that secretes the A4 nanobody showed that an enhanced response to several immune therapies requires near-complete blockade of CD47 in the tumor microenvironment.
28865999	Hepatocellular Carcinoma	GPC3	Inhibit immunity; candidate for immunotherapy target	Glypican-3 (GPC3) is a glycosylphosphatidylinositol-anchored glycoprotein that is overexpressed in most HCC tissues but not in normal tissues. Here, in C57/B6 mice, we demonstrated that intravenous infusion of GPC3-coupled lymphocytes (LC/GPC3+) elicited robust GPC3-specific antibody and CTL responses, which effectively restricted proliferation and lysed cultured-HCC cells. Administration of LC/GPC3+induced elevated levels of the cytotoxic T cell bioactive factors tumor necrosis factor alpha (TNF-α), interferon-γ (IFN-γ), granzyme B, and perforin, and substantially increased the number of infiltrating CD8+T cells in tumor tissues.
28855210	Breast Carcinoma	ERBB2	Resistant to immunotherapy	CD73 Promotes Resistance to HER2/ErbB2 Antibody Therapy. In a prospective, randomized phase III clinical trial evaluating the activity of trastuzumab, high levels of CD73 gene expression were associated significantly with poor clinical outcome. Gene ontology enrichment analysis from gene-expression data revealed a positive association of CD73 expression with extracellular matrix organization, TGFβ genes, epithelial-to-mesenchymal transition (EMT) transcription factors and hypoxia-inducible-factor (HIF)-1 gene signature.
28848066	Melanoma	TIMD4	Promote immunity (T cell function)	In contrast, TIM-4+ B cells decreased B16-F10 metastasis and s.c. tumor growth, and this was IFN-γ dependent. Moreover, TIM-4+B cells promoted proinflammatory Th differentiation in vivo, increasing IFN-γ while decreasing IL-4, IL-10, and Foxp3 expression by CD4+T cells-effects that are opposite from those of TIM-1+B cells.
28831000	Diffuse Large B-Cell Lymphoma	CREBBP	Promote immunity	Inactivation of CREBBP expands the germinal center B cell compartment, down-regulates MHCII expression and promotes DLBCL growth. CREBBP-mutant DLBCL clones exhibited reduced histone H3 acetylation, expressed significantly less MHCII, and grew faster than wild-type clones in s.c.
28822887	Non-Small Cell Lung Carcinoma	CD274	Inhibit immunity (T cell function); Immunotherapy target	Recently, immunotherapy based on programmed cell death 1 (PD-1) and its ligand (PD-L1) blockade prolong survival in patients with advanced NSCLC, especially in those patients with positive expression of PD-L1 and when used in the first-line setting.
28822012	Head and Neck Carcinoma	MTOR	Inhibit immunity	Indeed, mTOR inhibition exerts potent anti-tumor activity in HNSCC experimental systems, and mTOR targeting clinical trials show encouraging results. In addition, although counterintuitive, emerging evidence suggests that mTOR inhibition may enhance the anti-tumor immune response.
28819064	Non-Small Cell Lung Carcinoma	CD274	Inhibit immunity (T cell function); Immunotherapy target	Immune checkpoint inhibitors targeting the interaction between programmed cell death-1 (PD-1) and its ligand PD-L1 induce tumor regression in a subset of non-small cell lung cancer patients. Silencing PD-L1 expression in CMT167 cells resulted in smaller orthotopic tumors that remained sensitive to anti-PD-L1 therapy, whereas implantation of CMT167 cells into PD-L1-mice blocked orthotopic tumor growth, indicating a role for PD-L1 in both the cancer cell and the microenvironment.
28813417	Melanoma	CMTM6	Inhibit immunity	CMTM6 maintains the expression of PD-L1 and regulates anti-tumour immunity. CMTM6 is not required for PD-L1 maturation but co-localizes with PD-L1 at the plasma membrane and in recycling endosomes, where it prevents PD-L1 from being targeted for lysosome-mediated degradation. CMTM6 depletion, via the reduction of PD-L1, significantly alleviates the suppression of tumour-specific T cell activity in vitro and in vivo.
28811289	Melanoma	IL15	Promote immunity	Primary Tumors Limit Metastasis Formation through Induction of IL15-Mediated Cross-Talk between Patrolling Monocytes and NK Cells. The combined analysis of these approaches allowed us to establish a hierarchy in which patrolling monocytes, making IL15 in response to primary tumors, activate NK cells and IFNγ production that then inhibit lung metastasis formation. Critically, the protective effect on metastasis was lost upon patrolling monocyte or NK cell depletion, IL15 neutralization, or IFNγ ablation.
28809532	Pancreatic Carcinoma	CXCL12	Inhibit immunity (infiltration)	We also found that CXCL12 trap allowed T-cell penetration into the tumor
28809532	Pancreatic Carcinoma	CD274	Inhibit immunity (T cell function)	We also found that CXCL12 trap allowed T-cell penetration into the tumor, and PD-L1 trap allowed the infiltrated T-cells to kill the tumor cells.
28805662	Anaplastic Large Cell Lymphoma; Hodgkin Lymphoma	TNFRSF8	Inhibit immunity; Immunotherapy target	Targeting CD30 with monoclonal antibodies in Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL) has had profound clinical success. CD30.CAR-Ts are safe and can lead to clinical responses in patients with HL and ALCL, indicating that further assessment of this therapy is warranted.
28801234	Colon Adenocarcinoma	CD47	Inhibit immunity	Here we have shown that CD47-signal regulatory protein α (SIRPα) axis dictates the fate of ingested DNA in DCs for immune evasion. Mechanistically, CD47 blockade enabled the activation of NADPH oxidase NOX2 in DCs, which in turn inhibited phagosomal acidification and reduced the degradation of tumor mitochondrial DNA (mtDNA) in DCs. mtDNA was recognized by cyclic-GMP-AMP synthase (cGAS) in the DC cytosol, contributing to type I interferon (IFN) production and antitumor adaptive immunity.
28790115	Prostate Carcinoma	MSH2	Inhibit immunity (infiltration)	MSH2 Loss in Primary Prostate Cancer. Loss of MSH2 protein is correlated with MSH2 inactivation, hypermutation, and higher tumor-infiltrating lymphocyte density, and appears most common among very high-grade primary tumors, for which routine screening may be warranted if validated in additional cohorts.
28765120	Melanoma	PTGS2	Inhibit immunity; Resistant to immunotherapy	Here, we show that COX-2 expression drives constitutive expression of indoleamine 2,3-dioxygenase 1 (IDO1) in human tumor cells. In a series of seven human tumor lines, constitutive IDO1 expression depends on COX-2 and prostaglandin E2 (PGE2), which, upon autocrine signaling through the EP receptor, activates IDO1 via the PKC and PI3K pathways. Our results highlight the role of COX-2 in constitutive IDO1 expression by human tumors and substantiate the use of COX-2 inhibitors to improve the efficacy of cancer immunotherapy, by reducing constitutive IDO1 expression, which contributes to the lack of T-cell infiltration in "cold" tumors, which fail to respond to immunotherapy.
28765120	Ovarian Carcinoma	IDO1	Inhibit immunity (infiltration); Resistant to immunotherapy	Celecoxib treatment promoted immune rejection of IDO1-expressing human tumor xenografts in immunodeficient mice reconstituted with human allogeneic lymphocytes. This effect was associated with a reduced expression of IDO1 in those ovarian SKOV3 tumors and an increased infiltration of CD3+and CD8+cells. Our results highlight the role of COX-2 in constitutive IDO1 expression by human tumors and substantiate the use of COX-2 inhibitors to improve the efficacy of cancer immunotherapy, by reducing constitutive IDO1 expression, which contributes to the lack of T-cell infiltration in "cold" tumors, which fail to respond to immunotherapy.
28758198	Glioma	MTOR	Inhibit immunity (T cell function)	MiR-15a/16 deficiency enhances anti-tumor immunity of glioma-infiltrating CD8+ T cells through targeting mTOR. More importantly, tumor-infiltrating CD8+ T cells without miR-15a/16 showed lower expression of PD-1, Tim-3 and LAG-3, and stronger secretion of IFN-γ, IL-2 and TNF-α than WT tumor-infiltrating CD8+ T cells. Mechanismly, mTOR was identified as a target gene of miR-15a/16 to negatively regulate the activation of CD8+ T cells.
28754674	Breast Carcinoma	CSF2	Inhibit immunity	GM-CSF was identified as an upstream modulator. Breast cancer-derived GM-CSF induced GM-CSF and MMP9 release from WAT progenitors, and GM-CSF knockdown in breast cancer cells neutralized the protumorigenic activity of WAT progenitors in preclinical models. GM-CSF neutralization in diet-induced obese mice significantly reduced immunosuppression, intratumor vascularization, and local and metastatic breast cancer progression.
28754674	Breast Carcinoma	MMP9	Inhibit immunity	dipose Progenitor Cell Secretion of GM-CSF and MMP9 Promotes a Stromal and Immunological Microenvironment That Supports Breast Cancer Progression. Similarly, MMP9 inhibition reduced neoplastic angiogenesis and significantly decreased local and metastatic tumor growth.
28751450	Glioblastoma	IDO1	Inhibit immunity	GBM IDO1 mRNA levels positively correlated with increased gene expression for markers of cytolytic and regulatory T cells, in addition to decreased patient survival.
28740126	Bladder Carcinoma	PPARG	Inhibit immunity	Here, we report that the PPARγ/RXRα pathway constitutes a tumor-intrinsic mechanism underlying immune evasion in MIBC. Immune cell-infiltration is controlled by activated PPARγ/RXRα that inhibits expression/secretion of inflammatory cytokines. Knockdown of PPARγ or RXRα and pharmacological inhibition of PPARγ significantly increase cytokine expression suggesting therapeutic approaches to reviving immunosurveillance and sensitivity to immunotherapies.
28732079	Nasopharyngeal Carcinoma	PDLIM7	Inhibit immunity	LMP1-mediated glycolysis induces myeloid-derived suppressor cell expansion in nasopharyngeal carcinoma. LMP1 promotes the expression of multiple glycolytic genes, including GLUT1. This metabolic reprogramming results in increased expression of the Nod-like receptor family protein 3 (NLRP3) inflammasome, COX-2 and P-p65 and, consequently, increased production of IL-1β, IL-6 and GM-CSF. This work indicates that LMP1-mediated glycolysis regulates IL-1β, IL-6 and GM-CSF production through the NLRP3 inflammasome, COX-2 and P-p65 signaling pathways to enhance tumor-associated MDSC expansion, which leads to tumor immunosuppression in NPC.
28716895	Lymphoma	CTLA4	Inhibit immunity	CTLA4 activation resulted in lymphoma cell proliferation and tumor growth, whereas silencing or antibody-blockade of CTLA4 in B-cell lymphoma tumor cells in the absence of T cells inhibits tumor growth.
28716899	Squamous Cell Carcinoma	HDAC1	Inhibit immunity; Resistant to immunotherapy	HDAC1 Upregulation by NANOG Promotes Multidrug Resistance and a Stem-like Phenotype in Immune Edited Tumor Cells. Importantly, HDAC inhibition synergized with Ag-specific adoptive T-cell therapy to control immune refractory cancers.
28716899	Squamous Cell Carcinoma	NANOG	Inhibit immunity; Resistant to immunotherapy	NANOG upregulated HDAC1 through promoter occupancy, thereby decreasing histone H3 acetylation on K14 and K27. Our results reveal that NANOG influences the epigenetic state of tumor cells via HDAC1, and they encourage a rational application of epigenetic modulators and immunotherapy in treatment of NANOG+ refractory cancer types.
28716895	B-Cell Lymphoma	CTLA4	Inhibit immunity	CTLA4-CD86 ligation recruited and activated the JAK family member Tyk2, resulting in STAT3 activation and expression of genes critical for cancer immunosuppression and tumor growth and survival. CTLA4 activation resulted in lymphoma cell proliferation and tumor growth, whereas silencing or antibody-blockade of CTLA4 in B-cell lymphoma tumor cells in the absence of T cells inhibits tumor growth.
28714866	Chronic Lymphocytic Leukemia	BTK	Inhibit immunity	Peripheral blood mononuclear cells from chronic lymphocytic leukemia (CLL) patients on clinical trials of ibrutinib (BTK/ITK inhibitor; n = 19) or acalabrutinib (selective BTK inhibitor; n = 13) were collected serially. Both agents reduced expression of the immunosuppressive molecules CD200 and BTLA as well as IL-10 production by CLL cells. PD-1 and CTLA-4 expression was significantly markedly reduced in T cells by both agents.
28714866	Chronic Lymphocytic Leukemia	ITK	Inhibit immunity	Peripheral blood mononuclear cells from chronic lymphocytic leukemia (CLL) patients on clinical trials of ibrutinib (BTK/ITK inhibitor; n = 19) or acalabrutinib (selective BTK inhibitor; n = 13) were collected serially. Ibrutinib markedly increased CD4+ and CD8+ T cell numbers in CLL patients. This effect was more prominent in effector/effector memory subsets and was not observed with acalabrutinib. Ex vivo studies demonstrated that this may be due to diminished activation-induced cell death through ITK inhibition. Both agents reduced expression of the immunosuppressive molecules CD200 and BTLA as well as IL-10 production by CLL cells. PD-1 and CTLA-4 expression was significantly markedly reduced in T cells by both agents.
28698296	Ovarian Carcinoma	PRKCI	Inhibit immunity	PRKCI promotes immune suppression in ovarian cancer. Mechanistically, we show that the oncogenic activity of PRKCI relates in part to the up-regulation of TNFα to promote an immune-suppressive tumor microenvironment characterized by an abundance of myeloid-derived suppressor cells and inhibition of cytotoxic T-cell infiltration. In human ovarian cancers, high PRKCI expression also correlates with high expression of TNFα and YAP1 and low infiltration of cytotoxic T cells.
28698206	Hodgkin Lymphoma	PIM1	Inhibit immunity	Genetic or chemical PIM inhibition with a newly developed pan-PIM inhibitor, SEL24-B489, induced RS cell apoptosis. PIM inhibition decreased cap-dependent protein translation, blocked JAK-STAT signaling, and markedly attenuated NFκB-dependent gene expression. Taken together, our data indicate that PIM kinases in cHL exhibit pleiotropic effects, orchestrating tumor immune escape and supporting RS cell survival.
28694326	Primary Cutaneous T-Cell Non-Hodgkin Lymphoma	RLTPR	Promote immunity	We show that RLTPR (p.Q575E) increases binding of RLTPR to downstream components of the NF-κB signaling pathway, selectively upregulates the NF-κB pathway in activated T cells, and ultimately augments T-cell-receptor-dependent production of interleukin 2 by 34-fold.
28691927	Lung Carcinoma	WDR4	Inhibit immunity	The WDR4/PML axis induces a set of cell-surface or secreted factors, including CD73, urokinase-type plasminogen activator receptor (uPAR), and serum amyloid A2 (SAA2), which elicit paracrine effects to stimulate migration, invasion, and metastasis in multiple lung cancer models. Our study identifies WDR4 as an oncoprotein that negatively regulates PML via ubiquitination to promote lung cancer progression by fostering an immunosuppressive and prometastatic tumor microenvironment.
28687615	Glioblastoma	SOX5	Promote immunity	Elevated levels of SOX5/6/21 promoted SVZ cells to exit the cell cycle, whereas genetic ablation of SOX5/6/21 dramatically increased the capacity of these cells to form glioma-like tumors in an oncogene-driven mouse brain tumor model. Consistently, restoring high levels of SOX5/6/21 in human primary glioblastoma cells enabled expression of CDK inhibitors and decreased p53 protein turnover, which blocked their tumorigenic capacity through cellular senescence and apoptosis.
28685773	Lymphoma; Melanoma	CD276	Inhibit immunity (T cell function)	Inhibition of the B7-H3 immune checkpoint limits tumor growth by enhancing cytotoxic lymphocyte function. With a putative receptor expressed by cytotoxic lymphocytes, B7-H3 inhibited their activation, and its deficiency resulted in increased cytotoxic lymphocyte function in tumor-bearing mice.
28666115	Melanoma	SOCS2	Inhibit immunity	Suppressor-of-cytokine-2 (SOCS2) protein, a conserved program transcript, is expressed by mononuclear phagocytes infiltrating primary melanoma and is induced by IFNγ. SOCS2 limits adaptive anti-tumoral immunity and DC-based priming of T cells in vivo, indicating a critical regulatory role.
28655790	Melanoma	CDH5	Promote immunity	We developed an oligonucleotide-based inhibitor (CD5-2), which disrupted the interaction of VE-cadherin with its regulator miR-27a, resulting in increased VE-cadherin expression. Administration of CD5-2 in tumor-bearing mice enhanced expression of VE-cadherin in tumor endothelium, activating TIE-2 and tight junction pathways and normalizing vessel structure and function. Our work establishes a role for VE-cadherin in T-cell infiltration in tumors and offers a preclinical proof of concept for CD5-2 as a therapeutic modifier of cancer immunotherapy via effects on the tumor vasculature.
28652246	Melanoma	NT5E	Inhibit immunity; Resistant to immunotherapy	Here we found that induction of CD73, the enzyme that generates immunosuppressive adenosine, is linked to melanoma phenotype switching. We also detected CD73 upregulation in melanoma patients progressing under adoptive T-cell transfer or immune checkpoint blockade, arguing for an adaptive resistance mechanism.
28651374	Glioma	CD70	Inhibit immunity	CD70 was not detected in peripheral and brain normal tissues but was constitutively overexpressed by isocitrate dehydrogenase (IDH) wild-type primary LGGs and GBMs in the mesenchymal subgroup and recurrent tumors. CD70 was also associated with poor survival in these subgroups, which may link to its direct involvement in glioma chemokine productions and selective induction of CD8+ T-cell death.
28648905	Hepatocellular Carcinoma	HAVCR2	Inhibit immunity (T cell function)	Expression of PD-1, TIM3, LAG3, and CTLA4 was significantly higher on CD8+and CD4+T cells isolated from HCC tissue than control tissue or blood. Compared with TIL that did not express these inhibitory receptors, CD8+and CD4+TIL that did express these receptors had higher levels of markers of activation, but similar or decreased levels of granzyme B and effector cytokines.
28648905	Hepatocellular Carcinoma	CD274	Inhibit immunity (T cell function)	Expression of PD-1, TIM3, LAG3, and CTLA4 was significantly higher on CD8+and CD4+T cells isolated from HCC tissue than control tissue or blood. Compared with TIL that did not express these inhibitory receptors, CD8+and CD4+TIL that did express these receptors had higher levels of markers of activation, but similar or decreased levels of granzyme B and effector cytokines.
28648699	Uveal Melanoma	CRP	Inhibit immunity; Resistant to immunotherapy	Eighty-six patients were treated with PD-1 inhibitors only (n = 54 for pembrolizumab, n = 32 for nivolumab) with a centrally confirmed response rate of 4.7%. Patients with elevated CRP and LDH and a REC <1.5% were at highest risk for disease progression and death (p = 0.001).
28646023	Acute Lymphoblastic Leukemia	S100A6	Inhibit immunity; Resistant to immunotherapy	Amlexanox Downregulates S100A6 to SensitizeKMT2A/AFF1-Positive Acute Lymphoblastic Leukemia to TNFα Treatment. In KMT2A/AFF1-positive transgenic (Tg) mice, amlexanox enhanced tumor immunity and lowered the penetrance of leukemia development. Similarly, in a NOD/SCID mouse model of humanKMT2A/AFF1-positive ALL, amlexanox broadened GVL responses and extended survival.
28639285	Gastric Carcinoma	ERBB2	Inhibit immunity; Immunotherapy target	Human epidermal growth factor receptor-2 (HER2) is overexpressed in ∼20% of GC cases and anti-HER2 antibody trastuzumab in combination with conventional chemotherapy, is recognized as standard therapy for HER2-positive metastatic GC.
28634284	Melanoma	TNFSF11	Inhibit immunity; Immunotherapy target	Co-administration of RANKL and CTLA4 Antibodies Enhances Lymphocyte-Mediated Antitumor Immunity in Mice. RANKL blockade improved the efficacy of anti-CTLA4 mAbs against solid tumors and experimental metastases, with regulatory T-cell (Treg)-depleting anti-CTLA4 mAbs of the mouse IgG2a isotype showing greatest combinatorial activity.
28630054	Melanoma	SLC45A2	Immunotherapy target	Antigen-specific CTLs generated against HLA-A*0201- and HLA-A*2402-restricted SLC45A2 peptides effectively killed a majority of HLA-matched cutaneous, uveal, and mucosal melanoma cell lines tested (18/25).
28628092	Lung Carcinoma	ITGAE	Promote immunity	Tumors with a high density of CTLs showed enrichment for transcripts linked to tissue-resident memory cells (TRMcells), such as CD103, and CTLs from CD103hi tumors displayed features of enhanced cytotoxicity.
28625979	Hepatocellular Carcinoma	ISX	Inhibit immunity	We found that ISX-mediated IL6-induced expression of the tryptophan catabolic enzymes Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase in hepatocellular carcinoma cells, resulting in an ISX-dependent increase in the tryptophan catabolite kynurenine and its receptor aryl hydrocarbon receptor (AHR). Activation of this kynurenine/AHR signaling axis acted through a positive feedback mechanism to increase ISX expression and enhance cellular proliferation and tumorigenic potential. In an IDO1-dependent manner, ectopic expression of ISX induced expression of genes encoding the critical immune modulators CD86 (B7-2) and programmed death ligand-1 (PD-L1), through which ISX conferred a significant suppressive effect on the CD8+T-cell response.
28621802	Hepatocellular Carcinoma	GPC3	Inhibit immunity	However, in HCC patients, GPC3 is overexpressed at both the gene and protein levels, and its expression predicts a poor prognosis. Mechanistic studies have revealed that GPC3 functions in HCC progression by binding to molecules such as Wnt signaling proteins and growth factors.
28619999	Head and Neck Squamous Cell Carcinoma	PDCD1LG2	Inhibit immunity; Candidate for immunotherapy target	The prevalence and distribution of PD-L2 correlated significantly with PD-L1 (P= 0.0012-<0.0001); however, PD-L2 was detected in the absence of PD-L1 in some tumor types. Response was greater in patients positive for both PD-L1 and PD-L2 (27.5%) than those positive only for PD-L1 (11.4%). PD-L2 status was also a significant predictor of progression-free survival (PFS) with pembrolizumab independent of PD-L1 status.
28619711	Hepatocellular Carcinoma	IGFBP7	Promote immunity	IGFBP7 Deletion Promotes Hepatocellular Carcinoma. IGFBP7 abrogates tumors by inhibiting angiogenesis and inducing cancer-specific senescence and apoptosis. Here, we report that Igfbp7-deficient mice exhibit constitutively active IGF signaling, presenting with proinflammatory and immunosuppressive microenvironments and spontaneous liver and lung tumors occurring with increased incidence in carcinogen-treated subjects. Igfbp7 deletion increased proliferation and decreased senescence of hepatocytes and mouse embryonic fibroblasts, effects that were blocked by treatment with IGF1 receptor inhibitor.
28615225	Melanoma	AKT1	Inhibit immunity	Inhibition of specific Akt isoforms in CD8+T cells promotes favored differentiation into memory versus effector cells, the former of which are superior in mediating antitumor immunity. This effect was preserved in vivo after ex vivo PI3K-δ inhibition in CD8+ T cells destined for adoptive transfer, enhancing their survival and also the antitumor therapeutic activity of a tumor-specific peptide vaccine.
28614631	Prostate Carcinoma	TRPM4	Inhibit immunity	TRPM4 regulates Akt/GSK3-β activity and enhances β-catenin signaling and cell proliferation in prostate cancer cells. This work found that decreasing TRPM4 levels leads to the reduced proliferation of PC3 cells. This effect was associated with a decrease in total β-catenin protein levels and its nuclear localization, and a significant reduction in Tcf/Lef transcriptional activity. TRPM4 silencing increases the Ser33/Ser37/Thr41 β-catenin phosphorylated population and reduces the phosphorylation of GSK-3β at Ser9, suggesting an increase in β-catenin degradation as the underlying mechanism. PC3 cells with reduced levels of TRPM4 showed a decrease in basal and stimulated phosphoactivation of Akt1, which is likely responsible for the decrease in GSK-3β activity in these cells. Our results also suggest that the effect of TRPM4 on Akt1 is probably mediated by an alteration in the calcium/calmodulin-EGFR axis, linking TRPM4 activity with the observed effects in β-catenin-related signaling pathways.
28612394	Glioblastoma	CD70	Inhibit immunity	Tumor associated CD70 expression is involved in promoting tumor migration and macrophage infiltration in GBM. We found that the ablation of CD70 in primary GBM decreased CD44 and SOX2 gene expression, and inhibited tumor migration, growth and the ability to attract monocyte-derived M2 macrophages in vitro. Together, these data suggest that CD70 expression is involved in promoting tumor aggressiveness and immunosuppression via tumor-associated macrophage recruitment/activation.
28604752	Lung Carcinoma	HCAR1	Inhibit immunity	Lactate-induced PD-L1 induction was mediated by its receptor GPR81. The silencing of GPR81 signaling in lung cancer cells resulted in a decrease in PD-L1 protein levels and functional inactivation of PD-L1 promoter activity. We also demonstrated that activation of GPR81 decreases intracellular cAMP levels and inhibits protein kinase A (PKA) activity, leading to activation of the transcriptional coactivator TAZ. Interaction of TAZ with the transcription factor TEAD was essential for TAZ activation of PD-L1 and induction of its expression.
28108629	Lung Carcinoma	STAT3	Inhibit immunity	We found that antitumor type 1 CD4+T-helper (Th1) cells and CD8+T cells were directly counter balanced in lung cancer development with tumor-promoting myeloid-derived suppressor cells (MDSCs) and suppressive macrophages, and that activation of STAT3 in MDSCs and macrophages promoted tumorigenesis through pulmonary recruitment and increased resistance of suppressive cells to CD8+T cells, enhancement of cytotoxicity toward CD4+and CD8+T cells, induction of regulatory T cell (Treg), inhibition of dendritic cells (DC), and polarization of macrophages toward the M2 phenotype.
28108509	Lung Carcinoma	PIK3CD	Inhibit immunity; Resistant to immunotherapy	Conversely, PI3Kδ was functionally critical in Treg, acting there to control T-cell receptor signaling, cell proliferation, and survival. Notably, in a murine model of lung cancer, coadministration of a PI3Kδ-specific inhibitor with a tumor-specific vaccine decreased numbers of suppressive Treg and increased numbers of vaccine-induced CD8 T cells within the tumor microenvironment, eliciting potent antitumor efficacy.
28102051	Head and Neck Squamous Cell Carcinoma	HAVCR2	Inhibit immunity	In this study, we report that TIM3 expression was significantly up-regulated in patients with HNSCC and associated with lymph node metastasis. We also characterized CD8+T cells and CD11b+CD33+myeloid-derived suppressor cells (MDSCs) in human HNSCC, and found that their expression was positively correlated with TIM3 expression. Treatment with anti-TIM3 monoclonal antibody effectively suppressed tumor growth through restoring effector T-cell function by targeting CD4+TIM3+cells and CD8+TIM3+cells and decreasing MDSCs.
28096186	Melanoma	MITF	Inhibit immunity	In melanoma, low expression of the lineage survival oncogene microphthalmia-associated transcription factor (MITF) correlates with invasion, senescence, and drug resistance. Here we show that microenvironmental cues, including inflammation-mediated resistance to adoptive T-cell immunotherapy, transcriptionally repress MITF via ATF4 in response to inhibition of translation initiation factor eIF2B.
28096186	Melanoma	ATF4	Inhibit immunity; Resistant to immunotherapy	ATF4, a key transcription mediator of the integrated stress response, also activates AXL and suppresses senescence to impose the MITF-low/AXL-high drug-resistant phenotype observed in human tumors.
28092673	Melanoma; Lung Carcinoma	IRF7	Promote immunity	IRF7 deficiency caused significant elevation of G-MDSCs, and therefore enhanced tumor growth and metastasis in mice. Importantly, IRF7 expression levels negatively correlated with the G-MDSC frequency and tumor metastasis, as well as S100A9 expression, in cancer patients.
28092673	Melanoma; Lung Carcinoma	S100A9	Inhibit immunity	Mechanistic studies showed that S100A9, a negative regulator of myeloid cell differentiation, was transrepressed by the IRF7 protein. S100A9 knockdown almost completely abrogated the effects of IRF7 deletion on G-MDSC development and tumor metastasis.
28089377	Ovarian Carcinoma	CSF2	Promote immunity	Granulocyte macrophage colony-stimulating factor (GM-CSF) stimulates immunity via recruitment of antigen presenting cells and tumor specific T-cell stimulation.
28077676	Triple-Negative Breast Carcinoma; Ovarian Carcinoma; Non-Small Cell Lung Carcinoma	PTK7	Inhibit immunity	A PTK7-targeted antibody-drug conjugate reduces tumor-initiating cells and induces sustained tumor regressions. The PTK7-targeted ADC induced sustained tumor regressions and outperformed standard-of-care chemotherapy. In addition to reducing the TIC frequency, the PTK7-targeted ADC may have additional antitumor mechanisms of action, including the inhibition of angiogenesis and the stimulation of immune cells.
28077657	Lymphoma	PDLIM7	Inhibit immunity	Latent Membrane Protein 1 (LMP1) and LMP2A Collaborate To Promote Epstein-Barr Virus-Induced B Cell Lymphomas in a Cord Blood-Humanized Mouse Model but Are Not Essential. Thus, the expression of either LMP1 or LMP2A may be sufficient to promote early-onset EBV-induced tumors in this model. The simultaneous deletion of both LMP1 and LMP2A results in fewer tumors and a further delay in tumor onset.
28074066	T Acute Lymphoblastic Leukemia; Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma	CD5	Inhibit immunity	Additionally, CD5 is highly expressed in T-cell acute lymphoblastic leukemia (T-ALL) and peripheral T-cell lymphomas (PTCLs). We found that CD5CAR NK-92 cells possessed consistent, specific, and potent anti-tumor activity against a variety of T-cell leukemia and lymphoma cell lines as well as primary tumor cells. Furthermore, we were able to demonstrate significant inhibition and control of disease progression in xenograft mouse models of T-ALL.
28073774	Sarcoma	CD274	Inhibit immunity	Using CRISPR/Cas9-induced loss-of-function approaches and overexpression gain-of-function techniques, we confirmed that PD-L1 on tumor cells is key to promoting tumor escape.In addition, the capacity of PD-L1 to suppress antitumor responses was inversely proportional to tumor cell antigenicity. PD-L1 expression on host cells, particularly tumor-associated macrophages (TAM), was also important for tumor immune escape.
28069723	Colon Carcinoma	TNFRSF18	Promote immunity	Treatment of CT26 tumor-bearing mice with mGITRL-FP-mediated significant antitumor activity that was dependent on isotype, dose, and duration of exposure. The antitumor activity could be correlated with the increased proliferation of peripheral CD8+ and CD4+ T cells and a significant decrease in the frequency of intratumoral Tregs. In addition, these data provide, for the first time, early proof of concept for the potential combination of GITR targeting agents with OX40 agonists and PD-L1 antagonists.
28068326	Melanoma	KLF4	Inhibit immunity	KLF4 is regulated by RAS/RAF/MEK/ERK signaling through E2F1 and promotes melanoma cell growth. We find that KLF4 is highly expressed in a subset of human melanomas. Ectopic expression of KLF4 enhances melanoma cell growth by decreasing apoptosis.
28067913	Head and Neck Squamous Cell Carcinoma	NSD1	Promote immunity	The K36M substitution and NSD1 defects converge on altering methylation of histone H3 at K36 (H3K36), subsequently blocking cellular differentiation and promoting oncogenesis. Our data further indicate limited redundancy for NSD family members in HPV-negative HNSCCs and suggest a potential role for impaired H3K36 methylation in their development.
28062695	Squamous Cell Carcinoma; Colon Carcinoma	EGFR	Inhibit immunity; Candidate for immunotherapy target	Monoclonal Antibodies against Epidermal Growth Factor Receptor Acquire an Ability To Kill Tumor Cells through Complement Activation by Mutations That Selectively Facilitate the Hexamerization of IgG on Opsonized Cells. In this study we show that selective enhancement of C1q binding via avidity modulation is superior to the unattended increase in C1q binding via affinity approaches, particularly for target cells with reduced EGFR expression levels. Improving Fc:Fc interactions of Ag-bound IgG therefore represents a highly promising and novel approach for potentiating the anti-tumor activity of therapeutic mAb against EGFR and potentially other tumor targets.
28062694	Melanoma	CD40	Promote immunity	Using the mouse GD2+B78 melanoma model, we show that anti-CD40/CpG treatment led to upregulation of T cell activation markers in draining lymph nodes.
28053195	Melanoma	POU2AF1	Candidate for immunotherapy target	TCR-based therapy for multiple myeloma and other B-cell malignancies targeting intracellular transcription factor BOB1. TCR-transduced T cells efficiently lysed primary B-cell leukemia, mantle cell lymphoma, and multiple myeloma in vitro. Furthermore, clear in vivo antitumor reactivity was observed of BOB1-specific TCR-engineered T cells in a xenograft mouse model of established multiple myeloma.
28027521	Breast Carcinoma	IRF7	Promote immunity	Breast cancer cells which express an innate immune signature regulated by interferon regulatory factor 7 (IRF7) have reduced metastatic potential. Higher levels of the IRF7 signature were significantly associated with a decreased bone metastases risk: (HR = 0.76 for a 50 unit increase, 95% CI, 0.62-0.94, p = 0.012).
28027300	Prostate Carcinoma	CTLA4	Inhibit immunity	Further supporting a role of inflammation-induced immune-suppression in the development of early-onset prostate cancer, we observed significant up-regulation of CTLA4 and IDO1/TDO2 pathways in tumors of the young cohort. Moreover, over-expression of CTLA4 and IDO1 was significantly associated with biochemical recurrence.
28018343	Melanoma	ITGA1	Promote immunity	VLA-1-expressing TIL frequently co-express CD69 and CD103, indicating tissue-resident memory T cells (TRM) differentiation. In addition,in vivo blockade of either VLA-1 or CD103 significantly impaired control of subcutaneous tumors.
28011934	Melanoma	IL33	Promote immunity	We show that exogenous IL-33 can induce robust antitumor effect through a CD8+T cell-dependent mechanism. Notably, in addition to a direct action on CD8+T cell expansion and IFN-γ production, rIL-33 therapy activated myeloid dendritic cells (mDCs) in tumor-bearing mice, restored antitumor T cell activity, and increased Ag cross-presentation within the tumor microenvironment.
28011934	Melanoma	MYD88	Promote immunity	Specifically, MyD88, an essential component of the IL-33 signaling pathway, was required for the IL-33-mediated increase in mDC number and upregulation in expression of costimulatory molecules.
28011931	Adult T-Cell Leukemia/Lymphoma	CNTN2	Promote immunity	HTLV-1 Tax-Specific CTL Epitope-Pulsed Dendritic Cell Therapy Reduces Proviral Load in Infected Rats with Immune Tolerance against Tax. Even in the infected rats with immune unresponsiveness against Tax, Tax-specific CTL epitope-pulsed dendritic cell (DC) therapy reduced the PVL and induced Tax-specific CD8+T cells capable of proliferating and producing IFN-γ.
28011863	Hodgkin Lymphoma	CD70	Promote immunity	Inherited CD70 deficiency in humans reveals a critical role for the CD70-CD27 pathway in immunity to Epstein-Barr virus infection. We show that EBV-specific T lymphocytes did not expand properly when stimulated with CD70-deficient EBV-infected B cells, whereas expression of CD70 in B cells restored expansion, indicating that CD70 on B cells but not on T cells is required for efficient proliferation of T cells.
28011863	Hodgkin Lymphoma	CD27	Promote immunity	The proliferation of T cells triggered by CD70-expressing B cells was dependent on CD27 and CD3 on T cells. Importantly, CD27-deficient T cells failed to proliferate when stimulated with CD70-expressing B cells. Thus, the CD70-CD27 pathway appears to be a crucial component of EBV-specific T cell immunity and more generally for the immune surveillance of B cells and may be a target for immunotherapy of B cell malignancies.
28008925	Bladder Carcinoma	JAK1	Promote immunity	Cells from this patient exhibit reduced JAK1 and STAT phosphorylation following cytokine stimulations, reduced induction of expression of interferon-regulated genes and dysregulated cytokine production; which are indicative of signalling defects in multiple immune response pathways including Interferon-γ production.
27994058	Thyroid Gland Carcinoma	IDO1	Inhibit immunity	Recently, we demonstrated that IDO1 expression is significantly higher in all thyroid cancer histotypes compared with normal thyroid and that its expression levels correlate with T regulatory (Treg) lymphocyte densities in the tumor microenvironment. In cancer, it exerts an immunosuppressive function as part of an acquired mechanism of immune escape.
27994058	Thyroid Gland Carcinoma	RET	Inhibit immunity	Conversely, RET/PTC3-expressing cells were characterized by a high IDO1 expression. These data provide the first evidence of a direct link between IDO1 expression and the oncogenic activation of RET in thyroid carcinoma and describe the involved signal transduction pathways.
27994058	Thyroid Gland Carcinoma	STAT1	Inhibit immunity	Moreover, we found that, the STAT1-IRF1 pathway was instrumental for IDO1 expression in RET/PTC3 expressing cells. In detail, RET/PTC3 induced STAT1 overexpression and phosphorylation at Ser-727 and Tyr-701. STAT1 transcriptional regulation appeared to require activation of the canonical NF-κB pathway.
27993599	Breast Carcinoma	NT5E	Inhibit immunity; Resistant to immunotherapy	Our results showed that intravenous administration of CD73-specific siRNA-loaded NPs led to reduced expression of CD73 in tumor cells which was associated with decreased tumor growth and metastasis, and improved mice survival. In conclusion, our findings indicate that the use of CD73-specific siRNA-loaded NPs provides an immune potentiating function, thereby improves the efficacy of DC based cancer immunotherapy.
27991933	Pancreatic Ductal Adenocarcinoma	FOXP3	Inhibit immunity	Cancer-FOXP3 directly activated CCL5 to recruit FOXP3+Treg cells in pancreatic ductal adenocarcinoma. In addition, high cancer-FOXP3 expression was associated with increased tumor volumes and poor prognosis in PDAC especially combined with high levels of Treg cells.
27991933	Pancreatic Ductal Adenocarcinoma	CCL5	Inhibit immunity	Furthermore, CCL5 was directly trans-activated by cancer-FOXP3 and promoted the recruitment of Treg cells from peripheral blood to the tumor site in vitro and in vivo.
27980102	Hepatocellular Carcinoma	CCL2	Inhibit immunity; Candidate for immunotherapy target	C-C motif chemokine ligand 2 (CCL2/MCP1), a chemokine that recruits CCR2-positive immune cells to promote inflammation, is highly upregulated in hepatocellular carcinoma patients. Furthermore, treatment of tumor-bearing KO mice with CCL2 nAb for 8 weeks significantly reduced liver damage, hepatocellular carcinoma incidence, and tumor burden. Phospho-STAT3 (Y705) and c-MYC, the downstream targets of IL6, as well as NF-κB, the downstream target of TNFα, were downregulated upon CCL2 inhibition, which correlated with suppression of tumor growth. Collectively, these results demonstrate that CCL2 immunotherapy could be an effective therapeutic approach against inflammatory liver disease and hepatocellular carcinoma.
24480625	Melanoma	CSF2	Promote immunity; Essential for immunotherapy	In aggressive, therapeutic B16 models, the vaccine systems incorporating GM-CSF in combination with P(I:C) or CpG-ODN induced the complete regression of solid tumors (≤40 mm(2)), resulting in 33% long-term survival.
24480556	Breast Carcinoma	ERBB2	Inhibit immunity; Immunotherapy target	The monoclonal antibody trastuzumab targets the growth factor receptor HER2 and has profoundly improved the course of disease and survival of women with HER2-overexpressing breast cancer.
24477907	Melanoma	IFNG	Essential for immunotherapy	Although successful DC immunotherapy required IFN-γ, perforin expression was dispensable.
24476824	Melanoma	PPP2R2D	Inhibit immunity (T cell function)	In tumours, Ppp2r2d knockdown inhibited T-cell apoptosis and enhanced T-cell proliferation as well as cytokine production.
24469034	Squamous Cell Carcinoma	TP53	Promote immunity	Loss of epithelial p53 and αv integrin cooperate through Akt to induce squamous cell carcinoma yet prevent remodeling of the tumor microenvironment. Here we show that codeletion of the p53 and αv integrin genes in mouse stratified epithelia induced SCCs in 100% of the mice, more frequently and with much shorter latency than deletion of either gene alone.
24469034	Squamous Cell Carcinoma	AKT1	Inhibit immunity	Thus, tumors may arise in these mice as a result of the increased cell survival induced by Akt activation triggered by loss of αv and p53, and by the defective recruitment of immune cells to these tumors, which may allow immune evasion.
24455753	Melanoma	LPAR5	Inhibit immunity (T cell function)	Here, we demonstrate that LPA signaling via the LPA5 receptor expressed by CD8 T cells suppresses antigen receptor signaling, cell activation and proliferation in vitro and in vivo. Importantly, in a mouse melanoma model tumor-specific CD8 T cells that are LPA5-deficient are able to control tumor growth significantly better than wild-type tumor-specific CD8 T cells.
24452999	Melanoma; Lymphoma	IDO1	Inhibit immunity (infiltration)	Mesenchymal stem cells use IDO to regulate immunity in tumor microenvironment. These IDO-expressing humanized MSCs (MSC-IDO) were capable of suppressing T-lymphocyte proliferation in vitro. In melanoma and lymphoma tumor models, MSC-IDO promoted tumor growth in vivo, an effect that was reversed by the IDO inhibitor 1-methyl-tryptophan. We found that MSC-IDO dramatically reduced both tumor-infiltrating CD8(+) T cells and B cells.
24449872	Breast Carcinoma	TBK1	Inhibit immunity; Resistant to immunotherapy	Here, we report that an important innate immune response kinase, the IκB kinase-related TANK-binding kinase 1 (TBK1), is a crucial determinant of resistance to tamoxifen therapies. We show that TBK1 increases ERα transcriptional activity through phosphorylation modification of ERα at the Ser-305 site. Notably, patients with tumors highly expressing TBK1 respond poorly to tamoxifen treatment and show high potential for relapse.
24449212	Acute Myeloid Leukemia	PML	Inhibit immunity	PML-RARA and AML1-ETO are important oncogenic fusion proteins that play a central role in transformation to acute myeloid leukemia (AML).
24449212	Acute Myeloid Leukemia	RUNX1	Inhibit immunity	PML-RARA and AML1-ETO are important oncogenic fusion proteins that play a central role in transformation to acute myeloid leukemia (AML). Furthermore, by using chromatin immunoprecepitation (ChIP) experiments, we show that AML1-ETO directly interacts with CD48.
24449212	Acute Myeloid Leukemia	CD48	Promote immunity	Here we show that both oncogenic proteins specifically downregulate the expression of CD48, a ligand of the natural killer (NK) cell activating receptor 2B4, thereby leading to decreased killing by NK cells.
24448235	Pancreatic Carcinoma	ERBB2	Inhibit immunity (T cell function)	Because phosphorylated antigens did not optimally enhance γδ T-cell cytotoxicity, we designed bispecific antibodies that bind CD3 or Vγ9 on γδ T cells and Her2/neu (ERBB2) expressed by pancreatic tumor cells. Both antibodies enhanced γδ T-cell cytotoxicity with the Her2/Vγ9 antibody also selectively enhancing release of granzyme B and perforin.
24446520	Melanoma	TNF	Promote immunity	TNF-α-dependent hematopoiesis following Bcl11b deletion in T cells restricts metastatic melanoma. Moreover, TNF-α treatment of wild-type mice also reduced the tumor burden and increased hematopoiesis and the numbers and activity of NK cells in the lung. In vitro treatment with TNF-α of lineage-negative hematopoietic progenitors increased NK and myeloid differentiation, further supporting a role of TNF-α in promoting hematopoiesis.
24446520	Melanoma	BCL11B	Inhibit immunity	Using several tumor models, we demonstrate that mice deficient in Bcl11b in T cells, although having reduced numbers of T cells in the peripheral lymphoid organs, developed significantly less tumors compared with wild-type mice. Although the number of myeloid-derived suppressor cells was increased in the lungs with metastatic tumors of Bcl11b(F/F)/CD4-Cre mice, their arginase-1 levels were severely reduced.
24445867	Chronic Lymphocytic Leukemia	CD37	Inhibit immunity; Candidate for immunotherapy target	The CD37-targeted antibody-drug conjugate IMGN529 is highly active against human CLL and in a novel CD37 transgenic murine leukemia model. One promising target is CD37, a tetraspanin protein highly expressed on malignant B-cells in CLL and non-Hodgkin lymphoma. IMGN529 rapidly eliminated peripheral blood leukemia and improved overall survival.
24443555	Melanoma	IL27	Inhibit immunity	A requirement of dendritic cell-derived interleukin-27 for the tumor infiltration of regulatory T cells. Tumor-associated DCs were identified as the major source of CCL22 in tumor sites, and IL-27 could induce CCL22 expression in an IL-27R-dependent manner.
24443555	Melanoma	CCL22	Inhibit immunity	Further studies revealed that IL-27 promoted the expression of CCL22, which is established to mediate the recruitment of peripheral Tregs into tumors.
24416730	Melanoma	TNFRSF18	Promote immunity	GITR pathway activation abrogates tumor immune suppression through loss of regulatory T cell lineage stability. We have previously demonstrated that GITR ligation in vivo by agonist antibody DTA-1 causes a >50% reduction of intra-tumor Treg with down modulation of Foxp3 expression. GITR ligation also alters the expression of various transcription factors and cytokines important for Treg function.
24416730	Melanoma	FOXP3	Inhibit immunity	Complete Foxp3 loss in intra-tumor Treg correlates with a dramatic decrease in Helios expression and is associated with the upregulation of transcription factors T-Bet and Eomes. Changes in Helios correspond with a reduction in IL-10 and an increase in IFNγ expression in DTA-1-treated Treg.
24415778	Colorectal Carcinoma	KLRG1	Promote immunity	KLRG1+ NK cells protect T-bet-deficient mice from pulmonary metastatic colorectal carcinoma.
24415778	Colorectal Carcinoma	TBX21	Promote immunity	We found that mice deficient for the T-box transcription factor T-bet lack terminally differentiated antitumor CD27(low)KLRG1(+) NK cells, leading to a terminal course of rapid-onset pulmonary CRC metastases.
24415778	Colorectal Carcinoma	IL15	Promote immunity	Importantly, immunity to metastasis formation could also be restored in T-bet-deficient recipients by treating mice with IL-15 precomplexed to IL-15 receptor-α, which induced the development of eomesodermin(+)KLRG1(+) NK cells from existing NK cell populations.
24413734	Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma	FYN	Promote immunity	In addition, we describe new and recurrent, albeit less frequent, genetic defects including mutations in FYN, ATM, B2M and CD58 implicating SRC signaling, impaired DNA damage response and escape from immune surveillance mechanisms in the pathogenesis of PTCL.
24409177	Diffuse Large B-Cell Lymphoma	IFI30	Promote immunity	GILT reduces protein disulfide bonds in the endocytic compartment, exposing additional epitopes for binding to MHC class II and facilitating antigen presentation.
24396833	Melanoma	CTLA4	Inhibit immunity (T cell function)	Multiple NY-ESO-1 antigen-specific CD4(+) T cell responses with Th1 dominance were induced or enhanced after ipilimumab treatment in peripheral blood in all four patients. NY-ESO-1 antigen-specific CD4(+) T cell lines established from all 4 patients after ipilimumab treatment recognized naturally processed NY-ESO-1 protein in antigen-presenting cells, expressed master transcription factor Eomesodermin (Eomes) and secreted perforin and Granzyme B. Finally, we demonstrated that these NY-ESO-1 antigen-specific CD4(+) T cell lines directly lysed autologous melanoma cell lines expressing NY-ESO-1 in an MHC class II restricted manner.
24395820	Melanoma	TNFRSF8	Inhibit immunity (T cell function)	Transcriptional profiling of melanoma sentinel nodes identify patients with poor outcome and reveal an association of CD30(+) T lymphocytes with progression. Phenotypic profiling demonstrated that CD30(+) lymphocytes comprised a broad population of suppressive or exhausted immune cells, such as CD4(+)Foxp3(+) or PD1(+) subpopulations and CD4(-)CD8(-) T cells.
24388357	Plasma Cell Myeloma	SDC1	Candidate for immunotherapy target	Transfection of chimeric anti-CD138 gene enhances natural killer cell activation and killing of multiple myeloma cells. However, these retargeted NK-92MI (NK-92MI-scFv) displayed markedly enhanced cytotoxicity against CD138-positive human MM cell lines (RPMI8226, U266 and NCI-H929) and primary MM cells at various effector-to-target ratios (E:T) as compared to the empty vector-transfected NK-92MI (NK-92MI-mock).
24379122	Breast Carcinoma	TNFRSF1B	Inhibit immunity	Transmembrane TNF-α promotes suppressive activities of myeloid-derived suppressor cells via TNFR2. This effect of tmTNF-α was mediated by TNFR2, as TNFR2 deficiency significantly impaired tmTNF-α-induced release of IL-10 and NO and inhibition of T cell proliferation by MDSC supernatant.
24379122	Breast Carcinoma	TNF	Inhibit immunity	Indeed, we found that tmTNF-α, rather than secretory TNF-α (sTNF-α), activated MDSCs with enhanced suppressive activities, including upregulating arginase-1 and inducible NO synthase transcription, promoting secretion of NO, reactive oxygen species, IL-10, and TGF-β, and enhancing inhibition of lymphocyte proliferation.
24379122	Breast Carcinoma	NFKB1	Inhibit immunity	Furthermore, tmTNF-α caused p38 phosphorylation and NF-κB activation, whereas inhibition of NF-κB or p38 with an inhibitor pyrrolidine dithiocarbamate or SB203580 abrogated tmTNF-α-mediated increased suppression of lymphocyte proliferation by MDSCs.
24362551	Chronic Lymphocytic Leukemia	HLA-G	Inhibit immunity	In line with its role in immunomodulation, the percentage of regulatory T lymphocytes is higher in del/del patients than in patients with the other genotypes and correlates with the amounts of surface or soluble HLA-G. Furthermore, addition of sHLA-G-rich plasma from patients with chronic lymphocytic leukemia induces natural killer cell apoptosis and impairs natural killer cell lysis, with effects proportional to the amount of soluble HLA-G added. Lastly, the presence of an HLA-G 14 base pair polymorphism is of prognostic value, with del/del patients showing reduced overall survival, as compared to those with other genotypes. These results suggest that: (i) the HLA-G 14 base pair polymorphism influences the levels of surface and soluble HLA-G expression, and (ii) the over-expression of HLA-G molecules contributes to creating tolerogenic conditions.
24360797	Hepatocellular Carcinoma	DDX58	Promote immunity	We found that expression of retinoic acid-inducible gene-I (RIG-I), an IFN-stimulated gene, was significantly downregulated in human HCC tissues. Mechanistically, RIG-I enhances IFN-α response by amplifying IFN-α effector signaling via strengthening STAT1 activation. Furthermore, we found that RIG-I deficiency promotes HCC carcinogenesis and that hepatic RIG-I expression is lower in men than in women.
24356816	Acute Lymphoblastic Leukemia	SPN	Inhibit immunity; Immunotherapy target	Cancer-associated CD43 glycoforms as target of immunotherapy. CD43 is a sialoglycosylated membrane protein that is involved in cell proliferation and differentiation. The cancer association of UN1/CD43 epitope suggested the possibility to use the UN1 mAb for tumor diagnosis and therapy.
24346967	Lung Carcinoma	CXCL5	Inhibit immunity; Resistant to immunotherapy	CXCL5 not only potentiated the classical EGFR pathway and the AKT and ERK/RSK1/2 signaling pathways but also increased the phosphorylation of heat shock protein 27 (HSP27), which was slightly increased in A549 cells treated with either HB-EGF or CXCL5 only. Phosphorylated HSP27 stabilized sustained AKT activity by direct interaction, leading to enhanced tumor spheroid formation. In mice, CXCL5 antibody synergistically enhances the efficiency of the tyrosine kinase inhibitor, gefitinib, without increasing its toxicity.
24346967	Lung Carcinoma	HBEGF	Inhibit immunity	The combination of HB-EGF (heparin-binding EGF-like growth factor) and CXCL5 (CXCL5/epithelial neutrophil-activating peptide-78) produced a strong synergistic effect on cancer proliferation, epithelial-mesenchymal transition, migration and invasion.
24344220	Lymphoma	PDLIM7	Immunotherapy target	Tumor cells from approximately 40% of patients with Hodgkin or non-Hodgkin lymphoma express the type II latency Epstein-Barr virus (EBV) antigens latent membrane protein 1 (LMP1) and LMP2, which represent attractive targets for immunotherapy. Autologous T cells directed to the LMP2 or LMP1 and LMP2 antigens can induce durable complete responses without significant toxicity.
24344220	Lymphoma	PSMB9	Immunotherapy target	Tumor cells from approximately 40% of patients with Hodgkin or non-Hodgkin lymphoma express the type II latency Epstein-Barr virus (EBV) antigens latent membrane protein 1 (LMP1) and LMP2, which represent attractive targets for immunotherapy. Autologous T cells directed to the LMP2 or LMP1 and LMP2 antigens can induce durable complete responses without significant toxicity.
24338683	Prostate Carcinoma	ACPP	Promote immunity	Prostatic acid phosphatase (PAP) is a prostate-specific protein overexpressed in 95% of prostate tumours. The PAP-114-128 epitope elicits CD4(+) and CD8(+) T-cell-specific responses in C57BL/6 mice. Furthermore, when immunised in a DNA vector format (ImmunoBody®), PAP-114-128 prevents and reduces the growth of transgenic adenocarcinoma of mouse prostate-C1 prostate cancer cell-derived tumours in both prophylactic and therapeutic settings. This anti-tumour effect is associated with infiltration of CD8(+) tumour-infiltrating lymphocytes and the generation of high avidity T cells secreting elevated levels of IFN-γ.
24336127	Leukemia	KLRK1	Promote immunity	Upregulation of NKG2D (NK group 2, member D) ligands in MLL/ENL leukemia cells caused elimination of leukemia cells by NK cells.
24336068	Prostate Carcinoma	CD274	Inhibit immunity	Hypoxia-induced expression of PD-L1 in cancer cells increased their resistance to CTL-mediated lysis. We found that higher expression of PD-L1 induced in tumor cells by exposure to hypoxia led to increased apoptosis of cocultured CTLs and Jurkat leukemia T cells.
24336068	Prostate Carcinoma; Breast Carcinoma	HIF1A	Inhibit immunity	Exposure of human or murine cancer cells to hypoxia for 24 hours led to upregulation of the immune inhibitory molecule programmed cell death ligand-1 (PD-L1; also known as B7-H1), in a manner dependent on the transcription factor hypoxia-inducible factor-1α (HIF-1α). Using glyceryl trinitrate (GTN), an agonist of nitric oxide (NO) signaling known to block HIF-1α accumulation in hypoxic cells, we prevented hypoxia-induced PD-L1 expression and diminished resistance to CTL-mediated lysis.
24327582	Glioblastoma	ADAM10	Inhibit immunity (NK cell function)	Here,we show that ADAM10 and ADAM17 are expressed on the cell surface of GIC and contribute to an immunosuppressive phenotype by cleavage of ULBP2. And treatment with ADAM10 and ADAM17 specific inhibitors leads to enhanced immunerecognition of GIC by natural killer cells. Therefore, ADAM10 and ADAM17 constitute suitable targets to boost an immune response against GIC.
24327582	Glioblastoma	ADAM17	Inhibit immunity	Here,we show that ADAM10 and ADAM17 are expressed on the cell surface of GIC and contribute to an immunosuppressive phenotype by cleavage of ULBP2. And treatment with ADAM10 and ADAM17 specific inhibitors leads to enhanced immunerecognition of GIC by natural killer cells. Therefore, ADAM10 and ADAM17 constitute suitable targets to boost an immune response against GIC.
24327582	Glioblastoma	ULBP2	Promote immunity	Here,we show that ADAM10 and ADAM17 are expressed on the cell surface of GIC and contribute to an immunosuppressive phenotype by cleavage of ULBP2. The cell surface expression of ULBP2 is enhanced upon blocking ADAM10 and ADAM17, and treatment with ADAM10 and ADAM17specific inhibitors leads to enhanced immunerecognition of GIC by natural killer cells.
24324467	Melanoma	MAPK14	Inhibit immunity	Our lab has additionally identified p38-MAPK as an important signaling element in human DC suppression, and recently validated it as such in ex vivo cultures of single-cell suspensions from melanoma metastases.
24321786	Lung Carcinoma	TLR4	Inhibit immunity	Here we show that autophagy induced by TLR4 or TLR3 activation enhances various cytokine productions through promoting TRAF6 (TNF receptor-associated factor 6, E3 ubiquitin protein ligase) ubiquitination and thus facilitates migration and invasion of lung cancer cells. Remarkably, inhibition of autophagy by chemical or genetic approaches blocked TLR4- or TLR3-induced Lys63 (K63)-linked ubiquitination of TRAF6 that was essential for activation of MAPK and NFKB (nuclear factor of kappa light polypeptide gene enhancer in B-cells) pathways, both of which were involved in the increased production of the cytokines.
24321786	Lung Carcinoma	TLR3	Promote immunity	Here we show that autophagy induced by TLR4 or TLR3 activation enhances various cytokine productions through promoting TRAF6 (TNF receptor-associated factor 6, E3 ubiquitin protein ligase) ubiquitination and thus facilitates migration and invasion of lung cancer cells. Remarkably, inhibition of autophagy by chemical or genetic approaches blocked TLR4- or TLR3-induced Lys63 (K63)-linked ubiquitination of TRAF6 that was essential for activation of MAPK and NFKB (nuclear factor of kappa light polypeptide gene enhancer in B-cells) pathways, both of which were involved in the increased production of the cytokines.
24315994	Melanoma	TIMD4	Inhibit immunity	TIM-4 was found to be highly expressed on tumor-associated myeloid cells such as macrophages (TAMs) and dendritic cells (TADCs) and danger-associated molecular patterns (DAMPs) released from chemotherapy-damaged tumor cells induced TIM-4 on tumor-associated myeloid cells recruited from bone marrow-derived precursors. TIM-4 directly interacted with AMPKα1 and activated autophagy-mediated degradation of ingested tumors, leading to reduced antigen presentation and impaired CTL responses.
24304581	Hepatocellular Carcinoma	CCL21	Promote immunity	In this study, we proposed the combination therapy of intratumoral co-administration of SLC and anti-CD25 monoclonal antibodies (mAbs). Our experiments showed the combination therapy significantly decreased the frequency of Tregs, and increased CD8+ T cells and CD4+ T cells at tumor sites. These alterations were accompanied by an increased level of IL-12 and IFN-γ, and decreased level of IL-10 and TGF-β1. Furthermore, we confirmed SLC induced the maturation of DCs via NF-κB p65 and this maturation would benefit the combination therapy.
24304581	Hepatocellular Carcinoma	IL2RA	Inhibit immunity; Immunotherapy target	In this study, we proposed the combination therapy of intratumoral co-administration of SLC and anti-CD25 monoclonal antibodies (mAbs). Our experiments showed the combination therapy significantly decreased the frequency of Tregs, and increased CD8+ T cells and CD4+ T cells at tumor sites. These alterations were accompanied by an increased level of IL-12 and IFN-γ, and decreased level of IL-10 and TGF-β1.
24302925	Ovarian Carcinoma	CD274	Inhibit immunity	Expression of both B7-H1 and IDO are associated with differentiation and recruitment of Treg, and clinical studies have shown that each of these mechanisms correlates independently with increased morbidity and mortality in ovarian cancer patients.
24300852	Acute Myeloid Leukemia	CD33	Inhibit immunity; Candidate for immunotherapy target	In MS-5 feeder cell-based long-term cultures that supported the growth of primary AML blasts for up to 36 days, AMG 330 efficiently recruited and expanded residual CD3(+)/CD45RA(-)/CCR7(+) memory T cells within the patient sample. Targeting CD33 ex vivo using AMG 330 in primary AML samples led to T cell recruitment and expansion and remarkable antibody-mediated cytotoxicity, suggesting efficient therapeutic potential in vivo.
24297862	Acute Myeloid Leukemia	TNFRSF1B	Inhibit immunity	We report that TNFR2(+) Tregs are increased in AML and have a high migration potential toward the bone marrow. Reductions in TNFR2(+) Tregs were associated with increases in Interferon (IFN)-γ and interleukin (IL)-2 production by effector T cells within the bone marrow and beneficial clinical responses.
24292706	Melanoma	IL2	Inhibit immunity	IL-2 therapy promotes suppressive ICOS+ Treg expansion in melanoma patients. High-dose (HD) IL-2 therapy in patients with cancer increases the general population of Tregs, which are positive for CD4, CD25, and the Treg-specific marker Foxp3.
24277834	Pancreatic Ductal Adenocarcinoma	CXCL12	Inhibit immunity; Resistant to immunotherapy	Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Administering AMD3100, a CXCL12 receptor chemokine (C-X-C motif) receptor 4 inhibitor, induced rapid T-cell accumulation among cancer cells and acted synergistically with α-PD-L1 to greatly diminish cancer cells, which were identified by their loss of heterozygosity of Trp53 gene. Thus, a single protein, CXCL12, from a single stromal cell type, the FAP(+) CAF, may direct tumor immune evasion in a model of human PDA.
24277834	Pancreatic Ductal Adenocarcinoma	FAP	Inhibit immunity; Resistant to immunotherapy	Immune control of PDA growth was achieved, however, by depleting carcinoma-associated fibroblasts (CAFs) that express fibroblast activation protein (FAP). The depletion of the FAP(+) stromal cell also uncovered the antitumor effects of α-CTLA-4 and α-PD-L1, indicating that its immune suppressive activity accounts for the failure of these T-cell checkpoint antagonists.
24277698	Colorectal Carcinoma	IL4	Inhibit immunity	Cancer-initiating cells from colorectal cancer patients escape from T cell-mediated immunosurveillance in vitro through membrane-bound IL-4. CIC-associated IL-4 was found to be responsible for this negative function, which requires cell-to-cell contact with T lymphocytes and which is impaired by blocking IL-4 signaling.
24276238	Non-Small Cell Lung Carcinoma	KRAS	Inhibit immunity	Scrib heterozygosity predisposes to lung cancer and cooperates with KRas hyperactivation to accelerate lung cancer progression in vivo. We show that loss of Scrib and activated oncogenic KRas cooperate in vivo, resulting in more aggressive lung tumors, likely due to a synergistic elevation in RAS-MAPK signaling.
24276238	Non-Small Cell Lung Carcinoma	SCRIB	Inhibit immunity	Scrib heterozygosity predisposes to lung cancer and cooperates with KRas hyperactivation to accelerate lung cancer progression in vivo. A survey of genomic databases reveals deregulation of SCRIB in human lung cancer and we show that Scrib(+/-) mutant mice develop lung cancer by 540 days with a penetrance of 43%. We show that loss of Scrib and activated oncogenic KRas cooperate in vivo, resulting in more aggressive lung tumors, likely due to a synergistic elevation in RAS-MAPK signaling.
24265099	Ovarian Carcinoma	CSF2	Promote immunity	Granulocyte-macrophage colony-stimulating factor (GM-CSF) plays an important role in the maturation of specialized antigen-presenting cells. A mouse ovarian cancer cell line, OV2944-HM-1 (HM-1), was intraperitoneally injected, following which HF10 only or the mGM-CSF amplicon was injected intraperitoneally three times. Murine splenic cells after each treatment were stimulated with HM-1 cells, and the strongest immune response was observed in the mice that received mGM-CSF amplicon injections.
24259296	Lung Carcinoma	NOS3	Inhibit immunity	The production of PNT in G-MDSC depended on the expression of gp91(phox) and endothelial NO synthase (eNOS), while inducible NO synthase (iNOS) mediated the generation of NO in Mo-MDSC. Deletion of eNOS and gp91(phox) or scavenging of PNT blocked the suppressive function of G-MDSC and induced anti-tumoral effects, without altering Mo-MDSC inhibitory activity.
24249528	Esophageal Squamous Cell Carcinoma	TNFRSF14	Inhibit immunity	HVEM expression was found to be significantly correlated with depth of tumor invasion and lymph node metastasis. Furthermore, it was found to be inversely correlated with tumor-infiltrating CD4(+) , CD8(+) , and CD45RO(+) lymphocytes.
24247719	Melanoma	CSF1R	Inhibit immunity; Resistant to immunotherapy	Inhibition of CSF-1 receptor improves the antitumor efficacy of adoptive cell transfer immunotherapy. In mice receiving the combined treatment, a dramatic reduction of TIMs and a skewing of MHCII(low) to MHCII(hi) macrophages were observed. Furthermore, mice receiving the combined treatment exhibited an increase in tumor-infiltrating lymphocytes (TIL) and T cells, as revealed by real-time imaging in vivo. In conclusion, CSF-1R blockade with PLX3397 improved the efficacy of ACT immunotherapy by inhibiting the intratumoral accumulation of immunosuppressive macrophages.
24243648	Brain Neoplasm	PTGS2	Inhibit immunity; Resistant to immunotherapy	Intratumoral COX-2 inhibition enhances GM-CSF immunotherapy against established mouse GL261 brain tumors. Prostaglandin E2 (PGE2 ) is the key immunosuppressive product of cyclooxygenase-2 (COX-2) and increased levels of PGE2 and COX-2 have been shown in several tumor types, including brain tumors. In the current study, we report enhanced cure rate of mice with established mouse GL261 brain tumors when immunized with granulocyte macrophage-colony stimulating factor (GM-CSF) secreting tumor cells and simultaneously treated with the selective COX-2 inhibitors parecoxib systemically (5 mg/kg/day; 69% cure rate) or valdecoxib intratumorally (5.3 µg/kg/day; 63% cure rate).
24242212	Colon Carcinoma	ULBP2	Promote immunity	To this end we designed a fusion protein consisting of human ULBP2 and an antibody-derived single chain targeting the tumor carcinoembryonic antigen (CEA). The bispecific recombinant fusion protein re-directed NK cells towards malignant cells by binding to both, tumor cells and NK cells, and triggered NK cell-mediated target cell killing in vitro. Moreover, tumor growth was significantly delayed in a syngeneic colon carcinoma mouse model in response to immunoligand treatment.
24242212	Colon Carcinoma	CD69	Promote immunity	The anti-tumor activity could be attributed to the stimulation of immune cells with an elevated expression of the activation marker CD69 on NK, T and NKT cells and the infiltration of CD45+ immune cells into the solid tumor.
24231354	Osteosarcoma	RB1	Promote immunity	Immune response to RB1-regulated senescence limits radiation-induced osteosarcoma formation. Ionizing radiation (IR) and germline mutations in the retinoblastoma tumor suppressor gene (RB1) are the strongest risk factors for developing osteosarcoma. Recapitulating the human predisposition, we found that Rb1+/- mice exhibited accelerated development of IR-induced osteosarcoma, with a latency of 39 weeks.
24231354	Osteosarcoma	IL6	Promote immunity	In vivo, IL-6 was required for IR-induced senescence, which elicited NKT cell infiltration and a host inflammatory response. Mice lacking IL-6 or NKT cells had accelerated development of IR-induced osteosarcomas.
24227785	Melanoma	NANOG	Inhibit immunity	We observed that hypoxia-induced Nanog correlated with the acquisition of stem cell-like properties in B16-F10 cells. Nanog targeting significantly reduced immunosuppressive cells (regulatory T cells and macrophages) and increased CD8(+) T effector cells in tumor bed in part by modulating TGF-β1 production. Additionally, Nanog regulated TGF-β1 under hypoxia by directly binding the TGF-β1 proximal promoter.
24218449	Melanoma	HYOU1	Promote immunity	Directing the clinically relevant, melanoma Ag gp100 to mouse-derived DCs by molecular adjuvant and chaperone Grp170 substantially facilitates Ag access to the ER. Grp170 also strengthens the interaction of internalized protein Ag with molecular components involved in ER-associated protein dislocation and/or degradation, which culminates in cytosolic translocation for proteasome-dependent degradation and processing.
24216507	Myelodysplastic Syndrome	S100A9	Inhibit immunity	Using multiple transfected cell models, we found that MDSC expansion is driven by the interaction of the proinflammatory molecule S100A9 with CD33. S100A9 transgenic mice displayed bone marrow accumulation of MDSC accompanied by development of progressive multilineage cytopenias and cytological dysplasia. These findings indicate that primary bone marrow expansion of MDSC driven by the S100A9/CD33 pathway perturbs hematopoiesis and contributes to the development of MDS.
24216507	Myelodysplastic Syndrome	CD33	Inhibit immunity	Using multiple transfected cell models, we found that MDSC expansion is driven by the interaction of the proinflammatory molecule S100A9 with CD33. These findings indicate that primary bone marrow expansion of MDSC driven by the S100A9/CD33 pathway perturbs hematopoiesis and contributes to the development of MDS.
24216477	Colon Carcinoma	IL10	Inhibit immunity	The capacity of IL-10 and Tregs in the inflammatory tumor microenvironment to impair anticancer Th1 immunity makes them attractive targets for cancer immunotherapy. IL-10 production limited Th17 cell numbers in both spleen and tumor.
24190978	Ovarian Carcinoma	ITGAE	Promote immunity (T cell function)	Tumor-infiltrating lymphocytes expressing the tissue resident memory marker CD103 are associated with increased survival in high-grade serous ovarian cancer. Tumors containing CD8(+) TILs that were CD103(-) showed poor prognosis equivalent to tumors lacking CD8(+) TILs altogether. CD103(+) TILs comprise intraepithelial, activated CD8(+) T cells, and NK cells and are strongly associated with patient survival in HGSC.
24177177	Prostate Carcinoma	STAT3	Inhibit immunity	In human prostate tumor tissues, elevated cancer stem-like cell markers coincide with those cells exhibiting high STAT3 activity and low AR expression. AR downregulation-induced STAT3 activation is mediated through increased interleukin (IL)-6 expression. Treating mice with soluble IL-6 receptor fusion protein or silencing STAT3 in tumor cells significantly reduced prostate tumor growth and CSCs.
24169824	Acute Myeloid Leukemia	STAT3	Inhibit immunity	Leukemia cell-targeted STAT3 silencing and TLR9 triggering generate systemic antitumor immunity. CpG-Stat3 siRNA has direct immunogenic effect on AML cells in vivo upregulating major histocompatibility complex class-II, costimulatory and proinflammatory mediators, such as interleukin-12, while downregulating coinhibitory PD-L1 molecule. Systemic injections of CpG-Stat3 siRNA generate potent tumor antigen-specific immune responses, increase the ratio of tumor-infiltrating CD8(+) T cells to regulatory T cells in various organs, and result in CD8(+) T-cell-dependent regression of leukemia.
24145455	Squamous Cell Carcinoma	NDUFA13	Promote immunity	Monoallelic loss of tumor suppressor GRIM-19 promotes tumorigenesis in mice. Surprisingly, the deletion of a single copy of the Grim-19 gene was sufficient to promote carcinogenesis and formation of invasive squamous cell carcinomas.
24144734	Breast Carcinoma	KITLG	Inhibit immunity	A functional c-Kit/Kit ligand (KitL) signalling network is required for tumour angiogenesis and growth, and therefore the c-Kit/KitL system might well be a suitable target for the cancer immunotherapy approach. DNA vaccination, interferes with tumour vessel formation and transplanted tumour growth in vivo. Histological analysis demonstrates that, while tumour cell proliferation and vessel stabilisation are impaired, vessel permeability is increased in mice that produce mbKitL-targeting antibodies.
24141770	Melanoma	PTEN	Promote immunity	PTEN functions as a melanoma tumor suppressor by promoting host immune response. Mechanistically, PTEN represses the expression of immunosuppressive cytokines by blocking the phosphatidylinositide 3-kinase (PI3K) pathway. In melanoma cells lacking PTEN, signal transducer and activator of transcription 3 activates the transcription of immunosuppressive cytokines in a PI3K-dependent manner. Furthermore, we report that PTEN, as an alternative mechanism to promote the host immune response against cancer cells, represses the expression of programmed cell death 1 ligand, a known repressor of the host immune response.
24141010	B Acute Lymphoblastic Leukemia	KDM5D	Promote immunity	In contrast, restriction of HY expression to hematopoietic tissues restored MB49 responses but resulted in a loss of antileukemia responses.
24131405	Breast Carcinoma	STAT3	Inhibit immunity	Systemic delivery of PCPS/STAT3 siRNA in murine model of MDA-MB-231 breast cancer enriched particles in tumor tissues and reduced STAT3 expression in cancer cells, causing significant reduction of cancer stem cells in the residual tumor tissue.
24127572	Melanoma	CCR4	Inhibit immunity	Anti-CCR4 mAb selectively depletes effector-type FoxP3+CD4+ regulatory T cells, evoking antitumor immune responses in humans. In melanoma tissues, CCR4(+) eTreg cells were predominant among tumor-infiltrating FOXP3(+) T cells and much higher in frequency compared with those in peripheral blood. With peripheral blood lymphocytes from healthy individuals and melanoma patients, ex vivo depletion of CCR4(+) T cells and subsequent in vitro stimulation of the depleted cell population with the cancer/testis antigen NY-ESO-1 efficiently induced NY-ESO-1-specific CD4(+) T cells. CCR4(+) T-cell depletion also augmented in vitro induction of NY-ESO-1-specific CD8(+) T cells in melanoma patients.
24127488	Lung Carcinoma; Pancreatic Carcinoma	CTNNB1	Promote immunity	Consistent with a negative role for β-catenin in MDSCs, its deletion in the myeloid population leads to MDSC accumulation and supports tumor progression, whereas expression of β-catenin constitutively active reduces MDSC numbers and protects from tumor growth. Further emphasizing the clinical relevance of these findings, MDSCs isolated from pancreatic cancer patients show reduced p-PLCγ2 and β-catenin levels compared with healthy controls, similar to tumor-bearing mice.
24127488	Melanoma; Lung Carcinoma; Pancreatic Carcinoma	PLCG2	Promote immunity	We demonstrate that down-regulation of PLCγ2 signaling in MDSCs is responsible for their aberrant expansion during tumor progression. PLCγ2(-/-) MDSCs show stronger immune-suppressive activity against CD8(+) T cells than WT MDSCs and potently promote tumor growth when adoptively transferred into WT mice.
24122861	Hepatocellular Carcinoma	AFP	Promote immunity	Immunization with lentivector expressing optimized AFP, but not native AFP, completely protected mice from tumor challenge and reduced the incidence of carcinogen-induced autochthonous HCC. Epitope-optimization is required to break immune tolerance and potently activate AFP-specific CD8 T cells, generating effective antitumor effect to prevent clinically relevant carcinogen-induced autochthonous HCC in mice.
24107450	Hepatocellular Carcinoma	STAT3	Inhibit immunity	Targeting blockage of STAT3 in hepatocellular carcinoma cells augments NK cell functions via reverse hepatocellular carcinoma-induced immune suppression. In the case of STAT3-blocked hepatocellular carcinoma cells, NKG2D ligands were upregulated, which promoted recognition by NK cells. Indeed, the cytotoxicity of NK cells treated with supernatant from STAT3-blocked hepatocellular carcinoma cells was augmented, with a concomitant elevation of molecules associated with NK cytolysis.
24101526	Breast Carcinoma	BECN1	Inhibit immunity	Inhibition of autophagy by targeting beclin1 (BECN1) restored granzyme B levels in hypoxic cells in vitro and induced tumor regression in vivo by facilitating NK-mediated tumor cell killing.
24100387	Melanoma	PMEL	Immunotherapy target	Collectively, these results demonstrate that the TCR-like Ab, GPA7, could redirect NK cells to target the intracellular antigen gp100 and enhance anti-melanoma activity, providing a promising immunotherapeutic strategy to prevent and treat melanoma.
24097874	Neuroblastoma	IL7	Promote immunity (T cell function)	We found that IL-7, in sharp contrast with IL-2, supports the proliferation and antitumor activity of IL-7Rα.CAR-GD2(+) EBV-CTLs both in vitro and in vivo even in the presence of fully functional Treg. IL-7 selectively favors the survival, proliferation, and effector function of IL-7Rα-transgenic/CAR-redirected EBV-CTLs in the presence of Treg both in vitro and in vivo.
24089443	Melanoma	CD274	Inhibit immunity; Immunotherapy target	Immune checkpoint blockade with monoclonal antibodies directed at the inhibitory immune receptors CTLA-4, PD-1, and PD-L1 has emerged as a successful treatment approach for patients with advanced melanoma.
24089443	Melanoma	CTLA4	Inhibit immunity; Immunotherapy target	Immune checkpoint blockade with monoclonal antibodies directed at the inhibitory immune receptors CTLA-4, PD-1, and PD-L1 has emerged as a successful treatment approach for patients with advanced melanoma.
24081947	Lung Carcinoma	TNF	Inhibit immunity	TNF blockade in aged mice resulted in significant increases in survival and lessened pathology. Importantly, TNF blockade in tumor-bearing, aged mice receiving IT displayed significant anti-tumor effects.
24078774	Lung Neoplasm	EGFR	Inhibit immunity	We observed decreased CTLs and increased markers of T-cell exhaustion in mouse models of EGFR-driven lung cancer. Expression of mutant EGFR in bronchial epithelial cells induced PD-L1, and PD-L1 expression was reduced by EGFR inhibitors in non-small cell lung cancer cell lines with activated EGFR. These data suggest that oncogenic EGFR signaling remodels the tumor microenvironment to trigger immune escape and mechanistically link treatment response to PD-1 inhibition. We show that autochthonous EGFR-driven lung tumors inhibit antitumor immunity by activating the PD-1/PD-L1 pathway to suppress T-cell function and increase levels of proinflammatory cytokines.
24078774	Lung Neoplasm	PDCD1	Inhibit immunity	PD-1 antibody blockade improved the survival of mice with EGFR-driven adenocarcinomas by enhancing effector T-cell function and lowering the levels of tumor-promoting cytokines.
22975373	Hepatocellular Carcinoma	CCL22	Inhibit immunity	TGF-β-miR-34a-CCL22 signaling-induced Treg cell recruitment promotes venous metastases of HBV-positive hepatocellular carcinoma. Mechanistically, elevated TGF-β activity, associated with the persistent presence of HBV in the liver tissue, suppresses the expression of microRNA-34a, leading to enhanced production of chemokine CCL22, which recruits regulatory T (Treg) cells to facilitate immune escape.
22975165	Plasma Cell Myeloma	KLRK1	Promote immunity	NKG2D is a natural killer (NK) cell activating receptor that mediates non-MHC restricted and TCR-independent cell lysis. When compared to posttransplantation IL-2 therapy alone in this patient population, the addition of cells enriched for NKG2D(+)CD3(+)CD8(+) T cells increased tumor-specific immunity, as demonstrated by enhanced lysis of autologous myeloma cells (P = .02).
22972922	Colon Carcinoma	MIF	Inhibit immunity	The results showed that the tumor growth rate was significantly lower in MIF knockout (MIF(-/-)) mice than in wild-type (MIF(+/+)) mice. Flow cytometric analysis of both spleen and tumor cells revealed that MIF(-/-) mice had significantly lower levels of tumor-associated CD4(+)Tregs than MIF(+/+) mice. The splenic cells of MIF(-/-) mice also showed a decrease in CD8(+)Tregs, which was accompanied by an increase in CD8-induced tumor cytotoxicity.
22972922	Colon Carcinoma	IL2	Inhibit immunity	Moreover, the administration of IL-2 into tumor-bearing MIF(-/-) mice restored the generation of Tregs and tumor growth.
22964632	Ovarian Carcinoma	MUC1	Inhibit immunity; Candidate for immunotherapy target	Mucin 1 (MUC1) glycoprotein is a tumor-associated antigen overexpressed in ovarian cancer cells, making it a potential target for immune therapy. Compared with the KrasPten mice with tumors, the MUC1KrasPten mice show increased loco-regional metastasis and augmented accumulation of CD4+Foxp3+ immune-suppressive regulatory T cells. Vaccination of MUC1KrasPten mice with type 1 polarized dendritic cells (DC1) loaded with a MUC1 peptide (DC1-MUC1) can circumvent tumor-mediated immune suppression in the host, activate multiple immune effector genes and effectively prolong survival.
22962263	Lung Carcinoma; Melanoma	PTPN1	Promote immunity	A comprehensive approach using transcriptome analysis, argonaute protein immunoprecipitation, and luciferase reporter assay revealed that the genes PTPN1, HOXA1, and TP53I11 were miR-210 target genes regulated in hypoxic cells. In support of their primary importance in mediating the immunosuppressive effects of miR-210, coordinate silencing of PTPN1, HOXA1, and TP53I11 dramatically decreased tumor cell susceptibility to CTL-mediated lysis.
22962263	Lung Carcinoma; Melanoma	HOXA1	Promote immunity	A comprehensive approach using transcriptome analysis, argonaute protein immunoprecipitation, and luciferase reporter assay revealed that the genes PTPN1, HOXA1, and TP53I11 were miR-210 target genes regulated in hypoxic cells. In support of their primary importance in mediating the immunosuppressive effects of miR-210, coordinate silencing of PTPN1, HOXA1, and TP53I11 dramatically decreased tumor cell susceptibility to CTL-mediated lysis.
22962263	Lung Carcinoma; Melanoma	TP53I11	Promote immunity	A comprehensive approach using transcriptome analysis, argonaute protein immunoprecipitation, and luciferase reporter assay revealed that the genes PTPN1, HOXA1, and TP53I11 were miR-210 target genes regulated in hypoxic cells. In support of their primary importance in mediating the immunosuppressive effects of miR-210, coordinate silencing of PTPN1, HOXA1, and TP53I11 dramatically decreased tumor cell susceptibility to CTL-mediated lysis.
22955317	Non-Small Cell Lung Carcinoma	ITGAM	Inhibit immunity (T cell function)	Patients with NSCLC had a significantly higher ratio of CD11b(+)CD14(+) cells than healthy subjects, which was correlated with poor performance status and poor response to chemotherapy. Isolated CD11b(+)CD14(+) cells suppressed CD8(+) T-cell proliferation and IFN-γ production, and the former effect was attenuated by the inducible nitric oxide synthase (iNOS) inhibitor aminoguanidine hydrochloride, arginase inhibitor N-hydroxy-nor-l-arginine (nor-NOHA), and blocking antibodies for IL-4Rα(+) and IL-10.
22955317	Non-Small Cell Lung Carcinoma	CD14	Inhibit immunity (T cell function)	Patients with NSCLC had a significantly higher ratio of CD11b(+)CD14(+) cells than healthy subjects, which was correlated with poor performance status and poor response to chemotherapy. Isolated CD11b(+)CD14(+) cells suppressed CD8(+) T-cell proliferation and IFN-γ production, and the former effect was attenuated by the inducible nitric oxide synthase (iNOS) inhibitor aminoguanidine hydrochloride, arginase inhibitor N-hydroxy-nor-l-arginine (nor-NOHA), and blocking antibodies for IL-4Rα(+) and IL-10.
22955317	Non-Small Cell Lung Carcinoma	S100A9	Inhibit immunity	The ratio of S100A9(+) cells positively correlated with the suppressive ability of the CD11b(+)CD14(+) cells, was associated with poor response to chemotherapy, and predicted shorter progression-free survival. CD14(+)S100A9(+) inflammatory monocytes in patients with NSCLC are a distinct subset of MDSCs, which suppress T cells by arginase, iNOS, and the IL-13/IL-4Rα axis.
22945919	Acute Myeloid Leukemia	SIRPA	Inhibit immunity; Candidate for immunotherapy target	Disruption of SIRPα signaling in macrophages eliminates human acute myeloid leukemia stem cells in xenografts. In this study, we report that leukemia stem cell function in xenotransplant models of acute myeloid leukemia (AML) depends on SIRPα-mediated inhibition of macrophages through engagement with its ligand CD47. These findings support the development of therapeutics that antagonize SIRPα signaling to enhance macrophage-mediated elimination of AML.
22936666	Mastocytoma	KIT	Inhibit immunity	In this study, we report that the in vivo antitumor effects of the c-KIT inhibitor, dasatinib, on the c-KIT mutant P815 mastocytoma tumor were substantially dependent on T cell-mediated immunity. We found that dasatinib treatment significantly decreased levels of Tregs while specifically enhancing tumor antigen-specific T-cell responses.
22936666	Mastocytoma	TNFRSF4	Inhibit immunity	The combination of dasatinib and anti-OX40 antibody resulted in substantially better therapeutic efficacy compared with either drug alone, and this was associated with enhanced accumulation of tumor antigen-specific T cells in the tumor microenvironment. Furthermore, the combination regimen inhibited the function of Tregs and also resulted in significantly up-regulated expression of the IFN-γ-induced chemokines CXCL9, 10, and 11 in the tumor microenvironment, which provides a feasible mechanism for the enhanced intratumoral CTL infiltration.
22936657	Mouse Myelomonocytic Leukemia	LTB4R	Promote immunity	Absence of LTB4/BLT1 axis facilitates generation of mouse GM-CSF-induced long-lasting antitumor immunologic memory by enhancing innate and adaptive immune systems. We here demonstrated that BLT1-deficient mice rejected subcutaneous tumor challenge of GM-CSF gene-transduced WEHI3B (WGM) leukemia cells (KO/WGM) and elicited robust antitumor responses against second tumor challenge with WEHI3B cells. During GM-CSF-induced tumor regression, the defective LTB4/BLT1 signaling significantly reduced tumor-infiltrating myeloid-derived suppressor cells, increased the maturation status of dendritic cells in tumor tissues, enhanced their CD4(+) T-cell stimulation capacity and migration rate of dendritic cells that had phagocytosed tumor-associated antigens into tumor-draining lymph nodes, suggesting a positive impact on GM-CSF-sensitized innate immunity.
22936067	Myxoid Liposarcoma	CTAG1B	Promote immunity	In all, 7/8 (88%) and 16/18 (89%) myxoid and round cell expressed CTAG1B and NY-ESO-1 by quantitative real-time PCR and immunohistochemistry, respectively. Our study shows that both CTAG1B mRNA and protein are overexpressed with high frequency in myxoid and round cell liposarcoma, enabling the potential use of targeted immunotherapy in the treatment of this malignancy.
22932804	Breast Carcinoma; Colon Carcinoma; Prostate Carcinoma	CD40LG	Inhibit immunity	Elevated serum soluble CD40 ligand in cancer patients may play an immunosuppressive role. In this study, we showed that an extracellular portion of a membrane-bound ligand of CD40 (soluble CD40 ligand; sCD40L) was significantly elevated in the serum of cancer patients compared with healthy donors. In addition, PBMCs from cancer patients had a relatively larger population of myeloid-derived suppressor cells (MDSCs), defined as CD33(+)HLA-DR(-) cells, and these cells expressed higher levels of CD40. PBMCs cultured in vitro with sCD40L also showed an expansion of regulatory T cells (CD4(+)CD25(high)Foxp3(+)), as well as induction of cytokines, such as IL-10 and IL-6.
22932670	Glioma	IDO1	Inhibit immunity	IDO expression in brain tumors increases the recruitment of regulatory T cells and negatively impacts survival. Coincidently, both IDO-competent and deficient mice showed a survival advantage bearing IDO-deficient brain tumors, when compared with IDO-competent brain tumors. IDO deficiency was also associated with lower GITR expression levels on Tregs.
22932225	Melanoma	IL2	Promote immunity	Melanoma-specific T cells screened for high relative IL-2 production had a T(CM) phenotype and superior in vitro proliferative capacity compared to cells with low IL-2 production.
22925929	Melanoma	IFNA1	Promote immunity (T cell function); Essential for immunotherapy	In this study, we show that human naive CD8 T cells primed in the presence of IFN-α possess a heightened ability to respond to homeostatic cytokines and to secondary Ag stimulation, but rather than differentiating to effector or memory CTLs, they preserve nature-like phenotypic features. In humans, exposure to IFN-α during in vitro priming of naive HLA-A2(+) CD8 T cells with autologous dendritic cells loaded with MART1(26-35) peptide renders CD8 T cells with an improved capacity to respond to homeostatic cytokines and to specifically lyse MART1-expressing melanoma cells. Furthermore, in a mouse model of melanoma, adoptive transfer of tumor-specific CD8 T cells primed ex vivo in the presence of IFN-α exhibits an improved ability to contain tumor progression. Therefore, exposure to IFN-α during priming of naive CD8 T cells imprints decisive information on the expanded cells that can be exploited to improve the efficacy of adoptive T cell therapy.
22915761	Melanoma	PDCD1	Inhibit immunity (T cell function)	PD-1 blockade enhances T-cell migration to tumors by elevating IFN-γ inducible chemokines. While anti-PD-1 did not reduce the number of immunosuppressive regulatory T cells and myeloid-derived suppressor cells present in tumor-bearing mice, we found that it increased expression of IFN-γ and CXCL10 at the tumor site.
22915070	Mantle Cell Lymphoma	TLR4	Inhibit immunity; Candidate for immunotherapy target	The activation of TLR4 signaling in MCL cells by LPS induced MCL proliferation and up-regulated the secretion of cytokines like interleukin-6 (IL-6), IL-10, and vascular endothelial growth factor (VEGF). Knockdown of TLR4 on MCL cells abrogated the effect of LPS on MCL cells in term of cell growth or secretion of the cytokines and evasion of the immune system. Thus, TLR4 signaling molecules may be novel therapeutic targets in patients with MCL.
22911397	Hepatocellular Carcinoma; Colorectal Carcinoma	TNFRSF18	Promote immunity	We show that tumor Tregs up-regulate the expression of glucocorticoid-induced tumor necrosis factor receptor (GITR) compared with Tregs in tumor-free liver tissue and blood. Importantly, treatment with soluble GITR ligand (GITRL) induces a decrease in the suppression mediated by the activated tumor-infiltrating Tregs and restores the proliferative capacity and cytokine production of CD4+CD25- T cells.
22896667	Prostate Carcinoma	MSR1	Inhibit immunity	In situ vaccination with CD204 gene-silenced dendritic cell, not unmodified dendritic cell, enhances radiation therapy of prostate cancer. SRA/CD204-silenced DCs were highly efficient in generating antigen or tumor-specific T cells with increased effector functions (e.g., cytokine production and tumoricidal activity). SRA/CD204 silencing-enhanced tumor cell death was associated with elevated IFN-γ levels in tumor tissue and increased tumor-infiltrating CD8(+) cells.
22896667	Prostate Carcinoma	IFNA1	Promote immunity	IFN-γ neutralization or depletion of CD8(+) cells abrogated the SRA/CD204 downregulation-promoted antitumor efficacy, indicating a critical role of IFN-γ-producing CD8(+) T cells.
22893632	Malignant Mesothelioma	CSPG4	Inhibit immunity	CSPG4 was expressed on 6 out of 8 MM cell lines and in 25 out of 41 MM biopsies, with minimal expression in surrounding healthy cells. MM cell adhesion was mediated by CSPG4-dependent engagement of ECM. Cell adhesion was inhibited by mAb TP41.2 resulting in decreased phosphorylation of focal adhesion kinase (FAK) and AKT, reduced expression of cyclin D1 and apoptosis.
22890326	Squamous Cell Carcinoma	MTOR	Inhibit immunity	The mTOR inhibitor rapamycin opposes carcinogenic changes to epidermal Akt1/PKBα isoform signaling. We show that rapamycin selectively upregulates epidermal Akt1, while failing to upregulate epidermal Akt2. Epidermal Akt1 is commonly downregulated in SCC while Akt2 is upregulated. We show in skin culture that rapamycin does enhance restoration of Akt1 phosphorylation in skin recovering from UV radiation, suggesting a mechanism for rapamycin's antitumor activity in epidermis in spite of its efficient immunosuppressive properties.
22869886	Stage 4 Neuroblastoma	CSF2	Promote immunity	Anti-GD2 monoclonal antibody (MoAb) combined with granulocyte-macrophage colony-stimulating factor (GM-CSF) has shown efficacy against neuroblastoma (NB). Retrospective analysis of consecutive trials from a single center demonstrated that MoAb 3F8 + GM-CSF + CRA is effective against chemotherapy-resistant marrow MRD.
22869555	Primary Cutaneous T-Cell Non-Hodgkin Lymphoma	CCR4	Inhibit immunity	Humanization of an anti-CCR4 antibody that kills cutaneous T-cell lymphoma cells and abrogates suppression by T-regulatory cells. CCR4 is also highly expressed on T-regulatory cells (Tregs) that can migrate to several different types of chemotactic ligand CCL17- and CCL22-secreting tumors to facilitate tumor cell evasion from immune surveillance. Moreover, mAb1567 also effectively inhibits chemotaxis of CD4(+)CD25(high) Tregs via CCL22 and abrogates Treg suppression activity in vitro.
22865781	Breast Carcinoma	ERBB2	Inhibit immunity	Approximately 15%-23% of breast cancers overexpress human epidermal growth factor receptor 2 (HER2), which leads to the activation of signaling pathways that stimulate cell proliferation and survival.
22865456	Melanoma	NFATC2	Inhibit immunity (T cell function)	NFAT1 supports tumor-induced anergy of CD4(+) T cells. NFAT1 deficiency blunted the induction of anergy in tumor antigen-specific CD4+ T cells, enhancing antitumor responses.
22859216	Hepatocellular Carcinoma	TLR2	Promote immunity	Surprisingly, we found that the genetic deletion of TLR2 increased susceptibility to diethylnitrosamine (DEN), a genotoxic carcinogen that can induce HCC. Indeed, TLR2-deficient mice showed a significant increase in carcinogenesis and progression of HCC as indicated by increases in tumor nodule size, tumor volume, and animal death. We found that TLR2 deficiency caused a decrease in the infiltration of macrophages and an attenuation of apoptosis signal regulating kinase 1 (ASK1) / p38 mitogen-activated protein kinase (p38 MAPK) / nuclear factor kappa B (NF-κB) signaling, which led to a decrease in the expression of interferon-gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), interleukin (IL)-1α/β, IL-6, and Cxcl-2 as well as suppression of autophagy flux and increases in oxidative stress and p62 aggregation in liver tissue. The defects in immune networks resulted in suppressed p21- and p16/pRb-dependent senescence, which caused an increase in proliferation and a decrease in apoptotic and autophagy-associated cell death in mouse livers.
22851709	Lymphoma	NCR3	Promote immunity	An NKp30-based chimeric antigen receptor promotes T cell effector functions and antitumor efficacy in vivo. The data show that chimeric NKp30-expressing T cells responded to B7-H6+ tumor cells. NKp30 CAR-expressing T cells produced IFN-γ and killed B7-H6 ligand-expressing tumor cells; this response was dependent upon ligand expression on target cells but not on MHC expression.
22851709	Lymphoma	CD28	Promote immunity; Essential for immunotherapy	The addition of a CD28-signaling domain significantly enhanced the activity of the NKp30 CAR in a PI3K-dependent manner. Adoptive transfer of T cells expressing a chimeric NKp30 receptor containing a CD28-signaling domain inhibited the growth of a B7-H6-expressing murine lymphoma (RMA/B7-H6) in vivo.
22851172	Breast Carcinoma	ATP2A3	Inhibit immunity	Here, we show that human CD4(+) T cells in the presence of tumor conditions manifested an up-regulation of SERCA3 expression that resulted in development of endoplasmic reticulum stress leading to CD4(+) T cell apoptosis. Gene manipulation and pharmacological approaches further established that an increase in SERCA expression also resulted in subsequent inhibition of PKCα and -θ and retention of NFκB in the cytosol; however, down-modulation of SERCA3 expression by a dihydropyrimidone derivative, ethyl-4-(3-nitro)-phenyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5 carboxylate (nifetepimine), protected the CD4(+) T cells from tumor-induced apoptosis.
22850568	Melanoma	BRAF	Inhibit immunity	Expression of BRAF(V600E) induced transcription of interleukin 1 alpha (IL-1α) and IL-1β in melanocytes and melanoma cell lines. Treatment of melanoma-patient-derived TAFs with IL-1α/β significantly enhanced their ability to suppress the proliferation and function of melanoma-specific cytotoxic T cells, and this inhibition was partially attributable to upregulation by IL-1 of COX-2 and the PD-1 ligands PD-L1 and PD-L2 in TAFs.
22850568	Melanoma	IL1A	Inhibit immunity	Treatment of melanoma-patient-derived TAFs with IL-1α/β significantly enhanced their ability to suppress the proliferation and function of melanoma-specific cytotoxic T cells, and this inhibition was partially attributable to upregulation by IL-1 of COX-2 and the PD-1 ligands PD-L1 and PD-L2 in TAFs.
22850568	Melanoma	IL1B	Inhibit immunity	Treatment of melanoma-patient-derived TAFs with IL-1α/β significantly enhanced their ability to suppress the proliferation and function of melanoma-specific cytotoxic T cells, and this inhibition was partially attributable to upregulation by IL-1 of COX-2 and the PD-1 ligands PD-L1 and PD-L2 in TAFs.
22850422	Ovarian Carcinoma	FOXP3	Inhibit immunity	Plasmacytoid dendritic cells promote immunosuppression in ovarian cancer via ICOS costimulation of Foxp3(+) T-regulatory cells. Accordingly, ICOS(+) Foxp3(+) Treg cells were found to localize in close vicinity of tumor pDCs, and their number directly correlated with the numbers of pDCs in the tumors. Furthermore, pDCs and ICOS(+) Foxp3(+) Treg cells were found to be strong predictors for disease progression in patients with ovarian cancer, with ICOS(+) Treg cell subset being a stronger predictor than total Foxp3(+) Treg cells.
22850422	Ovarian Carcinoma	ICOSLG	Inhibit immunity	Accordingly, ICOS(+) Foxp3(+) Treg cells were found to localize in close vicinity of tumor pDCs, and their number directly correlated with the numbers of pDCs in the tumors. Furthermore, pDCs and ICOS(+) Foxp3(+) Treg cells were found to be strong predictors for disease progression in patients with ovarian cancer, with ICOS(+) Treg cell subset being a stronger predictor than total Foxp3(+) Treg cells. These findings suggest an essential role for pDCs and ICOS-L in immunosuppression mediated by ICOS(+) Foxp3(+) Treg cells, leading to tumor progression in ovarian cancer.
22836755	Breast Carcinoma	IFNA1	Promote immunity	Impaired IFN-α production by plasmacytoid dendritic cells favors regulatory T-cell expansion that may contribute to breast cancer progression. Of most importance, the selective suppression of IFN-α production endowed TApDC with the unique capacity to sustain FoxP3(+) Treg expansion, a capacity that was reverted by the addition of exogenous IFN-α. These findings indicate that IFN-α-deficient TApDC accumulating in aggressive tumors are involved in the expansion of TATreg in vivo, contributing to tumor immune tolerance and poor clinical outcome.
22826320	Melanoma	MTOR	Inhibit immunity	The improved performance of DCs in which mTOR has been inhibited is correlated with an extended life span after activation and prolonged, increased expression of costimulatory molecules. Therapeutic autologous vaccination with DCs treated with TLR agonists plus the mTOR inhibitor rapamycin results in improved generation of Ag-specific CD8+ T cells in vivo and improved antitumor immunity compared with that observed with DCs treated with TLR agonists alone.
22826317	Melanoma	NT5E	Inhibit immunity (T cell function)	Inhibition of CD73 improves B cell-mediated anti-tumor immunity in a mouse model of melanoma. CD73 is a cell surface enzyme that suppresses T cell-mediated immune responses by producing extracellular adenosine. In this study, we demonstrate that administration of a specific CD73 inhibitor, adenosine 5'-(α,β-methylene)diphosphate (APCP), to melanoma-bearing mice induced a significant tumor regression by promoting the release of Th1- and Th17-associated cytokines in the tumor microenvironment.
22822050	Lung Carcinoma	IDO1	Inhibit immunity	Investigating the impact of Ido1 gene disruption in mouse models of oncogenic KRAS-induced lung carcinoma and breast carcinoma-derived pulmonary metastasis, we have found that IDO deficiency resulted in reduced lung tumor burden and improved survival in both models. Micro-computed tomographic (CT) imaging further revealed that the density of the underlying pulmonary blood vessels was significantly reduced in Ido1-nullizygous mice. IDO deficiency in vivo negatively impacted both vascularization and IL-6–dependent, MDSC-driven immune escape, establishing IDO as an overarching factor directing the establishment of a protumorigenic environment.
22822050	Lung Carcinoma	IL6	Inhibit immunity	Biologically, this resulted in a consequential impairment of protumorigenic myeloid-derived suppressor cells (MDSC), as restoration of IL-6 recovered both MDSC suppressor function and metastasis susceptibility in Ido1-nullizygous mice.
22820642	Breast Carcinoma	IRF7	Promote immunity	Silencing of Irf7 pathways in breast cancer cells promotes bone metastasis through immune escape. Restoration of Irf7 in tumor cells or administration of interferon led to reduced bone metastases and prolonged survival time. We confirmed the clinical relevance of these findings in over 800 patients in which high expression of Irf7-regulated genes in primary tumors was associated with prolonged bone metastasis-free survival.
22819865	Pancreatic Adenocarcinoma	CD24	Promote immunity	Intratumor injection of human CD24 and Her2/neu-specific T-bodies completely eliminated the tumors from most animals. In contrast, the CD24-specific T-bodies prolonged survival of mice in which only a subpopulation of the tumor cells expressed the antigen. T-bodies specific to CD24, a putative cancer stem cell antigen, were effective against PAC xenografts that had only a subset of antigen-expressing cells.
22819865	Pancreatic Adenocarcinoma	ERBB2	Inhibit immunity	Intratumor injection of human CD24 and Her2/neu-specific T-bodies completely eliminated the tumors from most animals. A single administration of the Her2/neu-specific T-bodies prolonged the survival of mice with tumors in which most of the cells expressed the target antigen.
22817659	Osteosarcoma	CD1D	Promote immunity	iNKT cells were cytotoxic against OS cells through a CD1d-dependent mechanism. iNKT cell treatment enhanced drug-induced OS cell death in a concentration-dependent manner and this effect was reduced in CD1d-silenced OS cells.
22815287	Melanoma	CTNNB1	Inhibit immunity	Immune suppression and resistance mediated by constitutive activation of Wnt/β-catenin signaling in human melanoma cells. IL-10 expression was associated with β-catenin accumulation in human melanoma cell lines and tissues and was induced by direct β-catenin/TCF binding to the IL-10 promoter. Murine splenic and tumor-infiltrating DCs obtained from nude mice implanted with human mutant β-catenin-overexpressed melanoma cells had less ability to activate T cells than did DCs from mice with control melanoma cells, showing in vivo suppression of DCs by activated Wnt/β-catenin signaling in human melanoma. β-catenin-overexpressed melanoma inhibited IFN-γ production by melanoma-specific CTLs in an IL-10-independent manner and is more resistant to CTL lysis in vitro and in vivo.
22805310	Soft Tissue Sarcoma	STAT1	Inhibit immunity (uSTAT1); Promote immunity (pSTAT1)	Unphosphorylated STAT1 promotes sarcoma development through repressing expression of Fas and bad and conferring apoptotic resistance. RNAi-mediated silencing of STAT1 in STS cells was sufficient to increase expression of the apoptotic mediators Fas and Bad and to elevate the sensitivity of STS cells to Fas-mediated apoptosis. Together, our findings show how the phosphorylation status of pSTAT1 determines its function as a tumor suppressor, with uSTAT1 acting as a tumor promoter that acts by elevating resistance to Fas-mediated apoptosis to promote immune escape.
22805310	Soft Tissue Sarcoma	IRF8	Promote immunity	Using a murine model of soft tissue sarcoma (STS), we show that disruption of the IFN effector molecule IRF8 decreases pSTAT1 and increases uSTAT1 in STS cells, thereby increasing their metastatic potential. Mechanistic investigations revealed that IRF8 suppressed STAT1 transcription by binding the STAT1 promoter.
22798667	Leukemia	PTPN6	Inhibit immunity	We found that the abrogation of Src homology region 2 domain-containing phosphatase-1 (SHP-1) in tumor-reactive CD8(+) T cells improves the therapeutic outcome of adoptive immunotherapy in a mouse model of disseminated leukemia, with benefit observed in therapy employing transfer of CD8(+) T cells alone or in the context of also providing supplemental IL-2. Following transfer in vivo, the SHP-1(-/-) effector T cells exhibited enhanced short-term accumulation, followed by greater contraction, and they ultimately formed similar numbers of long-lived, functional memory cells. The increased therapeutic effectiveness of SHP-1(-/-) effector cells was also observed in recipients that expressed the tumor Ag as a self-antigen in the liver, without evidence of inducing autoimmune toxicity. SHP-1(-/-) effector CD8(+) T cells expressed higher levels of eomesodermin, which correlated with enhanced lysis of tumor cells.
22798340	Ovarian Carcinoma	CXCR3	Inhibit immunity	CXCR3+ T regulatory cells selectively accumulate in human ovarian carcinomas to limit type I immunity. Here, we show that CXCR3(+) Treg are highly enriched in human ovarian carcinomas, particularly in solid tumor masses, where they represent the majority of Treg. Tumor-associated CXCR3(+.) Treg coexpress T-bet but do not secrete IFN-γ ex vivo and suppress proliferation and IFN-γ secretion of T effectors.
22772464	Melanoma; Lung Carcinoma	IL9R	Promote immunity	Il9r(-/-) mice showed accelerated tumor growth, and administration of recombinant IL-9 (rIL-9) to tumor-bearing WT and Rag1(-/-) mice inhibited melanoma as well as lung carcinoma growth. Exogenous rIL-9 inhibited tumor growth in Rag1(-/-) mice but not in mast-cell-deficient mice, suggesting that the targets of IL-9 in this setting include mast cells but not T or B cells.
22767669	Breast Carcinoma	TLR7	Promote immunity	Topical TLR7 agonist imiquimod can induce immune-mediated rejection of skin metastases in patients with breast cancer. Toll-like receptor 7 agonist imiquimod is an immune response modifier and can induce immune-mediated rejection of primary skin malignancies when topically applied.
22753933	Breast Carcinoma	STAT3	Inhibit immunity	Therapeutic immunization with Stat3Y705F-breast cancer cells inhibited tumor growth, promoted tumor cell differentiation, and decreased metastasis. Furthermore, inhibition of Stat3 activation in breast cancer cells induced cellular senescence, contributing to their immunogenic phenotype. In this work, we provide preclinical proof of concept that ablating Stat3 signaling in breast cancer cells results in an effective immunotherapy against breast cancer growth and metastasis.
22753924	Melanoma	RARRES2	Promote immunity	In experiments using the B16 transplantable mouse melanoma, tumor-expressed chemerin inhibited in vivo tumor growth without altering in vitro proliferation. Intratumoral injection of chemerin also inhibited tumor growth, suggesting the potential for therapeutic application.
22753274	Colon Carcinoma	GCH1	Inhibit immunity	We found that inhibition or silencing of GCH1 reduced tumor cell proliferation and survival and the tube formation of human umbilical vein endothelial cells, which upon hypoxia increased GCH1 and endothelial NOS expression, the latter prevented by inhibition of GCH1. The treatment with the GCH1 inhibitor shifted the phenotype of tumor associated macrophages from the proangiogenic M2 towards M1, accompanied with a shift of plasma chemokine profiles towards tumor-attacking chemokines including CXCL10 and RANTES. GCH1 expression was increased in mouse AOM/DSS-induced colon tumors and in high grade human colon and skin cancer and oppositely, the growth of GCH1-deficient HT29-Luc tumor cells in mice was strongly reduced. The data suggest that GCH1 inhibition reduces tumor growth by (i) direct killing of tumor cells, (ii) by inhibiting angiogenesis, and (iii) by enhancing the antitumoral immune response.
22750462	Pancreatic Adenocarcinoma	CEACAM5	Promote immunity	Carcinoembryonic antigen (CEA) is highly expressed on the surface of pancreatic adenocarcinoma cells; we investigated the effects of cytolytic T cells that recognize CEA in a mouse model of pancreatic carcinoma. Injection of the anti-CEA CAR T cells reduced the size of pancreatic tumors to below the limit of detection in all mice and produced long-term tumor eradication in 67% of mice. T cells also eradicated CEA(+) fibrosarcoma cells injected 45 days later. Injection of T cells that target CEA can eradicate tumors grown from CEA(+) pancreatic carcinoma cells in the pancreas of CEAtg mice without autoimmune effects.
22745305	Diffuse Large B-Cell Lymphoma	S1PR1	Inhibit immunity	S1PR1 is an effective target to block STAT3 signaling in activated B cell-like diffuse large B-cell lymphoma. Here we demonstrate that persistent activated STAT3 colocalizes with elevated expression of S1PR1, a G-protein-coupled receptor for sphingosine-1-phosphate (S1P), in the tumor cells of the activated B cell-like subtype of diffuse large B-cell lymphoma patient specimens.Inhibition of S1PR1 expression by shRNA in the lymphoma cells validates that blocking S1PR1 affects expression of STAT3 downstream genes critically involved in tumor cell survival, proliferation, tumor invasion, and/or immunosuppression.
22745305	Diffuse Large B-Cell Lymphoma	STAT3	Inhibit immunity	STAT3 plays a crucial role in promoting progression of human cancers, including several types of B-cell lymphoma.
22735380	Melanoma; Lung Carcinoma	TNFRSF9	Immunotherapy target	In this study, we provide evidence for powerful synergistic effects of a combined strategy consisting of intratumoral injection of SFV-IL-12 and systemic delivery of agonist anti-CD137 monoclonal antibodies (mAbs), which was substantiated against poorly immunogenic B16 melanomas (B16-OVA and B16.F10) and TC-1 lung carcinomas. Importantly, we found that SFV-IL-12 intratumoral injection induces bright expression of CD137 on most tumor-infiltrating CD8(+) T lymphocytes, thereby providing more abundant targets for the action of the agonist antibody.
22232735	Lymphoma	TNFRSF9	Inhibit immunity	In a murine model of B-cell lymphoma, only CD137(neg)CD44(hi) CD4 T cells infiltrated tumor sites and provided protection. Conversely, the population of CD137(pos)CD44hi CD4 T cells consisted primarily of activated T(regs). Moreover, in vitro these CD137(pos) cells suppressed the proliferation of effector cells in a contact-dependent manner, and in vivo adding the CD137(pos)CD44(hi) CD4 cells to CD137(neg)CD44(hi) CD4 cells suppressed the antitumor immune response. Thus, CD137 expression on CD4 T cells defined a population of activated T(regs) that greatly limited antitumor immune responses.
22232214	Chronic Myelogenous Leukemia, BCR-ABL1 Positive	CD27	Inhibit immunity	CD27 signaling on chronic myelogenous leukemia stem cells activates Wnt target genes and promotes disease progression. Binding of CD27 by its ligand, CD70, increased expression of Wnt target genes in LSCs by enhancing nuclear localization of active β-catenin and TRAF2- and NCK-interacting kinase (TNIK). Blocking CD27 signaling in LSCs delayed disease progression and prolonged survival. Furthermore, CD27 was expressed on CML stem/progenitor cells in the bone marrow of CML patients, and CD27 signaling promoted growth of BCR/ABL+ human leukemia cells by activating the Wnt pathway.
22226154	Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue	IFNA1	Promote immunity	Local immunotherapy with IFN-α seems to be an effective and lasting treatment method and provides an alternative to radiotherapy for conjunctival MALT lymphomas.
22215017	Sarcoma	TBX21	Promote immunity (infiltration)	We have recently shown that intratumor (i.t.) injection of syngenic dendritic cells (DC) engineered to express the transcription factor Tbet (TBX21) promotes protective type-1 T cell-mediated immunity via a mechanism that is largely interleukin (IL)-12p70-independent. Mice bearing established subcutaneous (s.c.) tumors injected with DC concomitantly expressing ectopic Tbet and IL12 (i.e., DC.Tbet/IL12) displayed superior (i) rates of tumor rejection and extended overall survival, (ii) cross-priming of Tc1 reactive against antigens expressed within the tumor microenvironment, and (iii) infiltration of CD8(+) T cells into treated tumors in association with elevated locoregional production of CXCR3 ligand chemokines.
22205715	Melanoma	BTLA	Inhibit immunity	Here, we report that the upregulation of the inhibitory molecule BTLA also plays a critical role in restricting NY-ESO-1-specific CD8(+) T-cell expansion and function in melanoma. BTLA-expressing PD-1(+)Tim-3(-) CD8(+) T cells represented the largest subset of NY-ESO-1-specific CD8(+) T cells in patients with melanoma. These cells were partially dysfunctional, producing less IFN-γ than BTLA(-) T cells but more IFN-γ, TNF, and interleukin-2 than the highly dysfunctional subset expressing all three receptors.
22203761	Neuroblastoma	CSF2	Promote immunity	Adjuvant therapy using anti-GD2 monoclonal antibody and granulocyte-macrophage colony-stimulating factor (GM-CSF) has shown treatment success for patients with high-risk neuroblastoma (NB). GM-CSF-induced granulocyte activation in vivo is associated with improved patient outcome.
22203730	Gastric Carcinoma	STAT3	Inhibit immunity	Inhibition of STAT3 signaling pathway by nitidine chloride suppressed the angiogenesis and growth of human gastric cancer. Furthermore, nitidine chloride suppressed the constitutively activated STAT3 protein, its DNA-binding activity, and the expression of STAT3-dependent target genes, including cyclin D1, Bcl-xL, and VEGF in human gastric cancer cells.
22186993	Lymphoid Leukemia; Lymphoma	CXCR4	Inhibit immunity	The chemokine receptor CXCR4, which normally regulates stromal stem cell interactions in the bone marrow, is highly expressed on a variety of malignant hematologic cells, including lymphoma and lymphocytic leukemias. In the present study, we developed pepducins, cell-penetrating lipopeptide antagonists of CXCR4, to interdict CXCL12-CXCR4 transmembrane signaling to intracellular G-proteins. We demonstrate that pepducins targeting the first (i1) or third (i3) intracellular loops of CXCR4 completely abrogate CXCL12-mediated cell migration of lymphocytic leukemias and lymphomas.
22186896	Lung Adenocarcinoma	IL17A	Promote immunity	Here we show, in the lungs of patients with lung adenocarcinoma, an increase in interleukin-17A that is inversely correlated with the expression of T-bet and correlated with the T regulatory cell transcription factor Foxp3. Local targeting of interleukin-17A in experimental lung adenocarcinoma results in a reduction in tumour load, local expansion of interferon-γ-producing CD4(+) T cells and a reduction in lung CD4(+)CD25(+)Foxp3(+) regulatory T cells.
22184722	Hepatocellular Carcinoma	CD69	Inhibit immunity	In this study, we showed that, upon encountering autologous CD69(+) T cells, tumor macrophages (MΦs) acquired the ability to produce much greater amounts of IDO protein in cancer nests. The T cells isolated from the hepatocellular carcinoma tissues expressed significantly more CD69 molecules than did those on paired circulating and nontumor-infiltrating T cells; these tumor-derived CD69(+) T cells could induce considerable IDO in monocytes.
22172723	Skin Squamous Cell Carcinoma	IL10	Promote immunity	Defying those expectations we demonstrate that IL-10 induces several essential mechanisms for effective antitumor immune surveillance: infiltration and activation of intratumoral tumor-specific cytotoxic CD8(+) T cells, expression of the Th1 cytokine interferon-γ (IFNγ) and granzymes in CD8(+) T cells, and intratumoral antigen presentation molecules. Consequently, tumor immune surveillance is weakened in mice deficient for IL-10 whereas transgenic overexpression of IL-10 protects mice from carcinogenesis.
22156613	Melanoma	BRAF	Inhibit immunity (infiltration)	Selective BRAF inhibitors induce marked T-cell infiltration into human metastatic melanoma. Tumor infiltration by CD4(+) and CD8(+) lymphocytes increased markedly following BRAF inhibitor treatment (both ρ = 0.015).
22156347	Melanoma	SLAMF6	Promote immunity (T cell function)	Specific blocking of NTB-A on APCs markedly reduced cytokine production by CD8 lymphocytes, pointing to a possible contribution of NTB-A costimulation to T cell functional diversity.
22143889	Melanoma; Colon Carcinoma	CEACAM1	Inhibit immunity	CEACAM1 dampens antitumor immunity by down-regulating NKG2D ligand expression on tumor cells. We show that tumor cell-associated CEACAM1 causes intracellular retention of various NKG2D ligands in mouse and human tumor cells. CEACAM1-silenced tumor cells expressed more cell surface NKG2D ligands and exhibited greater sensitivity to natural killer cell-mediated cytolysis in vitro and rejection in vivo.
22139376	Melanoma	TLR4	Promote immunity	IFNβ produced by TLR4-activated tumor cells is involved in improving the antitumoral immune response. Transcriptional analysis showed that TLR4 activation on B16 cells induced changes in the expression of type I IFN and type I IFN-related genes. Most importantly, culture supernatants from LPS-B16 cells improved the maturation of bone marrow-derived dendritic cells (BMDC) from TLR4-deficient mice, upregulating the expression of interleukin-12 and costimulatory molecules on those cells.
22139080	Colon Adenocarcinoma	ST14	Promote immunity	Suppression of Tumorigenicity-14, encoding matriptase, is a critical suppressor of colitis and colitis-associated colon carcinogenesis. Here, we show that intestinal epithelial-specific ablation of St14 in mice causes formation of colon adenocarcinoma with very early onset and high penetrance.
22139074	Lung Carcinoma	FOXM1	Inhibit immunity	Ablation of Foxm1 in macrophages reduced the number and size of lung tumors in macFoxm1(-/-) mice. The expression levels of the pro-inflammatory genes iNOS, Cox-2, interleukin-1b (IL-1b) and IL-6, as well as the migration-related genes macrophage inflammatory protein-1 (MIP-1α), MIP-2 and MMP-12, were decreased in macrophages isolated from macFoxm1(-/-) mice. The chemokine receptors responsible for monocyte recruitment to the lung, CX(3)CR1 and CXCR4, were decreased in Foxm1-deficient monocytes. In co-transfection experiments, Foxm1 directly bound to and transcriptionally activated the CX(3)CR1 promoter. Expression of Foxm1 in macrophages is required for pulmonary inflammation, recruitment of macrophages into tumor sites and lung tumor growth.
22137796	Diffuse Large B-Cell Lymphoma	CD58	Promote immunity	Combined genetic inactivation of β2-Microglobulin and CD58 reveals frequent escape from immune recognition in diffuse large B cell lymphoma. In 21% of cases, analogous lesions involve the CD58 gene, which encodes a molecule involved in T and natural killer cell-mediated responses.
22117050	Ovarian Carcinoma; Breast Carcinoma	CD27	Promote immunity	CD27 costimulation augments the survival and antitumor activity of redirected human T cells in vivo. After antigen stimulation in vitro, CD27-bearing CAR-T cells also proliferated, up-regulated Bcl-X(L) protein expression, resisted apoptosis, and underwent increased numerical expansion. The greatest impact of CD27 was noted in vivo, where transferred CAR-T cells with CD27 demonstrated heightened persistence after infusion, facilitating improved regression of human cancer in a xenogeneic allograft model.
22108515	Colorectal Carcinoma	IDO1	Inhibit immunity	Carcinomas may create an immunosuppressive state via IDO1 expression. Higher IDO1 expression at the tumour invasion front is involved in CRC progression and correlates with impaired clinical outcome, suggesting that IDO1 is an independent prognostic indicator for CRC.
22102694	Melanoma	ULBP2	Promote immunity	Accordingly, treatment of cancer cells with miRNA inhibitors led to upregulation of ULBP2, whereas miR-34 mimics led to downregulation of ULBP2, diminishing tumor cell recognition by NK cells.
22090361	Osteosarcoma	EGFR	Inhibit immunity (T cell function)	Anti-EGFR antibody cetuximab enhances the cytolytic activity of natural killer cells toward osteosarcoma. In the presence of cetuximab, the cytolytic activity of resting NK cells against all EGFR-expressing sarcoma cells was substantially increased and comparable with that of IL-15-activated NK cells.
22087031	Lung Carcinoma	DCN	Inhibit immunity	First, decorin acted as an endogenous ligand of Toll-like receptors 2 and 4 and stimulated production of proinflammatory molecules, including PDCD4, in macrophages. Second, decorin prevented translational repression of PDCD4 by decreasing the activity of transforming growth factor-β1 and the abundance of oncogenic miR-21, a translational inhibitor of PDCD4. Moreover, increased PDCD4 abundance led to decreased release of the anti-inflammatory cytokine interleukin-10, thereby making the cytokine profile more proinflammatory.
22082959	Breast Carcinoma	RB1CC1	Promote immunity	In our recent study, we show that conditional knockout (KO) of FIP200 in the well-characterized MMTV-PyMT mouse model of human breast cancer significantly suppresses mammary tumorigenesis and progression. In addition to the intrinsic defects in proliferation of FIP200-null tumor cells, we also showed that FIP200 deletion in mammary tumor cells triggers increased host anti-tumor immune surveillance, which also contributes to the decreased mammary tumorigenesis and progression.
22080438	Glioma	CD276	Inhibit immunity	B7H3 expression by tumor and endothelial cells correlates with the grade of malignancy in gliomas and with poor survival. Both soluble 4IgB7H3 in the supernatant of glioma cells and cell-bound 4IgB7H3 are functional and suppress natural killer cell-mediated tumor cell lysis
22075702	Melanoma; Breast Carcinoma	IFNA1	Promote immunity	Th-1 lymphocytes induce dendritic cell tumor killing activity by an IFN-γ-dependent mechanism. IFN-γ was identified as the major factor responsible for Th-1-induced DC tumoricidal activity.
22075702	Melanoma; Breast Carcinoma	NOS2	Promote immunity	Tumor cell killing mediated by Th-1-activated killer DCs was dependent on inducible NO synthase expression and NO production.
22065720	Melanoma	TICAM2	Inhibit immunity (T cell function)	In tumors arising in the autochthonous TiRP transgenic model of melanoma associated with systemic chronic inflammation, endogenous CD8(+) TCs were nonfunctional.
22058147	Head and Neck Squamous Cell Carcinoma	TLR3	Promote immunity	Enhanced apoptosis in metastatic cells was dependent on double-stranded RNA and TLR3 and also the TLR3 effector signaling protein TRIF.
22049519	Plasma Cell Myeloma	DKK1	Promote immunity; Immunotherapy target	We used DKK1-DNA vaccine in the murine MOPC-21 myeloma model, and the results clearly showed that active vaccination using the DKK1 vaccine not only was able to protect mice from developing myeloma, but it was also therapeutic against established myeloma. Mechanistic studies revealed that DKK1 vaccine elicited a strong DKK1- and tumor-specific CD4+ and CD8+ immune responses, and treatment with B7H1 or OX40 Abs significantly reduced the numbers of IL-10-expressing and Foxp3+ regulatory T cells in vaccinated mice.
22037871	Breast Carcinoma; Lung Carcinoma	EGFL7	Inhibit immunity (infiltration)	Egfl7 promotes tumor escape from immunity by repressing endothelial cell activation. Here we show that expression of Egfl7 in breast and lung carcinoma cells accelerates tumor growth and metastasis in immunocompetent mice but not in immunodeficient mice. Tumors expressing Egfl7 were infiltrated relatively poorly by immune cells and were characterized by reduced levels of immunostimulatory cytokines [IFN-γ, interleukin-12 (IL-12)] and fewer endothelial adhesion molecules [intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1)]. In vitro studies revealed that Egfl7 inhibited the expression of leukocyte adhesion molecules by endothelial cells, preventing lymphocyte adhesion.
22037217	Head and Neck Squamous Cell Carcinoma	PTEN	Promote immunity	Loss of TGF-β signaling and PTEN promotes head and neck squamous cell carcinoma through cellular senescence evasion and cancer-related inflammation. Conditional activation of the PI3K/Akt pathway due to Pten deletion in the mouse head and neck epithelia gives rise to hyperproliferation, but only a few lesions progress to HNSCC. Molecular analysis revealed enhanced cell proliferation, decreased apoptosis, and increased expression of CCND1 in the basal layer of the head and neck epithelia, as well as in the tumors of Tgfbr1/Pten double conditional knockout (2cKO) mice.
22037217	Head and Neck Squamous Cell Carcinoma	TGFBR1	Inhibit immunity	Loss of TGF-β signaling and PTEN promotes head and neck squamous cell carcinoma through cellular senescence evasion and cancer-related inflammation. However, Pten-deficient mice developed full-penetrance HNSCC in combination with type I TGF-β receptor (Tgfbr1) deletion. Molecular analysis revealed enhanced cell proliferation, decreased apoptosis, and increased expression of CCND1 in the basal layer of the head and neck epithelia, as well as in the tumors of Tgfbr1/Pten double conditional knockout (2cKO) mice.
22037214	Colon Carcinoma	APLN	Promote immunity (infiltration); Essential for immunotherapy	The apelin/APJ system induces maturation of the tumor vasculature and improves the efficiency of immune therapy. This apelin-induced tumor vascular maturation enhances the efficacy of cancer dendritic cell-based immunotherapy and significantly suppresses tumor growth by promoting the infiltration of invariant natural killer T cells into the central region of the tumor and thereby robustly inducing apoptosis of tumor cells.
22033321	Melanoma	IDO1	Inhibit immunity	The expression of IDO and forkhead box P3 (Foxp3) in the sentinel lymph nodes was determined by immunohistochemistry and correlated with progression-free survival and overall survival. High IDO expression was correlated with a significant higher frequency of Foxp3-positive cells in uninvaded lymph nodes (p = 0.016). The presence of IDO expression in the sentinel nodes was not associated with an increased frequency of circulating regulatory T cells (Tregs) but was significantly correlated with an increased mean fluorescence intensity of Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) in Tregs (p = 0.019).
22030616	Colon Carcinoma	CD28	Promote immunity	Costimulation by chimeric antigen receptors revisited the T cell antitumor response benefits from combined CD28-OX40 signalling. CD28 reinforced T cell proliferation and is mandatory to induce IL-2. In the absence of added IL-2, CD28 and OX40 (CD137) but not 4-1BB (CD134) enhanced specific cytolysis. CD28 was superior to initiate the T cell response, OX40 and 4-1BB sustained the response in long term with OX40 being most effective.
22030616	Colon Carcinoma	TNFRSF4	Promote immunity	Costimulation by chimeric antigen receptors revisited the T cell antitumor response benefits from combined CD28-OX40 signalling. While CD28, 4-1BB and OX40 similarly improved pro-inflammatory cytokine secretion, OX40 most efficiently prevented activation induced cell death of CD62L(-) effector memory T cells. CD28 was superior to initiate the T cell response, OX40 and 4-1BB sustained the response in long term with OX40 being most effective.
22028176	Melanoma	CTLA4	Inhibit immunity	Enhancement of anti-tumor immunity through local modulation of CTLA-4 and GITR by dendritic cells. Using in vitro assays with human DCs, we demonstrated that DCs transfected with mRNA encoding a humanized anti-CTLA-4 mAb and mRNA encoding a soluble human GITR-L fusion protein enhance the induction of anti-tumor CTLs in response to DCs transfected with mRNAs encoding either melanoma or breast cancer antigens.
22028176	Melanoma	TNFRSF18	Promote immunity	Enhancement of anti-tumor immunity through local modulation of CTLA-4 and GITR by dendritic cells. Using in vitro assays with human DCs, we demonstrated that DCs transfected with mRNA encoding a humanized anti-CTLA-4 mAb and mRNA encoding a soluble human GITR-L fusion protein enhance the induction of anti-tumor CTLs in response to DCs transfected with mRNAs encoding either melanoma or breast cancer antigens.
22027835	Colon Carcinoma	GMDS	Promote immunity	GDP-mannose-4,6-dehydratase (GMDS) deficiency renders colon cancer cells resistant to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor- and CD95-mediated apoptosis by inhibiting complex II formation. DR4, but not DR5, was found to be fucosylated; however, GMDS deficiency inhibited both DR4- and DR5-mediated apoptosis despite the absence of fucosylation on DR5. In addition, GMDS deficiency also inhibited CD95-mediated apoptosis but not the intrinsic apoptosis pathway induced by anti-cancer drugs. Binding of TRAIL and CD95 ligand to their cognate receptors primarily leads to formation of a complex comprising the receptor, FADD, and caspase-8, referred to as the death-inducing signaling complex (DISC). GMDS deficiency did not affect formation of the primary DISC or recruitment to and activation of caspase-8 on the DISC. However, formation of secondary FADD-dependent complex II, comprising caspase-8 and cFLIP, was significantly inhibited by GMDS deficiency.
22027835	Colon Carcinoma	TNFSF10	Promote immunity	Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis through binding to TRAIL receptors, death receptor 4 (DR4), and DR5. Binding of TRAIL and CD95 ligand to their cognate receptors primarily leads to formation of a complex comprising the receptor, FADD, and caspase-8, referred to as the death-inducing signaling complex (DISC).
22027835	Colon Carcinoma	FAS	Promote immunity	Binding of TRAIL and CD95 ligand to their cognate receptors primarily leads to formation of a complex comprising the receptor, FADD, and caspase-8, referred to as the death-inducing signaling complex (DISC).
22025529	Leukemia	AURKA	Immunotherapy target	Aurora kinase A (AURKA) is overexpressed in leukemias. Previously, we demonstrated that AURKA-specific CD8(+) T cells specifically and selectively lysed leukemia cells, indicating that AURKA is an excellent target for immunotherapy. Furthermore, TCR-redirected CD8(+) T cells lysed AURKA-overexpressing human leukemic cells in an HLA-A*0201-restricted manner, but did not kill HLA-A*0201(+) normal cells, including hematopoietic progenitors.
22021614	Pancreatic Ductal Adenocarcinoma; Prostate Carcinoma; Breast Adenocarcinoma; Glioblastoma; Melanoma; Cervical Adenocarcinoma	PCNA	Inhibit immunity	Proliferating cell nuclear antigen is a novel inhibitory ligand for the natural cytotoxicity receptor NKp44. Proliferating cell nuclear Ag (PCNA) is overexpressed in cancer cells. Their interaction inhibits NK cell function through NKp44/ITIM. The physical interaction of NKp44 and PCNA is enabled by recruitment of target cell PCNA to the NK immunological synapse. We demonstrate that PCNA promotes cancer survival by immune evasion through inhibition of NKp44-mediated NK cell attack.
22020795	Neuroblastoma	LGALS1	Inhibit immunity	Neuroblastoma triggers an immunoevasive program involving galectin-1-dependent modulation of T cell and dendritic cell compartments. Human and mouse NB cells express and secrete Gal-1, which negatively regulates T cell and dendritic cell function. Immunohistochemical analysis revealed a six- to tenfold increase in the frequency of CD4+ and CD8+ T cells infiltrating tumors from mice receiving knockdown transfectants. Finally, supernatants of NXS2/H or NXS2 cells suppressed dendritic cell (DC) maturation and induce T cell apoptosis, whereas these effects were only marginal on DCs and T cells exposed to supernatants from NXS2/L cells.
22020332	Skin Papilloma	CD200	Inhibit immunity	Here, we show that mice lacking CD200, the exclusive ligand for CD200R, are resistant to chemical skin carcinogenesis.
22020332	Skin Papilloma	IL6	Promote immunity	Decreased tumor outgrowth is accompanied by increased expression of the proinflammatory cytokines interleukin (IL)-1β and IL-6 by the lymph node (LN) dendritic cells.
22020332	Skin Papilloma	CD200R1	Inhibit immunity	Importantly, CD200R controls tumor outgrowth independently of CD200 expression by the tumor cells themselves. We demonstrate for the first time that the absence of CD200R signaling inhibits outgrowth of an endogenous tumor irrespective of CD200 expression by the tumor cells.
22019587	Non-Hodgkin Lymphoma	IL10	Inhibit immunity; Resistant to immunotherapy	Regulatory B cell production of IL-10 inhibits lymphoma depletion during CD20 immunotherapy in mice. Even small numbers of adoptively transferred B10 cells dramatically suppressed CD20 mAb-mediated lymphoma depletion by inhibiting mAb-mediated monocyte activation and effector function through IL-10-dependent mechanisms.
21773885	Glioma	MIF	Inhibit immunity	Quantitative RT-PCR showed that MIF mRNA expression was elevated up to 800-fold in malignant glioma cells compared with normal brain. Stable knockdown of MIF by shRNA in glioma cells significantly increased tumour cell susceptibility towards NK cell-mediated cytotoxicity. We thus propose that human glioma cell-derived MIF contributes to the immune escape of malignant gliomas by counteracting NK and cytotoxic T-cell-mediated tumour immune surveillance.
21771875	Melanoma	PRAME	Essential for immunotherapy	PRAME-specific Allo-HLA-restricted T cells with potent antitumor reactivity useful for therapeutic T-cell receptor gene transfer. These T cells, however, also exerted low reactivity against mature dendritic cells (DC) and kidney epithelial cells, which was shown to be because of low PRAME expression.
21756848	Hepatocellular Carcinoma	ULBP1	Promote immunity	Remarkably, recurrence-free survival of patients with ULBP1-negative HCC was significantly shorter than that of patients with ULBP1-positive HCC (p=0.006). ULBP1 is prevalently expressed in DN to mod-HCC, but loss of its expression correlates with tumor progression and early recurrence.
21742973	T Lymphoblastic Lymphoma	IDO1	Inhibit immunity	Tryptophan depletion by IDO-expressing tumors is a common mechanism of immune evasion inducing regulatory T cells and inhibiting effector T cells. These findings highlight the ability of IDO-expressing tumor cells to thrive in a tryptophan-depleted microenvironment by expressing a novel, highly tryptophan-specific transporter, which is resistant to inhibition by most other amino acids.
21742774	Ovarian Carcinoma	CXCL12	Inhibit immunity	CXCL12/CXCR4 blockade induces multimodal antitumor effects that prolong survival in an immunocompetent mouse model of ovarian cancer. siRNA-mediated knockdown of CXCL12 in BR5-1 cells that constitutively express CXCL12 and CXCR4 reduced cell proliferation in vitro, and tumor growth in vivo.
21742774	Ovarian Carcinoma	CXCR4	Inhibit immunity	CXCL12/CXCR4 blockade induces multimodal antitumor effects that prolong survival in an immunocompetent mouse model of ovarian cancer. Similarly, treatment of BR5-1-derived tumors with AMD3100, a selective CXCR4 antagonist, resulted in increased tumor apoptosis and necrosis, reduction in intraperitoneal dissemination, and selective reduction of intratumoral FoxP3(+) regulatory T cells (Treg). Compared with controls, CXCR4 blockade greatly increased T-cell-mediated antitumor immune responses, conferring a significant survival advantage to AMD3100-treated mice.
21728171	Ovarian Carcinoma	IFIH1	Promote immunity	Monocytes and monocyte-derived DCs (MoDCs) engulfed MDA-5-activated cancer cells, and subsequently upregulated HLA-class I/II and costimulatory molecules, and secreted CXCL10 and IFN-α. Further, this proinflammatory milieu promoted cytolytic activity and IFN-γ secretion of NK cells. Thus, our data suggest that the engagement of MDA-5 in a whole tumor cell vaccine is a promising approach for the immunotherapy of ovarian cancer.
21724589	Melanoma	IL18	Inhibit immunity	In this study, we show that low levels of circulating IL-18, either exogenous or tumor derived, act to suppress the NK cell arm of tumor immunosurveillance. IL-18 produced by tumor cells promotes the development of NK-controlled metastases in a PD-1-dependent manner. RNAi-mediated knockdown of IL-18 in tumors, or its systemic depletion by IL-18-binding protein, are sufficient to stimulate NK cell-dependent immunosurveillance in various tumor models.
21715687	Plasma Cell Myeloma	CD28	Inhibit immunity	CD28 expressed on malignant plasma cells induces a prosurvival and immunosuppressive microenvironment. Engagement by CD28 to its ligand CD80/CD86 on stromal dendritic cell directly transduces a prosurvival signal to myeloma cell, protecting it against chemotherapy and growth factor withdrawal-induced death. Simultaneously, CD28-mediated ligation of CD80/CD86 induces the stromal dendritic cell to produce the prosurvival cytokine IL-6 (involving novel cross-talk with the Notch pathway) and the immunosuppressive enzyme IDO.
21715565	Fibrosarcoma	CCR5	Promote immunity	CCR5 activation in CD4(+) cells resulted in CD40L upregulation, leading to full maturation of antigen-presenting cells and enhanced CD8(+) T-cell crosspriming and tumor infiltration. CCR5 reduced chemical-induced fibrosarcoma incidence and growth, but did not affect the onset or progression of spontaneous breast cancers in tolerogenic Tg(MMTV-neu) mice. Our results indicate that CCR5 boosts T-cell responses to tumors by modulating helper-dependent CD8(+) T-cell activation.
21712812	Bladder Carcinoma	GCNT1	Inhibit immunity (NK cell function)	Here, we report that upregulation of C2GnT is closely correlated with progression of bladder tumours and that C2GnT-expressing bladder tumours use a novel strategy to increase their metastatic potential. Our results showed that C2GnT-expressing bladder tumour cells are highly metastatic due to their high ability to evade NK cell immunity and revealed the molecular mechanism of the immune evasion by C2GnT expression.
21712812	Bladder Carcinoma	LGALS3	Inhibit immunity	Engagement of an NK-activating receptor, NKG2D, by its tumour-associated ligand, Major histocompatibility complex class I-related chain A (MICA), is critical to tumour rejection by NK cells. In C2GnT-expressing bladder tumour cells, poly-N-acetyllactosamine was present on core2 O-glycans on MICA, and galectin-3 bound the NKG2D-binding site of MICA through this poly-N-acetyllactosamine. Galectin-3 reduced the affinity of MICA for NKG2D, thereby severely impairing NK cell activation and silencing the NK cells.
21712448	Melanoma; Breast Carcinoma; Floor of Mouth Squamous Cell Carcinoma	IL7	Promote immunity	Interleukin-7 inhibits tumor-induced CD27-CD28- suppressor T cells: implications for cancer immunotherapy. We found that IL-7 inhibits CD27/CD28 loss and maintains proliferative capacity, IL-2 production, and reduced suppressive function. The protective ability of IL-7 depended on activation of the PI3K/AKT pathway, which inhibited activation of glycogen synthase kinase 3β, which, in turn, prevented the phosphorylation and loss of Mcl-1.
21712448	Melanoma; Breast Carcinoma; Floor of Mouth Squamous Cell Carcinoma	MCL1	Inhibit immunity	We further showed a key role for Mcl-1 in that its knockdown or inhibition abrogated the effects of IL-7. In addition, knockdown of the Mcl-1 binding partner and proapoptotic protein Bim protected T cells from these dysfunctional alterations.
21712396	Melanoma	IFNG	Promote immunity	IFN-γ production by lung NK cells is critical for the natural resistance to pulmonary metastasis of B16 melanoma in mice. Lung metastases of IFN-γRDN B16 was also increased in NK cell-depleted or IFN-γ(-/-) mice, suggesting that the IFN-γ response of host cells was required in the NK cell and IFN-γ-mediated antimetastatic effect. Our results demonstrate that IFN-γ production from lung resident NK cells is a key response in the natural resistance to the experimental lung metastasis of NK cell-resistant tumor cells.
21697282	Lung Adenocarcinoma	CD5L	Inhibit immunity	Api6/AI M/Spα/CD5L overexpression in alveolar type II epithelial cells induces spontaneous lung adenocarcinoma. Here, we report that Api6 promotes malignant transformation by limiting lung epithelial cell apoptosis and promoting immune escape. Api6 overexpression inhibited apoptosis and activated oncogenic signaling in AT II lung epithelial cells, inducing emphysema and adenocarcinoma. In addition, Api6 overexpression in AT II cells increased the concentrations of proinflammatory cytokines/chemokines in bronchoalveolar lavage fluid and serum, promoting expansion of myeloid-derived suppressor cells (MDSC) in lung and blood but not in bone marrow or spleen.
21674477	Hepatocellular Carcinoma	IL17A	Inhibit immunity (T cell function)	Interleukin-17-educated monocytes suppress cytotoxic T-cell function through B7-H1 in hepatocellular carcinoma patients. Accordingly, IL-17 could activate monocytes to express B7-H1 in a dose-dependent manner.Moreover, these IL-17-exposed monocytes effectively suppressed cytotoxic T-cell immunity in vitro; the effect could be reversed by blocking B7-H1 on those monocytes.
21670304	Papilloma	TNF	Promote immunity	Resistance to papilloma development in Tnf(-/-) mice was associated with increased IFN-γ and CD8(+) T cells in skin and a significant reduction in IL-10-producing B regulatory cells alongside an increase in IFN-γ-producing CD8(+) T cells in the spleen.
21670203	Melanoma	FOXP3	Inhibit immunity	Foxp3-positive macrophages display immunosuppressive properties and promote tumor growth. Analysis of CD11b(+)F4/80(+)Foxp3(+) macrophage function indicated that these cells inhibited the proliferation of T cells, whereas Foxp3(-) macrophages did not. Foxp3(-) macrophages acquired Foxp3 expression after activation, which conferred inhibitory properties that were indistinguishable from natural Foxp3(+) macrophages. Functional in vivo analyses indicated that CD11b(+)F4/80(+)Foxp3(+) macrophages are important in tumor promotion and the induction of T reg cell conversion.
21665146	Breast Neoplasm	PIK3R5	Inhibit immunity	Once activated, p110γ promotes inside-out activation of a single integrin, α4β1, causing myeloid cell invasion into tumors. Pharmacological or genetic blockade of p110γ suppressed inflammation, growth, and metastasis of implanted and spontaneous tumors, revealing an important therapeutic target in oncology.
21659460	Leukemia	CD274	Inhibit immunity	PD-L1 was highly upregulated on immature human leukemic progenitor cells, whereas costimulatory molecules such as CD80 and CD86 were not expressed. Blocking PD-1 signaling using human antibodies led to elevated proliferation and IFN-γ production of MiHA-specific T cells cocultured with PD-L1-expressing leukemia cells. Taken together, our findings indicate that the PD-1/PD-L pathway can be hijacked as an immune escape mechanism in hematological malignancies.
21653835	Breast Carcinoma	FCAR	Promote immunity	The FcαRI represents the most potent FcR on neutrophils for induction of Ab-mediated tumor cell killing. Human mammary carcinoma cells were efficiently killed when incubated with human neutrophils and tumor-specific FcαRI bispecific or IgA Abs.
21652674	Chronic Lymphocytic Leukemia	SIGIRR	Promote immunity	Lack of TIR8/SIGIRR triggers progression of chronic lymphocytic leukemia in mouse models. We here report that in the absence of TIR8 the appearance of monoclonal B-cell expansions is accelerated and mouse life span is shortened.
21647874	Hepatocellular Carcinoma; Pancreatic Carcinoma	ITGB2	Promote immunity (infiltration)	The knockout of LFA-1 (also known as α(L) β(2) integrin) strongly suppressed recruitment of CD8(+) T cells whereas no significant differences of leukocyte adhesion and infiltration were found in ICAM-1(-/-) and Mac-1(-/-) mice. In contrast to acute inflammatory reaction, only LFA-1 controls recruitment of CD8(+) T-cells in both pancreatic and hepatocellular cancer, whereas ICAM-1 and Mac-1 are dispensable.
21646473	Breast Carcinoma	IPP	Promote immunity; Essential for immunotherapy	IPP/ApppI accumulation in ZOL-treated cancer cells may be recognized by Vγ9Vδ2 T cells as tumor phosphoantigens in vitro. Coculture with purified human Vγ9Vδ2 T cells led to IPP/ApppI-dependent near-complete killing of ZOL-treated breast cancer cells. In ZOL-treated mice bearing subcutaneous breast cancer xenografts, Vγ9Vδ2 T cells infiltrated and inhibited growth of tumors that produced high IPP/ApppI levels, but not those expressing low IPP/ApppI levels.
21642542	Breast Carcinoma; Lung Carcinoma	HMGB1	Inhibit immunity	Knockdown of HMGB1 in tumor cells attenuates their ability to induce regulatory T cells and uncovers naturally acquired CD8 T cell-dependent antitumor immunity. Short hairpin RNA-mediated knockdown of HMGB1 (HMGB1 KD) in tumor cells did not affect tumor cell growth but uncovered naturally acquired long-lasting tumor-specific IFN-γ- or TNF-α-producing CD8 T cell responses and attenuated their ability to induce Treg, leading to naturally acquired CD8 T cell- or IFN-γ-dependent tumor rejection. The data suggest that tumor cell-derived HMGB1 may suppress naturally acquired CD8 T cell-dependent antitumor immunity via enhancing Treg to produce IL-10, which is necessary for Treg-mediated immune suppression.
21633088	Lymphoid Leukemia	NCR3	Promote immunity	Differentiation of human peripheral blood Vδ1+ T cells expressing the natural cytotoxicity receptor NKp30 for recognition of lymphoid leukemia cells. Specific gain-of-function and loss-of-function experiments demonstrated that NKp30 makes the most important contribution to TCR-independent leukemia cell recognition.
21632716	Colon Adenocarcinoma	STAT3	Inhibit immunity	Intratumoral administration of STAT3-depleted DCs significantly inhibited MC38 tumor growth of both injected and nontreated remote tumors. STAT3-depleted human DCs with adenoviral STAT3 short hairpin RNA were also capable of producing more cytokines with TLR stimulation and more resistant to cancer-derived factors, and they induced tumor Ag-specific T cells more efficiently than control DCs.
21632715	Lung Carcinoma	IFNG	Promote immunity	Dichotomous effects of IFN-γ on dendritic cell function determine the extent of IL-12-driven antitumor T cell immunity. Importantly, the initial recruitment and activation of iDC as well as the subsequent switch to tolerogenic activity were both driven by IFN-γ, revealing the dichotomous role of this cytokine in regulating IL-12-mediated antitumor T cell immunity.
21631324	Melanoma	IL2	Promote immunity	In a previous phase 2 study, patients with metastatic melanoma receiving high-dose interleukin-2 plus the gp100:209-217(210M) peptide vaccine had a higher rate of response than the rate that is expected among patients who are treated with interleukin-2 alone. In patients with advanced melanoma, the response rate was higher and progression-free survival longer with vaccine and interleukin-2 than with interleukin-2 alone.
21631324	Melanoma	PMEL	Promote immunity	In a previous phase 2 study, patients with metastatic melanoma receiving high-dose interleukin-2 plus the gp100:209-217(210M) peptide vaccine had a higher rate of response than the rate that is expected among patients who are treated with interleukin-2 alone. In patients with advanced melanoma, the response rate was higher and progression-free survival longer with vaccine and interleukin-2 than with interleukin-2 alone.
21622855	Melanoma	CD5	Inhibit immunity	Compared with wild-type mice, CD5 knockout animals displayed delayed tumor growth, associated with tumor infiltration by T cell populations exhibiting a more activated phenotype and enhanced antitumor effector functions.
21622855	Melanoma	FAS	Promote immunity	Remarkably, in vivo protection of T cells from TCR-mediated apoptosis by an adenovirus engineered to produce soluble Fas resulted in a dramatic reduction in tumor growth.
21616522	Vulvar Squamous Cell Carcinoma	IDO1	Inhibit immunity	Expression of indoleamine 2,3-dioxygenase predicts shorter survival in patients with vulvar squamous cell carcinoma (vSCC) not influencing on the recruitment of FOXP3-expressing regulatory T cells in cancer nests. High IDO expression was associated with significantly worse overall survival among vSCC patients and was found to be an independent prognostic factor similarly to the tumor grade and patient's age.
21608083	Breast Carcinoma	SLC5A5	Promote immunity	Tumor bearing animals received an intravenous or intratumoral injection of NIS expressing MSCs (MSC-NIS), followed by (99m) Technetium pertechnetate imaging 3-14 days later using a BazookaSPECT γ-camera. Based on imaging/biodistribution data, animals received a therapeutic dose of (131) I 14 days after MSC-NIS injection. This resulted in a significant reduction in tumor growth (mean ± SEM, 236 ± 62 mm(3) vs. 665 ± 204 mm(3) in controls).
21607945	Lymphoma	KLRK1	Promote immunity	To address these issues, we made use of a transgenic mouse model (H2-K(b)-MICA mice) where the human NKG2D ligand MICA is ubiquitously and constitutively expressed resulting in a severe dysfunction of NKG2D. Both, ovalbumin (OVA)-specific (H2-K(b)/OVA(257-264)) memory CD8 T cells arisen from the endogenous T cell pool and adoptively transferred OVA-specific OT-I memory cells were unable to control growth of an OVA-expressing lymphoma in H2-K(b)-MICA mice.
21597388	Non-Small Cell Lung Carcinoma	CD276	Inhibit immunity	Non-small cell lung cancer induces an immunosuppressive phenotype of dendritic cells in tumor microenvironment by upregulating B7-H3. B7-H3 was significantly upregulated in tumor-residing DC, whereas the expression of other B7 molecules, such as B7-DC, B7-1, B7-2, B7-H1, remained unchanged. Significantly reduced levels of T cell proliferation in mixed lymphocyte reactions with tumor-derived DC were recorded. Moreover, elevated concentrations of IL-10 were measured in tumor-derived DC, whereas IL-12 levels were reduced.
21587210	Adenocarcinoma	CD160	Inhibit immunity; Resistant to immunotherapy	These results indicate that active immunization concomitantly with blockade of the immunoinhibitory HVEM-BTLA/CD160 pathways through HSV-1 gD may result in sustained tumor regression.
21555531	Lung Adenocarcinoma; Breast Carcinoma; Cutaneous Melanoma; Uveal Melanoma	CD80	Promote immunity	Using seven cell lines representing four histologically distinct solid tumors (lung adenocarcinoma, mammary carcinoma, cutaneous melanoma, and uveal melanoma), we demonstrate that transfection of human tumor cells with the gene encoding the costimulatory molecule CD80 prevents PDL1-mediated immune suppression by tumor cells and restores T cell activation. Mechanistically, CD80 mediates its effects through its extracellular domain, which blocks the cell surface expression of PDL1 but does not prevent intracellular expression of PDL1 protein.
21551365	Ovarian Carcinoma	PDCD1	Inhibit immunity	In this study, we found that ovarian cancer-infiltrating DCs progressively expressed increased levels of PD-1 over time in addition to B7-H1. These dual-positive PD-1(+) B7-H1(+) DCs have a classical DC phenotype (i.e., CD11c(+)CD11b(+)CD8(-)), but are immature, suppressive, and respond poorly to danger signals. Accumulation of PD-1(+)B7-H1(+) DCs in the tumor was associated with suppression of T cell activity and decreased infiltrating T cells in advancing tumors. T cell suppressor function of these DCs appeared to be mediated by T cell-associated PD-1.
21546571	Ovarian Carcinoma	TNFRSF9	Promote immunity; Essential for immunotherapy	In vivo persistence, tumor localization, and antitumor activity of CAR-engineered T cells is enhanced by costimulatory signaling through CD137 (4-1BB). Our results show that anti-FRα CAR outfitted with CD137 costimulatory signaling in tandem overcome issues of T-cell persistence and tumor localization that limit the conventional FRα T-cell targeting strategy to provide potent antitumor activity in vivo.
20696919	Melanoma	MAGEC1	Promote immunity	CT7-specific CD4(+) T-cell responses were detected in three patients (11.5%). These CT7-specific CD4(+) T-cell responses were detectable in melanoma patients' PBMCs exclusively from preexisting CD45RA(-) memory CD4(+) T-cell pool. Additional CT7-specific memory CD4(+) T-cell responses were detected in CT7(+) melanoma patients after depletion of CD4(+)CD25high Treg cells showing that Treg cells impact on CT7-specific CD4(+) T cells in melanoma patients. This study shows that CT7 can induce specific cellular immunity in melanoma patients.
20682796	Head and Neck Squamous Cell Carcinoma	STAT3	Inhibit immunity; Candidate for immunotherapy target	STAT3 inhibition in multiple primary and established human squamous carcinoma lines resulted in enhanced expression and secretion of both proinflammatory cytokines and chemokines. Moreover, supernatants from STAT3-silenced tumor cells were able to stimulate the migratory behavior of lymphocytes from human peripheral blood in vitro. These results show the importance of STAT3 activation in regulating the immunomodulatory mediators by human tumors and further validate STAT3 as a promising target for therapeutic intervention.
20682706	Colorectal Carcinoma	FOXP3	Inhibit immunity	The density of Foxp3(+) Tregs in TDLNs was dramatically higher than that in peripheral blood lymphocytes, but significantly lower than that in tumor-infiltrating lymphocytes. Importantly, the frequency of Foxp3(+) Tregs in TDLNs, rather than that in tumors and peripheral blood, was positively correlated with disease stage. Foxp3(+) Tregs in TDLNs are more correlated with disease progression and potentially influence CD8(+) T-cell functions.
20675592	Hepatocellular Carcinoma	TLR4	Inhibit immunity	Tumor cell-released TLR4 ligands stimulate Gr-1+CD11b+F4/80+ cells to induce apoptosis of activated T cells. Blockade of TLR4 signaling could further reduce the apoptosis-inducing capacity of Gr-1(+)CD11b(+)F4/80(+) cells and enhance the suppressive effect of 4-1BBL/soluble form of programmed death-1 on tumor growth.
20675592	Hepatocellular Carcinoma	IL10	Inhibit immunity	The apoptosis-inducing capacity was determined by higher expression levels of arginase I and IL-10 relative to those of NO synthase 2 and IL-12 in Gr-1(+)CD11b(+)F4/80(+) cells, which were induced by NTC-Ms through TLR4 signaling. The apoptosis-inducing capacity of NTC-Ms-stimulated Gr-1(+)CD11b(+)F4/80(+) cells could be enhanced by IL-10.
20670949	Ovarian Carcinoma	EMP2	Inhibit immunity	EMP2 was found to be highly expressed in >70% of serous and endometrioid ovarian tumors compared with nonmalignant ovarian epithelium using a human ovarian cancer tissue microarray. Treatment of human ovarian cancer cell lines with anti-EMP2 diabodies induced cell death and retarded cell growth, and these response rates correlated with cellular EMP2 expression.
20668228	Follicular Lymphoma	CD19	Promote immunity	Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. The patient's lymphoma underwent a dramatic regression, and B-cell precursors were selectively eliminated from the patient's bone marrow after infusion of anti-CD19-CAR-transduced T cells.
20667896	Glioblastoma	STAT3	Inhibit immunity	The role of the signal transducer and activator of transcription 3 (STAT3) in mediating innate immune suppression was evaluated in the context of the functional assays. The inhibition of phagocytosis and the secretion of IL-10 were reversed when the STAT3 pathway was blocked in the gCSCs. The gCSCs modulate innate immunity in glioblastoma by inducing immunosuppressive MΦs/microglia, and this capacity can be reversed by inhibiting phosphorylated STAT3.
20663902	Hepatocellular Carcinoma	CCR1	Promote immunity	Deficiency of CCR1 impairs accumulation of CD11c(+), CD4(+), and CD8(+) cells in RFA-treated tumors. Furthermore, in IFN-gamma-enzyme-linked immunospot assay, ECI301 augmented tumor-specific responses after RFA whereas deficiency of CCR1 abolished this augmentation.
20662098	Plasmacytoma; Mastocytoma	CD200	Promote immunity; Essential for immunotherapy	Tumor expression of CD200 inhibits IL-10 production by tumor-associated myeloid cells and prevents tumor immune evasion of CTL therapy. We found that established CD200-positive tumors were often completely rejected by adoptively transferred CTL without tumor recurrence; in contrast, CD200-negative tumors were initially rejected by adoptively transferred CTL but the majority of tumors recurred. Tumor expression of CD200 significantly inhibited suppressive activity and IL-10 production by tumor-associated myeloid cells (TAMC), and as a result, more CTL accumulated in the tumor and exhibited a greater capacity to produce IFN-gamma in CD200-positive tumors than in CD200-negative tumors.
20662098	Plasmacytoma; Mastocytoma	IL10	Inhibit immunity; Resistant to immunotherapy	Neutralization of IL-10 significantly inhibited the suppressor activity of TAMC, and IL-10-deficiency allowed TAMC to kill cancer cells and their antigenic variants, which prevented tumor recurrence during CTL therapy.
20651071	Lung Carcinoma	AREG	Inhibit immunity	ATP confers tumorigenic properties to dendritic cells by inducing amphiregulin secretion. Human monocyte-derived DCs and mouse bone marrow-derived DCs released amphiregulin (AREG) after purinergic receptor activation, with a contribution of P2Y(11) and A(2B) receptor, respectively. Supernatants of LPS+ATPγS-stimulated DCs induced smooth muscle cell and Lewis Lung Carcinoma (LLC) cell growth in vitro.
20651070	Plasma Cell Myeloma	SOCS1	Inhibit immunity	SOCS1 negatively regulates IL-6 signaling and is silenced by hypermethylation in MM cells. To define the mechanism of inhibitory-cytokine signaling in effector cells and MM cells, we next analyzed the interaction of immune cells with MM cells that were epigenetically modified to re-express SOCS1; IMiDs induced more potent CTL responses against SOCS1 re-expressing-MM cells than unmodified MM cells.
20635390	Mesothelioma; Ovarian Carcinoma; Lung Adenocarcinoma; Pancreatic Carcinoma	MSLN	Inhibit immunity	Mesothelin is a glycosylphosphatidylinositol-anchored glycoprotein that is highly expressed on the cell surface of mesothelioma, ovarian cancer and other malignant tumors. The interaction between mesothelin and CA125 (also called MUC16) may facilitate the implantation and metastasis of tumors in the peritoneal cavity.
20631379	Lymphoma	CD19	Promote immunity	Adoptive transfer of syngeneic T cells transduced with a chimeric antigen receptor that recognizes murine CD19 can eradicate lymphoma and normal B cells. Anti-CD19-CAR-transduced T cells eradicated intraperitoneally injected lymphoma cells and large subcutaneous lymphoma masses.
20631300	Acute Myeloid Leukemia	WT1	Promote immunity	Two patients in partial remission after chemotherapy were brought into complete remission after intradermal administration of full-length WT1 mRNA-electroporated dendritic cells. Clinical responses were correlated with vaccine-associated increases in WT1-specific CD8+ T cell frequencies, as detected by peptide/HLA-A*0201 tetramer staining, and elevated levels of activated natural killer cells postvaccination.
20631075	Melanoma	VEGFA	Inhibit immunity; Resistant to immunotherapy	The administration of an antibody against mouse VEGF synergized with ACT to enhance inhibition of established, vascularized, B16 melanoma (P = 0.009) and improve survival (P = 0.003). Thus, normalization of tumor vasculature through disruption of the VEGF/VEGFR-2 axis can increase extravasation of adoptively transferred T cells into the tumor and improve ACT-based immunotherapy.
20630741	Follicular Lymphoma	PECAM1	Inhibit immunity	Increased CD31+ MVD correlated positively with the number of tumour infiltrating MCs and CD34+ vessels, and negatively with the outcome. Overall survival and progression-free survival were significantly better among patients with low CD31+ MVDs. Consistent with the immunohistochemical data, high CD31/PECAM1 mRNA levels were associated with adverse outcome.
20628381	Esophageal Squamous Cell Carcinoma	ERBB2	Inhibit immunity	There was an inverse correlation between HER2 and MHC class I expressions in both tumour tissues and cell lines. Downregulation of HER2 with siRNA resulted in the upregulation of MHC class I expression, leading to increased CTL recognition by tumour antigen-specific CTLs. HER2-overexpressing ESCC tumour cells showed a reduced sensitivity for CTLs through the downregulation of MHC class I.
20628372	Mesothelioma	CD40	Promote immunity	CD40-activated B cells contribute to mesothelioma tumor regression. In this study, we show that injecting lower doses of anti-CD40 Ab directly into the tumor bed avoided toxic side effects and prolonged survival in 60% of mice, with most cured. Adoptive transfer of tumor antigen-experienced, CD40-activated B cells, or their immunoglobulin products, which recognized autoantigens on mesothelioma cells, protected against tumor challenge.
20626886	Breast Carcinoma	CD274	Inhibit immunity	Interestingly, siRNA knock down of B7-H1 lead to an increase in spontaneous apoptosis, as well as doxorubicin-induced apoptosis, which indicates an anti-apoptotic role for B7-H1 in breast cancer cells.
20622113	Glioblastoma	TNC	Inhibit immunity (infiltration)	Knocking down the tenascin-C gene using the short hairpin RNA strategy converted glioma cells to a transmigration-permissive phenotype for Jurkat cells regarding ERK activation, transmigration, and amoeba-like shape formation. In addition, exogenous tenascin-C protein reduced the amoeba-like shape formation and transmigration of Jurkat cells through MCF-7 and HepG2 cell monolayers.
20613784	Chronic Lymphocytic Leukemia	TNF	Inhibit immunity; Immunotherapy target	B-cell chronic lymphocytic leukemia (CLL) is characterized by slow accumulation of malignant cells, which are supported in the microenvironment by cell-cell interactions and soluble cytokines such as tumor necrosis factor (TNF). We evaluated the effect of the small molecule TNF inhibitor LMP-420 on primary CLL cells. These changes were associated with decreased expression of anti-apoptotic proteins Mcl-1, Bcl-xL and Bcl-2. In addition, LMP-420 potentiated the cytotoxic effect of fludarabine and inhibited in vitro proliferation of stimulated CLL cells. Gene expression profiling indicated that the mechanism of action of LMP-420 may involve suppression of nuclear factor-kappaB and immune response pathways in CLL cells.
20585039	B Lymphoblastic Leukemia/Lymphoma	IRF8	Inhibit immunity	Cooperation between deficiencies of IRF-4 and IRF-8 promotes both myeloid and lymphoid tumorigenesis. We found that mice deficient in both IRF-4 and IRF-8 develop from a very early age a more aggressive chronic myelogenous leukemia-like disease than mice deficient in IRF-8 alone, correlating with a greater expansion of granulocyte-monocyte progenitors.
20585039	B Lymphoblastic Leukemia/Lymphoma	IRF4	Promote immunity (alone); Inhibit immunity (combine with IRF8)	Cooperation between deficiencies of IRF-4 and IRF-8 promotes both myeloid and lymphoid tumorigenesis. Although these results demonstrate, for the first time, that IRF-4 can function as tumor suppressor in myeloid cells, interestingly, all mice deficient in both IRF-4 and IRF-8 eventually develop and die of a B-lymphoblastic leukemia/lymphoma.
20581241	Colorectal Carcinoma	STAT1	Promote immunity	There was a direct correlation between nSTAT1 expression and ITTC (p<0.001). Patients whose tumours had a high level of ITTC and nSTAT1 survived 20 months longer than those whose tumours had a low level of ITTC and no nSTAT1.
20581241	Colorectal Carcinoma	HLA-E	Promote immunity	In contrast, downregulation of MHC class I by allele loss results in loss of T cell recognition. A strong correlation was seen between ITTC and MHC class I expression (p=0.0002). A mean survival advantage of 26.1 months was seen in patients whose tumours had strong MHC I expression and high levels of ITTC over those who had weak MHC I and low levels of ITTC (log-rank test=12.023, p=0.034).
20581239	Colorectal Carcinoma	LGALS3BP	Promote immunity	Secreted 90K suppresses CRC cell invasion, but this action of 90K is masked through binding with extracellular galectins. In a syngeneic mouse colon tumour model, tumour growth and lung metastasis were increased with 90K knockdown. 90K itself has antitumour activity in CRC cells via suppression of Wnt signalling with a novel mechanism of ISGylation-dependent ubiquitination of beta-catenin when it interacts with CD9/CD82, but is downregulated in advanced CRC tissues.
20580220	Colorectal Carcinoma	TNFSF10	Inhibit immunity	Among the immune cells, preferentially CD8+ T cells were found to express TRAIL-R1 while serial immunostaining in the same patient tumours showed abundant apoptotic (TUNEL-positive) immune cells. In conclusion, our results in tumour samples from CRC patients suggest TRAIL-R1-mediated apoptotic depletion of infiltrating immune cells (CD8+) in response to TRAIL expression by the tumour itself.
20570888	Melanoma	GPNMB	Inhibit immunity	DC-HIL/glycoprotein Nmb promotes growth of melanoma in mice by inhibiting the activation of tumor-reactive T cells. We generated small interfering RNA-transfected B16F10 melanoma cells to completely knock down DC-HIL/Gpnmb expression, with no alteration in cell morphology, melanin synthesis, or MHC class I expression. This knockdown had no effect on B16F10 proliferation in vitro or entry into the cell cycle following growth stimulation, but it markedly reduced the growth of these cells in vivo following their s.c. injection into syngeneic immunocompetent (but not immunodeficient) mice. This reduction in tumor growth was due most likely to an augmented capacity of DC-HIL-knocked down B16F10 cells (compared with controls) to activate melanoma-reactive T cells as documented in vitro and in mice.
20570856	Acute Myeloid Leukemia	CD274	Inhibit immunity (T cell function)	Program death-1 signaling and regulatory T cells collaborate to resist the function of adoptively transferred cytotoxic T lymphocytes in advanced acute myeloid leukemia. These data demonstrated that interaction between PD-1 and PD-L1 can facilitate Treg-induced suppression of T-effector cells and dampen the antitumor immune response.
20551066	Lung Carcinoma	DKK1	Inhibit immunity	Using an original ELISA system, high levels of DKK1 protein were found in serologic samples from 906 patients with cancers of the pancreas, stomach, liver, bile duct, breast, and cervix, which also showed elevated expression levels of DKK1. Additionally, anti-DKK1 antibody inhibited the invasive activity and the growth of cancer cells in vitro and suppressed the growth of engrafted tumors in vivo. Tumor tissues treated with anti-DKK1 displayed significant fibrotic changes and a decrease in viable cancer cells without apparent toxicity in mice.
20551064	Ovarian Carcinoma	DDX58	Promote immunity	Here, we show that targeted delivery of RIG-I agonists induced ovarian cancer cells to upregulate HLA class I and to secrete the proinflammatory cytokines CXCL10, CCL5, interleukin-6, tumor necrosis factor-alpha, and IFN-beta. Ovarian cancer cells stimulated via RIG-I became apoptotic and were readily phagocytosed by monocytes and monocyte-derived dendritic cells, which in turn upregulated HLA class I/II and costimulatory molecules and released CXCL10 and IFN-alpha.
20551059	Melanoma	BRAF	Inhibit immunity	We show that inhibition of the MAPK pathway with MAPK/extracellular signal-regulated kinase kinase (MEK) inhibitors or a specific inhibitor of BRAF(V600E) in melanoma cell lines and tumor digests results in increased levels of MDAs, which is associated with improved recognition by antigen-specific T lymphocytes. These findings suggest that immune evasion of melanomas mediated by oncogenic BRAF may be reversed by targeted BRAF inhibition without compromising T-cell function.
20546740	Melanoma	ENTPD1	Inhibit immunity (T cell function)	We demonstrate that hepatic growth of melanoma metastatic tumors was strongly inhibited in mice with Cd39 null vasculature or in wt mice with circulating Cd39 null bone marrow-derived cells. We show functional CD39 expression on CD4(+)Foxp3(+) Tregs suppressed antitumor immunity mediated by natural killer (NK) cells in vitro and in vivo. CD39 expression on Tregs inhibits NK activity and is permissive for metastatic growth.
20534737	Malignant Glioma	GDF15	Inhibit immunity	GDF-15 contributes to proliferation and immune escape of malignant gliomas. The high expression of GDF-15 in tumor tissue translates into elevated GDF-15 serum levels in glioblastoma patients compared with healthy controls. Silencing of GDF-15 by RNA interference reduces the proliferation of malignant glioma cells. Although previous studies focusing on ectopic overexpression of GDF-15 have proposed unclear or antitumorigenic effects of GDF-15 in glioma cells, we here show that GDF-15 at endogenous levels contributes to proliferation and immune escape of malignant gliomas in an immunocompetent host.
20530676	Hematopoietic and Lymphoid Cell Neoplasm	TFRC	Inhibit immunity	Development of human single-chain antibodies to the transferrin receptor that effectively antagonize the growth of leukemias and lymphomas. The major route of iron uptake by cells occurs through transferrin receptor (TfR)-mediated endocytosis of diferric-charged plasma transferrin (holo-Tf). In support of this hypothesis, the anti-TfR scFvs identified were antagonists of TfR binding to holo-Tf, particularly two of the most potent antibodies, 3TF12 and 3GH7, which blocked the in vitro proliferation of a number of hematopoietic cancer cell lines. Together, our findings define a new class of fully human anti-TfR antibodies suitable for immunotherapy against tumors whose proliferation relies on high levels of TfR and iron uptake, such as acute lymphoid and myeloid leukemias.
20525896	Melanoma	EOMES	Promote immunity (T cell function)	Naturally activated V gamma 4 gamma delta T cells play a protective role in tumor immunity through expression of eomesodermin. Indeed, CD44(high) Vgamma4 gammadelta T cells produced significantly more IFN-gamma and perforin on activation, and showed greater cytolytic activity than did CD44(high) Vgamma1 gammadelta T cells, apparently due to the high level of eomesodermin (Eomes) in these activated Vgamma4 gammadelta T cells. Consistently, transfection of dominant-negative Eomes in Vgamma4 gammadelta T cells diminished the level of IFN-gamma secretion, indicating a critical role of Eomes in the effector function of these gammadelta T cells.
20525892	Breast Neoplasm; Lung Carcinoma	TNFRSF1B	Inhibit immunity (expressed by Tregs); Promote immunity (expressed by Tconv)	TNFR2 is associated with greater suppressive functions when expressed by Tregs and is associated with greater resistance to suppression when expressed by Tconv cells. In mice bearing 4T1 breast tumor or Lewis lung carcinoma, intratumoral Tconv cells expressing elevated levels of TNFR2 acquired the capacity to resist suppression by lymph node-derived Tregs. However, intratumoral Tregs expressing more TNFR2 are able to overcome the greater resistance to suppression of intratumoral Tconv cells, resulting in a dominant immunosuppressive tumor environment.
20525891	Adult T-Cell Leukemia/Lymphoma	FOXP3	Inhibit immunity	Finally, we show that FoxP3(+) cells inhibit the proliferation of ex vivo, autologous leukemic clones from patients with ATLL. We conclude that HTLV-1-induced CCL22 causes the high frequency of FoxP3(+) cells observed in HTLV-1 infection; these FoxP3(+) cells may both retard the progression of ATLL and HTLV-1-associated inflammatory diseases and contribute to the immune suppression seen in HTLV-1 infection, especially in ATLL.
20525891	Adult T-Cell Leukemia/Lymphoma	CCL22	Inhibit immunity	Further, we show that CCL22 is produced by cells that express the HTLV-1 transactivator protein Tax, and that the increased CCL22 enhances the migration and survival of FoxP3(+) cells in vitro. We conclude that HTLV-1-induced CCL22 causes the high frequency of FoxP3(+) cells observed in HTLV-1 infection; these FoxP3(+) cells may both retard the progression of ATLL and HTLV-1-associated inflammatory diseases and contribute to the immune suppression seen in HTLV-1 infection, especially in ATLL.
20515950	Colon Carcinoma; Lung Carcinoma	TLR7	Promote immunity (T cell function)	Peritoneal administration of dual TLR7/8 agonist in mice bearing CT26.CL25 colon carcinomas had potent dose-dependent antitumor activity, which was associated with a marked decrease in CD4(+)CD25(+)Foxp3(+) T regulatory cells and a significant increase in tumor antigen-specific IFN-gamma-secreting effector cell responses in splenocytes and local tumor-infiltrating cells. Administration of TLR7/8 agonist effectively prevented lung metastasis of tumors in the CT26.CL25 pulmonary metastasis model. These studies show that the dual TLR7/8 agonist induced Th1-type immune responses and potent antitumor activity in mice via TLR7 and through the MyD88-dependent pathway.
20513002	Colon Carcinoma	ICAM1	Inhibit immunity	ManR expression and endocytosis increased in tumor-activated LSECs through a two-step mechanism: (1) Release of COX-2-dependent IL-1-stimulating factors by lymphocyte function-associated antigen-1-expressing C26 cells in response to intercellular adhesion molecule-1 (ICAM-1), which was expressed and secreted by tumor-activated LSECs; and (2) widespread up-regulation of ManR in LSECs through tumor-induced IL-1. ICAM-1-induced tumor COX-2 decreased antitumor activity during hepatic metastasis through IL-1-induced ManR.
20513002	Colon Carcinoma	IL1B	Inhibit immunity	Colon carcinoma cell interaction with liver sinusoidal endothelium inhibits organ-specific antitumor immunity through interleukin-1-induced mannose receptor in mice. ManR expression and endocytosis increased in tumor-activated LSECs through a two-step mechanism: (1) Release of COX-2-dependent IL-1-stimulating factors by lymphocyte function-associated antigen-1-expressing C26 cells in response to intercellular adhesion molecule-1 (ICAM-1), which was expressed and secreted by tumor-activated LSECs; and (2) widespread up-regulation of ManR in LSECs through tumor-induced IL-1.
20501618	Prostate Carcinoma	PSCA	Inhibit immunity	The expression of PSCA is positively correlated with advanced clinical stage and metastasis in prostate cancers and is also associated with malignant progression of premalignant prostate lesions.
20501618	Esophageal Carcinoma; Gastric Carcinoma	PSCA	Promote immunity	In contrast, PSCA is down-regulated in esophageal and gastric cancer and may have a tumor-suppressing function in the gastric epithelium.
20495537	Ovarian Carcinoma	CD276	Inhibit immunity	Tumor associated endothelial expression of B7-H3 predicts survival in ovarian carcinomas. Analysis of cumulative survival time and recurrence incidence revealed that carcinomas with B7-H3-positive tumor vasculature were associated with a significantly shorter survival time (P=0.02) and a higher incidence of recurrence (P=0.03). These results show that ovarian borderline tumors and carcinomas aberrantly express B7-H3 and B7x, and that B7-H3-positive tumor vasculature is associated with high-grade serous histological subtype, increased recurrence and reduced survival.
20483744	Prostate Carcinoma	TLR3	Promote immunity	Overall, these data show for the first time that TLR3 and TLR5 stimulation of human prostate cancer cells triggers the production of chemokines, which, in turn, favor the attraction of immune effectors, thereby representing a tool to enhance the efficacy of conventional therapies by stimulating anticancer immune responses.
20483744	Prostate Carcinoma	TLR5	Promote immunity	Overall, these data show for the first time that TLR3 and TLR5 stimulation of human prostate cancer cells triggers the production of chemokines, which, in turn, favor the attraction of immune effectors, thereby representing a tool to enhance the efficacy of conventional therapies by stimulating anticancer immune responses.
20473905	Pancreatic Ductal Adenocarcinoma	IL2	Promote immunity	We demonstrate here that IL-2-activated human NK cells are able to kill PDAC cells.
20473905	Pancreatic Ductal Adenocarcinoma	KLRK1	Promote immunity	Indeed, blocking of the natural cytotoxicity receptors-NKp30, 44 and 46 in combination, and NKG2D and DNAM1 alone inhibit the killing of Panc-1 cells.
20466887	Prostate Carcinoma	ERBB2	Inhibit immunity	Seventy-five percent of patients developed augmented immunity to the AE37 vaccine and 65% to the unmodified AE36 peptide as detected in the IFN-gamma-based ELISPOT assay. Intracellular IFN-gamma analyses revealed that AE37 elicited both CD4(+) and CD8(+) T-cell responses. AE37 vaccine is safe and can induce HER-2/neu-specific cellular immune responses in patients with castrate-sensitive and castrate-resistant prostate cancer, thus emphasizing the potential of AE37 to target HER-2/neu for the immunotherapy of prostate cancer.
20460483	Colon Carcinoma; Fibrosarcoma	TNFRSF18	Inhibit immunity; Immunotherapy target	Anti-CTLA-4/anti-GITR mAb combination treatment exhibited far stronger antitumor effects compared with either antibody alone. This strong antitumor effect was attributed to (a) increased numbers of CD8+ T cells infiltrating tumor sites in anti-CTLA-4 mAb-treated mice and (b) increased cytokine secretion and Treg resistance of tumor-specific CD8+ T cells with strongly upregulated CD25 expression in anti-GITR mAb-treated mice, indicating distinct quantitative/qualitative changes induced by modulating CTLA-4 and GITR signaling.
20460483	Colon Carcinoma; Fibrosarcoma	CTLA4	Inhibit immunity (infiltration); Immunotherapy target	Anti-CTLA-4/anti-GITR mAb combination treatment exhibited far stronger antitumor effects compared with either antibody alone. This strong antitumor effect was attributed to (a) increased numbers of CD8+ T cells infiltrating tumor sites in anti-CTLA-4 mAb-treated mice and (b) increased cytokine secretion and Treg resistance of tumor-specific CD8+ T cells with strongly upregulated CD25 expression in anti-GITR mAb-treated mice, indicating distinct quantitative/qualitative changes induced by modulating CTLA-4 and GITR signaling.
20460472	Melanoma	CD28	Promote immunity; Essential for immunotherapy	We show that this Tandem sFv-CD28/TCRzeta receptor on T cells confers advantages of improved cytokine secretion, cytotoxicity, proliferation, and clonal expansion on tumor contact versus the same CAR without costimulation. In an adoptive transfer model using established melanoma tumors, designer T cells with CD28 showed a 50% rate of complete remissions but only where IL2 was supplemented.
20427766	Ovarian Carcinoma	ITGAM	Promote immunity	However, we show that CD11b(+)Gr-1(+) cells found in ascites of epithelial ovarian cancer-bearing mice at advanced stages of disease are immunostimulatory rather than being immunosuppressive. Moreover, like dendritic cells, immunostimulatory CD11b(+)Gr-1(+) cells can strongly cross-prime, augmenting the proliferation of functional CTLs via signaling through the expression of costimulatory molecule CD80.
20421648	Melanoma; Colorectal Carcinoma	LAG3	Inhibit immunity	LAG-3 expression defines a subset of CD4(+)CD25(high)Foxp3(+) regulatory T cells that are expanded at tumor sites. Ex vivo analysis showed that CD4(+)CD25(high)Foxp3(+)LAG-3(+) T cells are functionally active cells that release the immunosuppressive cytokines IL-10 and TGF-beta1, but not IL-2. Our data show that LAG-3 defines an active CD4(+)CD25(high)Foxp3(+) regulatory T cell subset whose frequency is enhanced in the PBMCs of patients with cancer and is expanded at tumor sites.
20420708	Melanoma; Lung Carcinoma; Sarcoma; Hepatocellular Carcinoma	RBPJ	Promote immunity	Indeed, tumors containing the RBP-J deficient DCs had fewer infiltrating T-cells, B-cells and NK-cells. At the molecular level, the RBP-J deficient DCs expressed lower MHC II, CD80, CD86, and CCR7, resulting in inefficient DC migration and T-cell activation in vitro and in vivo. The RBP-J-mediated Notch signaling is essential for DC-dependent anti-tumor immune responses. The deficiency of RBP-J impairs the DC-based anti-tumor immunity through affecting series of processes including maturation, migration, antigen presentation and T-cell activation.
20418497	Melanoma	PLTP	Promote immunity	After 1 wk, onset of B16-induced melanoma was observed in only 30% of lipid A-treated WT mice, whereas >80% of the untreated WT, untreated PLTP-deficient, or lipid A-treated PLTP-deficient animals bore tumors (P<0.05 in all cases). It is concluded that PLTP is essential in mediating the association of triacyl lipid A with lipoproteins, leading to extension of its residence time and to magnification of its proinflammatory and anticancer properties.
20406987	Primary Effusion Lymphoma	BSG	Inhibit immunity	We also found that emmprin promotes invasiveness, as well as colony formation, by primary effusion lymphoma cells derived from human tumors. Collectively, these data implicate KSHV activation of emmprin as an important mechanism for cancer progression and support the potential utility of targeting emmprin as a novel therapeutic approach for KSHV-associated tumors.
20406899	Glioma	FASLG	Inhibit immunity (infiltration)	Here, we show that FasL expression can support the growth of experimental intracranial glioma. FasL was found to be expressed by three well-characterized rat glioma cell lines (9L, F98, and C6) and glioma cell-derived FasL mediated the death of phytohemagglutinin-stimulated Jurkat T-lymphocytes when cocultured with glioma cells in vitro. FasL expression knockdown using shRNA reduced the growth of subcutaneous and intracranial 9L gliomas by approximately 50% in immune competent Fisher 344 rats. These results demonstrate that down-regulating FasL expression and/or function in glial malignancies can enhance T-cell tumor infiltration and inhibit tumor growth.
20404277	Plasmacytoma	CDA	Inhibit immunity; Resistant to immunotherapy	In this study, we report that small interfering RNA silencing of AID in plasmacytoma dramatically increased its susceptibility to immunotherapy by CTLs. Gene-array analysis showed dramatically altered expression of a number of genes in AID-silenced plasmacytoma cells, and upregulation of CD200 was shown to be in favor of tumor eradication by CTLs.
20404142	Metastatic Malignant Neoplasm in the Lung; Skin Papilloma; Fibrosarcoma	IL23A	Inhibit immunity	IL-23 suppresses innate immune response independently of IL-17A during carcinogenesis and metastasis. IL-23-deficient mice were resistant to experimental tumor metastases in three models where host NK cells controlled disease. Further investigation revealed that loss of IL-23 promoted perforin and IFN-gamma antitumor effector function in both metastasis models examined. IL-23-deficiency also strikingly protected mice from tumor formation in two distinct mouse models of carcinogenesis where the dependence on host IL-12p40 and IL-17A was quite different.
20400704	Ovarian Carcinoma	CCL5	Promote immunity	Our results unveil a therapeutic mechanism whereby tumor-primed CD4(+) T cells transferred into ovarian cancer-bearing mice secrete high levels of CCL5, which recruits endogenous CCR5(+) dendritic cells to tumor locations and activate them through CD40-CD40L interactions. These newly matured dendritic cells are then able to prime tumor-specific endogenous CD8(+) T cells, which mediate long-term protection.
20400704	Ovarian Carcinoma	CD40LG	Promote immunity	CD4+ T cells elicit host immune responses to MHC class II-negative ovarian cancer through CCL5 secretion and CD40-mediated licensing of dendritic cells. Our results unveil a therapeutic mechanism whereby tumor-primed CD4(+) T cells transferred into ovarian cancer-bearing mice secrete high levels of CCL5, which recruits endogenous CCR5(+) dendritic cells to tumor locations and activate them through CD40-CD40L interactions. These newly matured dendritic cells are then able to prime tumor-specific endogenous CD8(+) T cells, which mediate long-term protection.
20395201	Lung Carcinoma	AKT1	Inhibit immunity	Furthermore, the retroviral transduction of XLR in parental tumor cells led to activation of Akt, resulting in upregulation of antiapoptotic proteins and the induction of immune resistance phenotype in parental tumor cells.
20388845	Metastatic Melanoma	STAT3	Inhibit immunity; Resistant to immunotherapy	Inhibition of p-STAT3 enhances IFN-alpha efficacy against metastatic melanoma in a murine model. Activation of the signal transducer and activator of transcription 3 (STAT3) has been identified as a key mediator that drives the fundamental components of melanoma malignancy, including immune suppression in melanoma patients. The immune modulatory effects of STAT3 blockade can enhance the therapeutic efficacy of IFN-alpha immunotherapy by enhancing both innate and adaptive cytotoxic T-cell activities.
20386569	Breast Carcinoma	FOSL1	Inhibit immunity	Fra-1 protooncogene regulates IL-6 expression in macrophages and promotes the generation of M2d macrophages. The 4T1 cells stimulate de novo overexpression of Fra-1 in RAW264.7 cells, and then Fra-1 binds to the interleukin 6 (IL-6) promoter to increase the production of the cytokine IL-6 in RAW264.7 cells.
20386569	Breast Carcinoma	IL6	Inhibit immunity	IL-6 acts in an autocrine fashion to skew RAW264.7 macrophage cell differentiation into M2d macrophages.
20378565	Rhabdomyosarcoma	KLRK1	Promote immunity	Antibody-mediated masking of either NKG2D molecule on cytokine-induced killer cells or its ligands on rhabdomyosarcoma cells (major histocompatibility antigen related chain A and B and UL16 binding protein 2) diminished this effect by 50%, suggesting a major role for the NKG2D molecule in rhabdomyosarcoma cell killing.
20378565	Rhabdomyosarcoma	TNFSF10	Promote immunity	Remarkably, cytokine-induced killer cells used tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to activate caspase-3, as the main caspase responsible for the execution of apoptosis. Accordingly, blocking TRAIL receptors on embryonic rhabdomyosarcoma cell lines significantly reduced the anti-tumor effect of cytokine-induced killer cells.
20372104	Primary Cutaneous Lymphoma	IFNG	Promote immunity	Twenty-one patients were enrolled in a prospective open-label, dose-escalation multicenter study evaluating the effects of repeated TG1042 [adenovirus-interferon (IFN)-gamma] intralesional injections in patients with primary CLs, of which 18 were of T-cell and 3 of B-cell type. Repeated intralesional therapy using TG1042 consistently results in local tumor regressions in about half of treated patients and one-third of patients also in regressions in noninjected distant lesions, likely reflecting the systemic immune activation after intralesional therapy.
20351182	Thymoma	NOTCH2	Promote immunity	Notch2(flox/flox) mice crossed with E8I-cre transgenic (N2F/F-E8I) mice, in which the Notch2 gene is absent only in CD8(+) T cells, die earlier than control mice after inoculation with OVA-expressing EG7 thymoma cells. In contrast, Notch1(flox/flox) mice crossed with E8I-cre transgenic mice inoculated with EG7 cells die comparable to control mice, indicating that Notch2 is crucial for exerting antitumor CTL responses. These findings indicate that Notch2 signaling in CD8(+) T cells is required for generating potent antitumor CTLs, thus providing a crucial target for augmenting tumor immune responses.
20350764	Infiltrating Cervical Carcinoma	IDO1	Inhibit immunity	IDO expression was positively correlated with clinical stage, lymph node metastasis, and lymph-vascular space invasion, but not with histological type. Patients with diffuse IDO expression had significantly reduced overall survival (OS) and disease-free survival (DFS) compared to patients with no IDO expression.
20339029	Melanoma	CCL21	Inhibit immunity	CCL21 expression by melanoma tumors in mice was associated with an immunotolerant microenvironment, which included the induction of lymphoid-like reticular stromal networks, an altered cytokine milieu, and the recruitment of regulatory leukocyte populations. In contrast, CCL21-deficient tumors induced antigen-specific immunity. We suggest that by altering the tumor microenvironment, CCL21-secreting tumors shift the host immune response from immunogenic to tolerogenic, which facilitates tumor progression.
20308630	Breast Carcinoma	IL10	Inhibit immunity; Resistant to immunotherapy	Blockade of IL-10, but not TGF-beta, enhanced the antitumor effect of imiquimod by significantly prolonging survival in treated mice. These data suggest that the excessive inflammation induced by TLR agonists may result in a self-regulatory immunosuppression via IL-10 induction and that blocking IL-10 could enhance the therapeutic efficacy of these agents.
20308315	Glioma	TNF	Promote immunity	In vitro, pDC produced more TNF-alpha than uDC: addition of TNF-alpha to the medium decreased the proliferation of glioma cells. Overall, the results suggest that IT-pDC potentiates the anti-tumor immune response elicited by SC-pDC by pro-immune modulation of cytokines in the tumor microenvironment, decrease of Treg cells, and direct inhibition of tumor proliferation by TNF-alpha.
20303532	Renal Cell Carcinoma; Bladder Carcinoma	STEAP1	Promote immunity	STEAP peptides induced helper T-lymphocyte responses using lymphocytes from healthy individuals that directly recognized STEAP expressing, DR positive renal cell and bladder cancer cells, and autologous dendritic cells pulsed with STEAP expressing tumor cell lysates in a major histocompatibility complex class II restricted manner. Results show that STEAP helper T-lymphocyte epitopes could be used to optimize T-cell based immunotherapy against STEAP expressing renal cell and bladder cancer.
20237413	Lung Carcinoma	TLR7	Inhibit immunity	Triggering of TLR7 and TLR8 expressed by human lung cancer cells induces cell survival and chemoresistance. Stimulation with TLR7 or TLR8 agonists led to activated NF-kappaB, upregulated expression of the antiapoptotic protein Bcl-2, increased tumor cell survival, and chemoresistance.
20237413	Lung Carcinoma	TLR8	Inhibit immunity	Triggering of TLR7 and TLR8 expressed by human lung cancer cells induces cell survival and chemoresistance. Stimulation with TLR7 or TLR8 agonists led to activated NF-kappaB, upregulated expression of the antiapoptotic protein Bcl-2, increased tumor cell survival, and chemoresistance.
20234320	Non-Small Cell Lung Carcinoma	FOXP3	Inhibit immunity	Tumor-infiltrating Foxp3-positive lymphocytes were positively correlated with COX-2 expression. The RFS of patients with tumors containing >or=3 Foxp3-positive cells (Foxp3 expression group) was significantly worse than that of patients with tumors containing <3 Foxp3-positive cells.
20234320	Non-Small Cell Lung Carcinoma	PTGS2	Inhibit immunity	The recurrence-free survival (RFS) of patients with elevated COX-2 expression was significantly worse than that of patients without COX-2 expression.
20233880	Prostate Carcinoma	TLR3	Promote immunity	In our study, we implicate TLR3 in mediating immune surveillance with increased growth of implanted transgenic adenocarcinoma of the mouse prostate (TRAMP) tumors in TLR3(-/-) compared with TLR3(+/+) mice. Activation of TLR3 by polyinosinic-polycytidylic acid (polyI:C) leads to induction of multiple inflammatory pathways, including NF-kappaB, mitogen-activated protein kinases, and interferon (IFN) regulatory factors.
20233880	Prostate Carcinoma	IFNAR1	Promote immunity	Like TLR3(-/-) mice, IFN-alpha receptor 1 (IFNAR1)(-/-) mice exhibited reduced tumor surveillance and impaired tumor suppression following polyI:C treatment.
20233867	Breast Carcinoma	FASLG	Promote immunity	Intratumoral administration of anti-FasL antibody promoted tumor growth. The decrease in Tregs (Fas(+)) was due to apoptosis induced by cell contact with Fas ligand(+) (L)(+) Th.
20220777	Chronic Lymphocytic Leukemia	HMMR	Immunotherapy target	CD8(+) T cells primed with the RHAMM-derived epitope R3, which is restricted by human leukocyte antigen (HLA)-A2, effectively lyse RHAMM(+) CLL cells. Thus peptide vaccination in six CLL patients was safe and could elicit to some extent specific CD8(+) T-cell responses against the tumor antigen RHAMM.
20200275	Prostate Carcinoma	CD40LG	Promote immunity	Tumor-reactive CD8(+) T cells expressing the truncated form of CD40L stimulated maturation of dendritic cells in vitro and in the prostate draining lymph nodes in vivo. Following dendritic cell maturation, a significantly higher fraction of adoptively transferred, tumor-reactive (reporter) CD8(+) T cells was stimulated to express IFN-gamma and infiltrate the prostate tissue.
20194714	Melanoma	CD274	Inhibit immunity (T cell function)	In this study, in vitro blockade of PD-L1 interaction on DCs led to enhanced IFN-gamma production and cytotoxicity by Ag-specific T cells. Together, these studies support the blocking of PD-L1 signaling as a means to enhance combined immunotherapy approaches against melanoma.
20186876	Melanoma	IL2RB	Inhibit immunity; Resistant to immunotherapy	We found that the major population that underwent lymphopenia-driven proliferation was the CD122+ memory-like T-cell population (CD122+CD8+ Treg), and these cells competed with Ag-driven proliferation of melanoma-specific T cells. Removal of CD122+CD8+ Treg resulted in a greater expansion of tumor-specific T cells and tumor infiltration of functional effector/memory T cells. Our results demonstrate the lymphopenia-driven proliferation of CD122+CD8+ Treg in reconstituted lymphodepleted mice limited the antitumor efficacy of DC vaccination in conjunction with adoptive transfer of tumor-specific T cells.
20179192	Ovarian Carcinoma	NT5E	Inhibit immunity	CD73 on tumor cells impairs antitumor T-cell responses: a novel mechanism of tumor-induced immune suppression. Because the ecto-5'-nucleotidase activity of CD73 catalyzes AMP breakdown to immunosuppressive adenosine, we hypothesized that CD73-generated adenosine prevents tumor destruction by inhibiting antitumor immunity. We confirmed this hypothesis by showing that combining tumor CD73 knockdown and tumor-specific T-cell transfer cured all tumor-bearing mice.
20176801	Lymphoma	HAVCR2	Inhibit immunity	Lymphoma endothelium preferentially expresses Tim-3 and facilitates the progression of lymphoma by mediating immune evasion. In vitro, Tim-3(+) ECs modulated T cell response to lymphoma surrogate antigens by suppressing activation of CD4(+) T lymphocytes through the activation of the interleukin-6-STAT3 pathway, inhibiting Th1 polarization, and providing protective immunity. In a lymphoma mouse model, Tim-3-expressing ECs promoted the onset, growth, and dissemination of lymphoma by inhibiting activation of CD4(+) T cells and Th1 polarization.
29887396	Colorectal Neoplasm	TNF	Promote immunity; Essential for immunotherapy	We further demonstrate that T cell-derived tumor necrosis factor alpha (TNF-α) can synergize with chemotherapy to intensify oxidative stress and tumor cell death in an NADPH (nicotinamide adenine dinucleotide phosphate hydrogen) oxidase-dependent manner. Reduction of oxidative stress, by preventing TNF-α-signaling in tumor cells or scavenging ROS, antagonized the therapeutic effects of adoptive immunotherapy.
29885053	Gastrointestinal Stromal Tumor	SH3BP2	Inhibit immunity	Our current study shows that SH3BP2 is expressed in primary tumors and cell lines from GIST patients and that SH3BP2 silencing leads to a downregulation of oncogenic KIT and PDGFRA expression and an increase in apoptosis in imatinib-sensitive and -resistant GIST cells. Furthermore, SH3BP2 silencing significantly reduces cell migration and tumor growth of imatinib-sensitive and resistant cells in vivo.
29884726	Triple-Negative Breast Carcinoma	EYA3	Inhibit immunity	A recent study indicates that the protein Eya3 influences the adaptive immune response to promote tumor growth, not only decreasing the number of tumor-infiltrating CD8+ T cells, but also driving their exhaustion through PD-L1 upregulation.
29875777	Metastatic Melanoma	MIF	Inhibit immunity	Blockade of MIF-CD74 Signalling on Macrophages and Dendritic Cells Restores the Antitumour Immune Response Against Metastatic Melanoma. Interfering with MIF-CD74 signaling on MOs and DCs leads to a decrease in the expression of immunosuppressive factors from MOs and an increase in the capacity of DCs to activate cytotoxic T cells.
29873070	Hepatocellular Carcinoma	ADAM17	Inhibit immunity	Natural killer cells eliminate various cancer cells, including HCC, by suppressing MICA shedding. ADAM17 knockdown reduced sMICA levels and increased membrane-bound MICA (mMICA) expression in HCC cells.
29872580	Melanoma	JAK1	Promote immunity; Essential for immunotherapy	Melanoma response to anti-PD-L1 immunotherapy requires JAK1 signaling, but not JAK2. In this study, we dissected the specific roles of individual JAK/STAT pathway members on the IFN-γ response, and identified JAK1 as the primary mediator of JAK/STAT signaling associated with IFN-γ-induced expression of antigen-presenting molecules MHC-I and MHC-II, as well as PD-L1 and the cytostatic response to IFN-γ.
29872580	Melanoma	SOAT1	Promote immunity; Essential for immunotherapy	Amplification of JAK/STAT signaling in tumor cells through genetic inhibition of the negative regulator PTPN2 potentiated IFN-γ response in vitro and in vivo, and may be a target to enhance immunotherapy efficacy.
29872577	Lung Carcinoma	VTCN1	Inhibit immunity	TAMs suppress CTLs through the T-cell inhibitory molecule B7x (B7-H4/B7S1) in a cell-cell contact manner, whereas CTLs kill TAMs in a tumor antigen-specific manner.
29872577	Lung Carcinoma	IL10	Promote immunity	Remarkably, TAMs secrete the known T-cell suppressive cytokine interleukin-10 (IL-10) to activate, but not to repress, CTLs.
29872577	Lung Carcinoma	RELA	Inhibit immunity	NF-κB RelA renders tumor-associated macrophages resistant to and capable of directly suppressing CD8+ T cells for tumor promotion. It induces B7x expression in TAMs directly, and restricts IL-10 expression indirectly by repressing expression of the NF-κB cofactor Bcl3 and subsequent Bcl3/NF-κB1-mediated transcription of IL-10. It also renders TAMs resistant to CTLs by up-regulating anti-apoptotic genes.
29872559	Melanoma; Prostate Carcinoma; Colon Carcinoma	TNFSF11	Inhibit immunity; Resistant to immunotherapy	RANKL blockade improves efficacy of PD1-PD-L1 blockade or dual PD1-PD-L1 and CTLA4 blockade in mouse models of cancer. Furthermore, addition of anti-RANKL to anti-PD1 and anti-CTLA4 resulted in superior anti-tumor responses, irrespective of the ability of anti-CTLA4 isotype to engage activating FcR, and concurrent or delayed RANKL blockade was most effective. Early-during-treatment assessment reveals this triple combination therapy compared to dual anti-PD1 and anti-CTLA4 combination therapy further increased the proportion of tumor-infiltrating CD4+ and CD8+ T cells that can produce both IFN-γ and TNF. Finally, RANKL expression appears to identify tumor-specific CD8+ T cells expressing higher levels of PD1 which can be modulated by anti-PD1.
29872558	Colon Carcinoma	TFAM	Promote immunity	TFAM is a novel mediator of immunogenic cancer cell death. Importantly, the release of TFAM, a mitochondrial DAMP, by apoptotic cells may contribute to spautin-1-induced ICD via its action on the receptor AGER. This immunogenic effect of spautin-1-treated cancer cells was lost when TFAM or AGER were neutralized by specific antibodies.
29872558	Colon Carcinoma	JUN	Promote immunity	Mechanistically, activation of JUN by spautin-1 leads to apoptosis by upregulation of pro-apoptotic BAD expression.
29872044	Colon Carcinoma	VENTX	Promote immunity	The homeobox protein VentX reverts immune suppression in the tumor microenvironment. We show here that VentX promotes M1 differentiation of TAMs, and that VentX-regulated TAMs, in turn, revert immune suppression at the TME. Using a NSG mouse model of human colon cancers, we demonstrate that VentX regulates TAM function in tumorigenesis in vivo.
29866746	Colorectal Carcinoma	GPA33	Essential for immunotherapy	MGD007 displays the anticipated bispecific binding properties and mediates potent lysis of gpA33-positive cancer cell lines, including models of colorectal cancer stem cells, through recruitment of T-cells. Both CD8 and CD4 T cells mediated lysis of gpA33-expressing tumor cells, with activity accompanied by increases in granzyme and perforin. No cytokine activation was observed with human PBMC alone, consistent with the absence of gpA33 expression on peripheral blood cell populations. Following prolonged exposure to MGD007 and gpA33 positive tumor cells, T cells express PD 1 and LAG-3 and acquire a memory phenotype but retain ability to support potent cell killing.
29866045	Squamous Cell Lung Carcinoma	TP63	Inhibit immunity	We found that the TP63/SOX2/DMRT3 module was specific to LUSC, corresponding to squamous epithelial differentiation and/or survival.
29866045	Lung Adenocarcinoma	LEF1	Inhibit immunity	Moreover, the LEF1/MSC module was specifically activated in LUAD and likely to confer epithelial-to-mesenchymal transition, known important for cancer malignant progression and metastasis.
29866045	Small Cell Lung Carcinoma	ID2	Inhibit immunity	Also, ID2 was differentially regulated between SCLC and LUSC, with its up-regulation in SCLC linking to energy supply for fast mitosis and its down-regulation in LUSC linking to the attenuation of immune response.
29866045	Squamous Cell Lung Carcinoma	ID2	Promote immunity	Also, ID2 was differentially regulated between SCLC and LUSC, with its up-regulation in SCLC linking to energy supply for fast mitosis and its down-regulation in LUSC linking to the attenuation of immune response.
29858021	Lung Adenocarcinoma	HAVCR2	Inhibit immunity	TIM-3 positivity was significantly associated with worse recurrence-free survival (RFS) (hazard ratio [HR], 2.32; 95% confidence interval [CI], 1.44-3.73, p = 0.001) and overall survival (OS) (HR, 2.04; 95% CI, 1.29-3.20, p = 0.002).
29856956	Acute Myeloid Leukemia	CD33	Resistant to immunotherapy	Genetic Inactivation of CD33 in Hematopoietic Stem Cells to Enable CAR T Cell Immunotherapy for Acute Myeloid Leukemia. For example, targeting the canonical myeloid marker CD33 in acute myeloid leukemia (AML) results in toxicity from destruction of normal myeloid cells. CD33-deficient cells were impervious to CD33-targeting CAR T cells, allowing for efficient elimination of leukemia without myelotoxicity.
29855617	Cervical Carcinoma	CD274	Inhibit immunity	We report that PD-L1 is overexpressed in CC, and shRNA-mediated PD-L1 depletion suppresses the proliferation, invasion, and tumorigenesis of CC cells.
29855617	Cervical Carcinoma	POU5F1	Inhibit immunity	Control of PD-L1 expression by miR-140/142/340/383 and oncogenic activation of the OCT4-miR-18a pathway in cervical cancer. miR-18a overexpression in CC cells is triggered by OCT4 overexpression.
29849141	Chronic Lymphocytic Leukemia	TET2	Resistant to immunotherapy	TET2-disrupted CAR T cells exhibited an epigenetic profile consistent with altered T cell differentiation and, at the peak of expansion, displayed a central memory phenotype. Experimental knockdown of TET2 recapitulated the potency-enhancing effect of TET2 dysfunction in this patient's CAR T cells.
29845474	Triple-Negative Breast Carcinoma	SDCBP	Inhibit immunity	Syntenin1/MDA-9 (SDCBP) induces immune evasion in triple-negative breast cancer by upregulating PD-L1. Western blot and flow cytometry analyses demonstrated that syntenin1 induced CD8+ T cell apoptosis in vitro and in vivo through upregulating PD-L1.
29844122	Pancreatic Ductal Adenocarcinoma	CD40	Promote immunity	Radiotherapy and CD40 activation separately augment immunity to checkpoint blockade in cancer. The combination of an agonist αCD40 antibody, RT, and dual ICB eradicated irradiated and unirradiated (i.e. abscopal) tumors, generating long-term immunity.
29843107	Melanoma	MAP2K7	Resistant to immunotherapy	MEK inhibition may increase survival of NRAS-mutated melanoma patients treated with checkpoint blockade: Results of a retrospective multicentre analysis of 364 patients. Therapy with oral MEK inhibitors before or after checkpoint inhibitor therapy showed a trend toward a survival benefit in patients with NRAS mutant melanoma.
29805749	Esophageal Carcinoma	IDO1	Inhibit immunity	High IDO1 mRNA levels were associated with worse overall survival (OS) in both esophageal squamous cell carcinoma (SCC) (P = 0.02) and adenocarcinoma (AC) (P = 0.036). EC with high IDO1 and PD-L1 expression is significantly correlated with decreased patient survival, and may correlate with increased T-cells.
29805109	Chronic Myelogenous Leukemia, BCR-ABL1 Positive	CD4	Promote immunity	CD4 gene transduction into iPS-T cells enhanced b3a2 peptide-specific responses via b3a2 peptide-specific TCR. Thus, CD4 modification of CD40Lhigh iPS-T cells generates innate lymphoid helper-like cells inducing bcr-abl-specific TCR signaling that mediates effectiveanti-leukemic CTL responses via DC maturation, showing potential for adjuvant immunotherapy against leukemia.
29805099	Triple-Negative Breast Carcinoma	CSF3	Inhibit immunity	In two TNBC mouse models, 4T1 and Py8119, glycolysis restriction inhibits tumor granulocyte colony-stimulating factor (G-CSF) and granulocyte macrophage colony-stimulating factor (GM-CSF) expression and reduces MDSCs. These are accompanied with enhanced T cell immunity, reduced tumor growth and metastasis, and prolonged mouse survival.
29805099	Triple-Negative Breast Carcinoma	CSF2	Inhibit immunity	In two TNBC mouse models, 4T1 and Py8119, glycolysis restriction inhibits tumor granulocyte colony-stimulating factor (G-CSF) and granulocyte macrophage colony-stimulating factor (GM-CSF) expression and reduces MDSCs. These are accompanied with enhanced T cell immunity, reduced tumor growth and metastasis, and prolonged mouse survival.
29804818	Neuroblastoma	PTGES	Inhibit immunity	Inhibition of Microsomal Prostaglandin E Synthase-1 in Cancer-Associated Fibroblasts Suppresses Neuroblastoma Tumor Growth. By specifically targeting microsomal prostaglandin E synthase-1 (mPGES-1) activity with a small molecule inhibitor we could block CAF-derived PGE2 production leading to reduced tumor growth, impaired angiogenesis, inhibited CAF migration and infiltration, reduced tumor cell proliferation and a favorable shift in the M1/M2 macrophage ratio.
29802128	Sarcoma	ADORA2A	Inhibit immunity (T cell function); Resistant to immunotherapy	In studies of A2AR and/or A2BR gene-deficient mice, we found that A2AR deletion-but not A2BR deletion-liberates endogenous CD8+ T cell antitumor immunity against weakly immunogenic MCA205 sarcomas. Studies of adoptively transferred A2AR-/-, A2BR-/-, or A2AR-/-/A2BR-/- tumor-reactive T cells confirmed that immunosuppression in the tumor microenvironment was mediated by A2AR on CD8+ T cells. The blockade of the A2AR on adoptively transferred T cells by synthetic A2AR antagonist led to higher levels of IFN-γ secretion by tumor-infiltrating CD8+ T cells.
29793878	Metastatic Melanoma	TP53	Promote immunity	TP53 Mutation as Potential Negative Predictor for Response of Anti-CTLA-4 Therapy in Metastatic Melanoma. TP53 mutation was associated with significant poorer progression-free survival (HR, 2.25; 95% CI, 1.15-4.37; P = 0.014), poorer overall survival (HR, 2.05; 95% CI, 1.02-4.13; P = 0.040) and trend of poorer response (OR, 0.20; 95% CI, 0.02-1.62; P = 0.131).
29789418	Breast Carcinoma	EPHA10	Inhibit immunity	Here we show that tumor cell contact upregulates PD-L1 expression and reduces T cell-mediated cell killing through the membrane receptor tyrosine kinase ephrin receptor A10 (EphA10), which is not expressed in normal tissues except testis and is known to mediate cell contact-dependent juxtacrine signaling. Knockout of EphA10 in tumor cells increased T cell-mediated antitumor immunity in syngeneic mouse models. EphA10 expression also correlated positively with PD-L1 in human breast tumor tissues.
29789416	Pancreatic Carcinoma	GRN	Inhibit immunity (infiltration); Resistant to immunotherapy	Macrophage-derived granulin drives resistance to immune checkpoint inhibition in metastatic pancreatic cancer. In this study we find that macrophage-derived granulin contributes to cytotoxic CD8+ T cell exclusion in metastatic livers. Genetic depletion of granulin reduced the formation of a fibrotic stroma, thereby allowing T cell entry at the metastatic site. While metastatic PDAC tumors are largely resistant to anti-PD-1 therapy, blockade of PD-1 in granulin-depleted tumors restored the anti-tumor immune defense and dramatically decreased metastatic tumor burden.
29786078	Melanoma	NFE2L2	Inhibit immunity (infiltration)	Depletion of NRF2 significantly induces tumor infiltration by both CD8+ and CD4+ T cells to suppress melanoma progression, and combining NRF2 inhibition with anti-PD-1 treatment enhanced its anti-tumor function.
29774202	Large Cell Lung Carcinoma	CDKN1A	Promote immunity	Loss of the Cyclin-Dependent Kinase Inhibitor 1 in the Context of Brachyury-Mediated Phenotypic Plasticity Drives Tumor Resistance to Immune Attack. Our results demonstrate that very high levels of brachyury expression drive the loss of the cyclin-dependent kinase inhibitor 1 (p21CIP1, p21), an event that results in decreased tumor susceptibility to immune-mediated lysis.
29771768	Pancreatic Carcinoma	C10orf54	Inhibit immunity	We conclude that VISTA is predominantly expressed and up-regulated in the high-density infiltrated immune cells but minimal in human pancreatic cancerous cells. Our results for the first time highlight pancreatic immunosuppressive tumor microenvironment contributed by VISTA and its potential as a prominent target for pancreatic cancer immunotherapy.
29771197	Head and Neck Carcinoma	CTNNB1	Inhibit immunity	In addition to its effects on tumor epithelia, β-catenin activity regulates the tumor microenvironment by regulating extracellular matrix remodeling, fibrotic processes, and immune response.
29769207	Head and Neck Squamous Cell Carcinoma	SOX2	Inhibit immunity	SOX2 potentiates an immunosuppressive microenvironment and promotes HNSCC growth in vivo in an IFN-I-dependent fashion. SOX2 dampens the immunogenicity of HNSCC by targeting the STING pathway for degradation.
29764837	Lung Carcinoma	IL22	Promote immunity	We then showed that genetic ablation of Il22 in CC-LR mice (CC-LR/IL22KO mice) caused a significant reduction in tumor number and size. This was accompanied by significantly lower tumor cell proliferation, angiogenesis, and STAT3 activation. Il22 ablation was also associated with significant reduction in lung-infiltrating inflammatory cells and expression of protumor inflammatory cytokines. Thus, we conclude that IL22 promotes Kras-mutant lung tumorigenesis by driving a protumor inflammatory microenvironment with proliferative, angiogenic, and stemness contextual cues in epithelial/tumor cells.
29764444	Glioma	PTPN2	Inhibit immunity	Specifically, PTPN2 was positively associated with HCK, LCK, MHC II, and STAT1 but negatively related to IgG and interferon. Moreover, canonical correlation analysis showed a positive correlation of PTPN2 with infiltrating immune cells, such as macrophages, neutrophils, and CD8+ T cells. Clinically, higher levels of PTPN2 were associated with a worse overall survival both in patients with gliomas and glioblastomas.
29757193	Triple-Negative Breast Carcinoma	EYA3	Inhibit immunity (infiltration)	Eya3 promotes breast tumor-associated immune suppression via threonine phosphatase-mediated PD-L1 upregulation. Eya3 loss decreases tumor growth in immune-competent mice and is associated with increased numbers of infiltrated CD8+ T cells, which, when depleted, reverse the effects of Eya3 knockdown. Mechanistically, Eya3 utilizes its Thr phosphatase activity to dephosphorylate Myc at pT58, resulting in a stabilized form. We show that Myc is required for Eya3-mediated increases in PD-L1, and that rescue of PD-L1 in Eya3-knockdown cells restores tumor progression. Finally, we demonstrate that Eya3 significantly correlates with PD-L1 in human breast tumors, and that tumors expressing high levels of Eya3 have a decreased CD8+ T cell signature.
29757193	Triple-Negative Breast Carcinoma	MYC	Inhibit immunity	Mechanistically, Eya3 utilizes its Thr phosphatase activity to dephosphorylate Myc at pT58, resulting in a stabilized form. We show that Myc is required for Eya3-mediated increases in PD-L1, and that rescue of PD-L1 in Eya3-knockdown cells restores tumor progression.
29757193	Triple-Negative Breast Carcinoma	CD274	Inhibit immunity	Eya3 promotes breast tumor-associated immune suppression via threonine phosphatase-mediated PD-L1 upregulation. We show that Myc is required for Eya3-mediated increases in PD-L1, and that rescue of PD-L1 in Eya3-knockdown cells restores tumor progression.
29757192	Melanoma; Colon Adenocarcinoma; Fibrosarcoma	PVR	Inhibit immunity (T cell function); Resistant to immunotherapy	CD155 loss enhances tumor suppression via combined host and tumor-intrinsic mechanisms. Cd155-/- mice displayed reduced tumor growth and metastasis via DNAM-1 upregulation and enhanced effector function of CD8+ T and NK cells, respectively. CD155-deleted tumor cells also displayed slower tumor growth and reduced metastases, demonstrating the importance of a tumor-intrinsic role of CD155. CD155 absence on host and tumor cells exerted an even greater inhibition of tumor growth and metastasis. Blockade of PD-1 or both PD-1 and CTLA4 was more effective in settings in which CD155 was limiting, suggesting the clinical potential of cotargeting PD-L1 and CD155 function.
29755681	Glioblastoma	TLR3	Promote immunity; Essential for immunotherapy	We show that activating DCs through TLR3 agonists enhances the anti-tumor immune response to CB and increases survival in GBM. Mice treated with TLR3 agonist poly(I:C) and anti-PD-1 demonstrated increased DC activation and increased T cell proliferation in tumor draining lymph nodes.
29746927	Lung Carcinoma	IDO1	Inhibit immunity	Indoleamine 2,3-dioxygenase 1 inhibition targets anti-PD1-resistant lung tumors by blocking myeloid-derived suppressor cells. IDO1 was overexpressed in tumor-infiltrating leukocytes, and plasma Kyn levels were increased, in 344SQ_R vs. 344SQ_P. The IDO1 inhibitor INCB023843 retarded tumor growth and reduced lung metastases in 344SQ_R. IDO1 was expressed at higher levels in F4/80+Gr1intCD11b+ myeloid-derived suppressor cells (MDSCs) that were prominent in 344SQ_R. The INCB023843 reduced IDO1 expression and percentages of these MDSCs while increasing CD8+ T cells infiltration, hence reactivating antitumor T-cell responses in 344SQ_R.
29745428	Ovarian Carcinoma	WFDC2	Inhibit immunity	HE4 suppresses the expression of osteopontin in mononuclear cells and compromises their cytotoxicity against ovarian cancer cells. SKOV3 and OVCAR8, human ovarian carcinoma cell lines, exhibited enhanced proliferation in conditioned media from HE4-exposed PBMCs, an effect that was attenuated by the addition of recombinant OPN or OPN-inducible cytokines (IL-12 and IFN-γ).
29745428	Ovarian Carcinoma	SPP1	Promote immunity	SKOV3 and OVCAR8, human ovarian carcinoma cell lines, exhibited enhanced proliferation in conditioned media from HE4-exposed PBMCs, an effect that was attenuated by the addition of recombinant OPN or OPN-inducible cytokines (IL-12 and IFN-γ). In these biopsy specimens, the number of OPN+ T cells correlated positively with progression free survival (PFS) and inversely with serum HE4 level.
29739434	Gastric Carcinoma	TLR7	Promote immunity	Gastric cancer vaccines were synthesized by the covalent attachment of our TLR7 agonist with the gastric cancer antigen MG7-Ag tetra-epitope, leading to T7 - ML (linear tetra-epitope) and T7 - MB (branched tetra-epitope). In vitro, rapid TNF-α and IL-12 inductions occurred in BMDCs treated with the vaccines. In vivo, among all the vaccines tested, T7 - MB most effectively reduced EAC tumor burdens and induced CTLs, antibodies and ADCC activity in BALB/c mice.
29737430	Leukemia	IL15	Promote immunity	hIL-15-gene modified human natural killer cells (NKL-IL15) exhibit anti-human leukemia functions. We found NKL-IL15 cells displayed a significant high cytolysis activity against both human leukemia cell lines and primary leukemia cells from patients, accompanied with up-regulated expression of molecules related to NK cell cytotoxicity such as perforin, granzyme B and NKp80. Moreover, cytokines secreted by NKL-IL15 cells, including TNF-α and IFN-γ, could induce the expression of NKG2D ligands on target cells, which increased the susceptibility of leukemia cells to NK cell-mediated cytolysis.
29737375	Cutaneous Melanoma	C10orf54	Inhibit immunity	VISTA expression on tumor-infiltrating inflammatory cells in primary cutaneous melanoma correlates with poor disease-specific survival.
29735547	Osteosarcoma	CXCL12	Promote immunity (infiltration)	Here we show for the first time that osteosarcomas epigenetically downregulate CXCL12 expression via DNA methyltransferase 1 (DNMT1) and consequently acquire the ability to metastasize and impair cytotoxic T-cell homing to the tumor site. Evaluations on fresh human chemotherapy-free osteosarcoma samples also showed a positive correlation between CXCL12 concentration and the number of intratumoral lymphocytes.
29735547	Osteosarcoma	DNMT1	Inhibit immunity	Here we show for the first time that osteosarcomas epigenetically downregulate CXCL12 expression via DNA methyltransferase 1 (DNMT1) and consequently acquire the ability to metastasize and impair cytotoxic T-cell homing to the tumor site. Critically, treatment targeting DNMT1 in immunocompetent mouse models significantly elevated expression of CXCL12 in tumors, resulting in a robust immune response and consequently eradicating early lung metastases in addition to suppressing subcutaneous tumor growth.
29730384	Colorectal Carcinoma	IL10RA	Inhibit immunity	There was a positive correlation between the IL10RA expression and Ki-67 proliferation index (R = 0.63, p < 0.001) and a negative correlation between the IL10RA expression and the clinical stage of CRC (R = -0.21, p = 0.022). IL10RA correlated positively with pSTAT3 and IL10 in neoplastic tissue and tumor margin (with p < 0.01 for all correlations). The correlations between the expression of IL10RA and the proliferation index or the clinical stage of CRC seem to confirm the importance of IL10RA in the pathogenesis of CRC. The higher expression of IL10RA in healthy surgical margins than in the tumor itself may suggest that IL10RA plays a role in regulating immune response to the neoplasm.
29725336	Breast Carcinoma; Pancreatic Ductal Adenocarcinoma; Ovarian Neoplasm	ERBB2	Inhibit immunity; Immunotherapy target	Commonly, HER2 expression is associated with poor clinical outcome or chemoresistance in ovarian and breast cancer patients. Our results revealed the superiority of tribody [(HER2)2xCD16] compared to trastuzumab in triggering γδ T cell and NK cell-mediated lysis of HER2-expressing tumor cells, such as PDAC, breast cancer, and autologous primary ovarian tumors.
29721396	Breast Carcinoma; Colon Carcinoma	TGFB1	Inhibit immunity; Immunotherapy target	Secretion of TGFβ and upregulation of immune checkpoint programmed cell death ligand-1 (PD-L1) are two main contributors to immune evasion and tumor progression. Here, we examined the efficacy of a first-in-class bifunctional checkpoint inhibitor, the fusion protein M7824, comprising the extracellular domain of human TGFβRII (TGFβ Trap) linked to the C-terminus of human anti-PD-L1 heavy chain (αPD-L1). We demonstrate that M7824 reduces plasma TGFβ1, binds to PD-L1 in the tumor, and decreases TGFβ-induced signaling in the tumor microenvironment in mice. These findings demonstrate the value of using M7824 to simultaneously target TGFβ and PD-L1/PD-1 immunosuppressive pathways to promote anti-tumor responses and efficacy.
29721396	Breast Carcinoma; Colon Carcinoma	CD274	Inhibit immunity; Immunotherapy target	Secretion of TGFβ and upregulation of immune checkpoint programmed cell death ligand-1 (PD-L1) are two main contributors to immune evasion and tumor progression. Here, we examined the efficacy of a first-in-class bifunctional checkpoint inhibitor, the fusion protein M7824, comprising the extracellular domain of human TGFβRII (TGFβ Trap) linked to the C-terminus of human anti-PD-L1 heavy chain (αPD-L1). We demonstrate that M7824 reduces plasma TGFβ1, binds to PD-L1 in the tumor, and decreases TGFβ-induced signaling in the tumor microenvironment in mice. These findings demonstrate the value of using M7824 to simultaneously target TGFβ and PD-L1/PD-1 immunosuppressive pathways to promote anti-tumor responses and efficacy.
29721393	Glioblastoma	IGFBP2	Inhibit immunity; Candidate for immunotherapy target	We further selected specific immunologic related gene sets and found IGFBP2 predominated immunosuppressive activities in GBM. We discovered that IGFBP2 was correlated with CHI3L1, TNFRSF1A, LGALS1, TIMP1, VEGFA, ANXA1 and LGALS3, which were classic immunosuppressive biomarkers. Higher IGFBP2 expression predicted unfavorable survival for patients with GBM. IGFBP2 is a potential immunotherapeutic target for GBM in future clinical trials.
29721392	Hepatocellular Carcinoma	TLR3	Promote immunity	In consistent with previous reports, we found that poly (I:C) triggering of TLR3 inhibited cell proliferation and induced apoptosis in HCC cells.
29721392	Hepatocellular Carcinoma	TBK1	Resistant to immunotherapy	Inhibitor for TBK1 but not NF-κB suppressed poly (I:C)-inspired migration and invasion, which was further supported by using TBK1 deficient (Tbk1-/- ) cells. Our data suggest that bufalin can suppress the metastasis of HCC cells in poly (I:C) therapy by impairing TBK1 activation, indicating that bufalin may be used in combination with poly (I:C) therapy in HCC treatment for the sake of reversing poly (I:C)-triggered metastasis of HCC cells.
29721382	Lung Carcinoma	CLEC2D	Promote immunity	Expression of LLT1 and its receptor CD161 in lung cancer is associated with better clinical outcome. We show that LLT1 expression is restricted to germinal center (GC) B cells within tertiary lymphoid structures (TLS), representing a new hallmark of the presence of active TLS in the tumor microenvironment. Finally, a meta-analysis revealed a positive association of CLEC2D (coding for LLT1) and KLRB1 (coding for CD161) gene expression with favorable outcome in NSCLC, independently of the size of T and B cell infiltrates.
29721382	Lung Carcinoma	KLRB1	Promote immunity (T cell function)	Expression of LLT1 and its receptor CD161 in lung cancer is associated with better clinical outcome. CD161+ CD4+ T cells are more activated and produce Th1-cytokines at a higher frequency than their matched CD161-negative counterparts. Interestingly, CD161+ CD4+ T cells highly express OX40 co-stimulatory receptor, less frequently 4-1BB, and display an activated but not completely exhausted PD-1-positive Tim-3-negative phenotype. Finally, a meta-analysis revealed a positive association of CLEC2D (coding for LLT1) and KLRB1 (coding for CD161) gene expression with favorable outcome in NSCLC, independently of the size of T and B cell infiltrates.
29721376	Non-Small Cell Lung Carcinoma	VIM	Inhibit immunity	Moreover PD-L1 is overexpressed in VIMENTIN positive NSCLC tissues.
29721376	Non-Small Cell Lung Carcinoma	TGFB1	Inhibit immunity	We also demonstrated that the expression of PD-L1 required both TNFα and TGFβ1. Indeed, TGFβ1 decreased DNMT1 content and that resulted in PD-L1 promoter demethylation whereas TNFα induced the NF-κB pathway that promoted expression of demethylated PD-L1 promoter.
29721376	Non-Small Cell Lung Carcinoma	TNF	Inhibit immunity	We also demonstrated that the expression of PD-L1 required both TNFα and TGFβ1. Indeed, TGFβ1 decreased DNMT1 content and that resulted in PD-L1 promoter demethylation whereas TNFα induced the NF-κB pathway that promoted expression of demethylated PD-L1 promoter.
29721374	Traditional Serrated Adenoma	PPARG	Promote immunity	PPARγ-activation increases intestinal M1 macrophages and mitigates formation of serrated adenomas in mutant KRAS mice. Treatment of mutant KRASG12V mice with the PPARγ-agonist rosiglitazone augmented M1 macrophage numbers, reduced IL4 expression and diminished polyp load in mice. Rosiglitazone also promoted M1 polarisation of human THP1-derived macrophages and decreased Il4 mRNA in isolated murine lymphocytes.
29721366	Melanoma	TNF	Promote immunity; Essential for immunotherapy	TNFa and IL-2 armed adenoviruses enable complete responses by anti-PD-1 checkpoint blockade. Viral expression of IL2 and TNFa altered the cytokine balance in the tumor microenvironment towards Th1 and increased the intratumoral proportion of CD8+ and conventional CD4+ T cells.
29721366	Melanoma	IL2	Promote immunity; Essential for immunotherapy	TNFa and IL-2 armed adenoviruses enable complete responses by anti-PD-1 checkpoint blockade. Viral expression of IL2 and TNFa altered the cytokine balance in the tumor microenvironment towards Th1 and increased the intratumoral proportion of CD8+ and conventional CD4+ T cells.
29721192	Medulloblastoma	CD274	Inhibit immunity	MB expresses low levels of PD-L1 facilitating immune escape.
29721190	Breast Carcinoma	CD200	Promote immunity	CD200fc enhances anti-tumoral immune response and inhibits visceral metastasis of breast carcinoma. Tumor infiltrating Gr1+Cd11b+ cells were decreased while CD8+ cells were increased in CD200fc-treated animals. CD200fc injection enhanced the tumor-induced IFN-g response while suppressing the IL-10 response.We observed excessive basal IL-6 secretion in MLC which was significantly decreased in CD200fc treated mice 12 days after injection of 4TM cells.
29721178	Metastatic Melanoma	NAMPT	Inhibit immunity; Resistant to immunotherapy	Furthermore, cells that become resistant to BRAF inhibitors (BiR) show a significant increase of eNAMPT levels. Lastly, high eNAMPT levels correlate with a significantly shorter overall survival. Our findings suggest that eNAMPT is a novel marker of tumor burden and response to therapy in patients with metastatic melanoma carrying BRAF mutations.
29719533	Breast Carcinoma	IDO1	Inhibit immunity	Concentrating on IDO and MVD, the patients with IDO expression or high MVD level had poorer prognosis compared with no IDO expression [P = 0.047 for progress-free survival (PFS)] and low MVD level (P = 0.019 for OS); the patients with IDO expression and high MVD level had a tendency with shorter overall survival when compared with non IDO expression, low MVD level, or both (P = 0.062 for OS). MCF-7 cells, which produce high level of IDO and metabolize tryptophan, promoted human umbilical vein endothelial cells (HUVEC) proliferation significantly in co-culture system. These results suggest that IDO could promote angiogenesis in breast cancer, providing a novel, potentially effective molecular or gene therapy target for angiogenesis inhibition in the future.
29713085	Chronic Lymphocytic Leukemia	IL6	Essential for immunotherapy	Transcriptomic profiling revealed that CAR T cells from complete-responding patients with CLL were enriched in memory-related genes, including IL-6/STAT3 signatures, whereas T cells from nonresponders upregulated programs involved in effector differentiation, glycolysis, exhaustion and apoptosis. IL-6/STAT3 blockade diminished CAR T cell proliferation.
29712773	Chronic Lymphocytic Leukemia	IL10	Inhibit immunity	In IL-10R-/- mice, wherein the host immune cells are unresponsive to IL-10-mediated suppressive effects, there was a significant reduction in CLL cell growth compared with wild type mice. IL-10 reduced the generation of effector CD4 and CD8 T cells.
29712685	Head and Neck Carcinoma	HAVCR2	Inhibit immunity	Novel effector phenotype of Tim-3+ regulatory T cells leads to enhanced suppressive function in head and neck cancer patients. Tim-3+ Treg from human HNSCC TIL also displayed an effector-like phenotype, with more robust expression of CTLA-4, PD-1, CD39 and IFN-γ receptor. Tim-3+ Treg are functionally and phenotypically distinct in HNSCC TIL, and are highly effective at inhibiting T cell proliferation despite high PD-1 expression.
29708510	Melanoma	PROS1	Inhibit immunity	Tumor-secreted Pros1 inhibits macrophage M1 polarization to reduce antitumor immune response. We demonstrate that tumor-secreted protein S (Pros1), a Mer/Tyro3 ligand, decreased macrophage M1 cytokine expression in vitro and in vivo. Mice bearing Pros1-deficient tumors showed increased innate and adaptive immune infiltration, as well as increased median survival.
29708510	Melanoma	TYRO3	Inhibit immunity	Tyro3, Axl, Mer (TAM) receptor tyrosine kinases reduce inflammatory, innate immune responses. We demonstrate that tumor-secreted protein S (Pros1), a Mer/Tyro3 ligand, decreased macrophage M1 cytokine expression in vitro and in vivo. Tumor cell-associated Pros1 action was abrogated in macrophages from Mer- and Tyro3- but not Axl-KO mice.
29708510	Melanoma	MERTK	Inhibit immunity	Tyro3, Axl, Mer (TAM) receptor tyrosine kinases reduce inflammatory, innate immune responses. We demonstrate that tumor-secreted protein S (Pros1), a Mer/Tyro3 ligand, decreased macrophage M1 cytokine expression in vitro and in vivo. Tumor cell-associated Pros1 action was abrogated in macrophages from Mer- and Tyro3- but not Axl-KO mice.
29708510	Melanoma	PTPN1	Inhibit immunity	Investigation of the suppressive pathway demonstrated a role for PTP1b complexing with Mer. Substantiating the role of PTP1b, M1 cytokine suppression was also lost in macrophages from PTP1b-KO mice.
29704427	Breast Carcinoma	PLAC1	Inhibit immunity	Cancer/testis Antigen-Plac1 Promotes Invasion and Metastasis of Breast Cancer through Furin/NICD/PTEN Signaling Pathway. Overexpression of Plac1 promoted invasion and metastasis of breast cancer cells in vitro and in vivo. Co-immunoprecipitation and immunofluorescence cell staining assays revealed that interaction of Plac1 and Furin degraded Notch1 and generated Notch1 intracellular domain (NICD) that could inhibit PTEN activity.
29704427	Breast Carcinoma	FURIN	Inhibit immunity	Co-immunoprecipitation and immunofluorescence cell staining assays revealed that interaction of Plac1 and Furin degraded Notch1 and generated Notch1 intracellular domain (NICD) that could inhibit PTEN activity. A rescue study showed that inhibition of Furin and overexpression of PTEN in Plac1 overexpression cells blocked Plac1-induced tumor cell progression.
29704427	Breast Carcinoma	PTEN	Promote immunity	Co-immunoprecipitation and immunofluorescence cell staining assays revealed that interaction of Plac1 and Furin degraded Notch1 and generated Notch1 intracellular domain (NICD) that could inhibit PTEN activity. A rescue study showed that inhibition of Furin and overexpression of PTEN in Plac1 overexpression cells blocked Plac1-induced tumor cell progression.
29702007	Breast Carcinoma	STAT1	Inhibit immunity	Dual inhibition of STAT1 and STAT3 activation downregulates expression of PD-L1 in human breast cancer cells. We found that individual inhibition of STAT1 and STAT3 activation partially downregulated PD-L1, while combined inhibition completely downregulated PD-L1 expression.
29702007	Breast Carcinoma	STAT3	Inhibit immunity	Dual inhibition of STAT1 and STAT3 activation downregulates expression of PD-L1 in human breast cancer cells. We found that individual inhibition of STAT1 and STAT3 activation partially downregulated PD-L1, while combined inhibition completely downregulated PD-L1 expression.
29699516	Lung Carcinoma	HLA-E	Promote immunity	Reduction of MHC-I expression limits T-lymphocyte-mediated killing of Cancer-initiating cells. Following treatment with IFN-γ, both CIC enriched and non-enriched TC-1 cells expressed similar levels of MHC-I, and the increased MHC-I expression on CICs resulted in greater CTL-mediated tumor lysis and improved tumor-free survival in mice. These results suggest that the attenuated expression of MHC-I molecules by CICs represents a potential strategy of CICs to escape immune recognition, and that the development of successful immunotherapy strategies targeting CICs may decrease their resistance to T cell-mediated immune detection by enhancing CIC MHC-I expression.
29692776	Acute Myeloid Leukemia	IL15	Promote immunity	Interleukin-15-Cultured Dendritic Cells Enhance Anti-Tumor Gamma Delta T Cell Functions through IL-15 Secretion. IL-15 DCs of healthy donors and of AML patients in remission induce the upregulation of cytotoxicity-associated and co-stimulatory molecules on the γδ T cell surface, but not of co-inhibitory molecules, incite γδ T cell proliferation and stimulate their interferon-γ production in the presence of blood cancer cells and phosphoantigens. Moreover, the innate cytotoxic capacity of γδ T cells is significantly enhanced upon interaction with IL-15 DCs, both towards leukemic cell lines and allogeneic primary AML blasts.
29691234	Plasma Cell Myeloma	IL15	Promote immunity	The increased IL15 was accompanied by enhanced expression of the IL15/IL15RA complex on the membrane of senescent myeloma cells, allowing the functional trans-presentation of this cytokine to neighboring NK cells, which consequently underwent activation and proliferation. We demonstrated that MM cell-derived exosomes, the release of which was augmented by melphalan (MEL) treatment in senescent cells, also expressed IL15RA and IL15, and their interaction with NK cells in the presence of exogenous IL15 resulted in increased proliferation.
29689621	Breast Carcinoma	SALL2	Promote immunity	Compared to Sall2+/+ MEFs, Sall2-/- MEFs exhibit enhanced cell proliferation and faster postmitotic progression through G1 and S phases. In addition, the analysis of tissues from Sall2+/+ and Sall2-/- mice confirmed the inverse correlation between expression of SALL2 and G1-S cyclins. Consistent with an antiproliferative function of SALL2, immortalized Sall2-/- MEFs showed enhanced growth rate, foci formation, and anchorage-independent growth, confirming tumor suppressor properties for SALL2.
19008445	Fibrosarcoma	BATF3	Promote immunity	Batf3 deficiency reveals a critical role for CD8alpha+ dendritic cells in cytotoxic T cell immunity. Importantly, rejection of highly immunogenic syngeneic tumors was impaired in Batf3-/- mice.
19001145	Melanoma	CD28	Promote immunity	CD28 provides positive modulatory signals in the early stages of an immune response, while CTLA-4 signaling inhibits T-cell activation, particularly during strong T-cell responses.
19001145	Melanoma	CTLA4	Inhibit immunity (T cell function); Immunotherapy target	CD28 provides positive modulatory signals in the early stages of an immune response, while CTLA-4 signaling inhibits T-cell activation, particularly during strong T-cell responses. CTLA-4 blockade using anti-CTLA-4 monoclonal antibody therapy has great appeal because suppression of inhibitory signals results in the generation of an antitumor T-cell response. Both clinical and preclinical data indicate that CTLA-4 blockade results in direct activation of CD4+ and CD8+ effector cells, and anti-CTLA-4 monoclonal antibody therapy has shown promise in a number of cancers, particularly melanoma.
19005181	Nasopharyngeal Carcinoma	LGALS9	Inhibit immunity	Our previous in vitro studies have shown that NPC cells release exosomes containing high amounts of galectin-9, a ligand of the membrane receptor Tim-3, which is able to induce apoptosis in mature Th1 lymphocytes. Importantly, NPC exosomes induce massive apoptosis in EBV-specific CD4(+) cells used as a model of target T cells. This effect is inhibited by both anti-Tim-3 and antigalectin-9 blocking antibodies. These results indicate that blocking galectin-9/Tim-3 interaction in vivo might alleviate the Th1-suppressive effect of NPC exosomes and sustain antitumoral T-cell responses and thereby improve clinical efficacy of immunotherapeutic approaches against NPC.
18995891	Ovarian Carcinoma	IFNA2	Promote immunity	IFNalpha-2b showed an inhibitory effect on OC cell proliferation. IFNalpha-2b had a synergistic effect with IL-2 and PBMC increasing the cytotoxicity by an average of 20%.
18981089	Glioma	TLR9	Essential for immunotherapy	Remarkably, CpG-oligonucleotides (CpG-ODN, TLR9) appeared to inhibit GL261 cell proliferation in a cell-type specific, but CpG-motif and TLR9-independent manner. Additional studies using TLR9(+/+) wild-type and TLR9(-/-) knockout mice revealed that the efficacy of local CpG-ODN treatment in vivo required TLR9 expression on nontumor cells.
18980986	Renal Cell Carcinoma	EGLN3	Promote immunity	HIFPH3 was overexpressed in many RCC cell lines and primary RCC tissues, whereas it was not detectable in normal adult tissues by reverse transcription-PCR. Furthermore, HIFPH3-8 peptide-specific CTLs showed cytotoxicity against HIFPH3(+) RCC cell lines in a HLA-A24-restricted manner. HIFPH3 may be a target antigen in immunotherapy for RCC and HIFPH3-8 peptide could be used as a peptide vaccine for HLA-A*2402(+)/HIFPH3(+) RCC patients.
18980984	Plasma Cell Myeloma	TNFRSF9	Inhibit immunity; Immunotherapy target	Anti-CD137 mAbs induced complete eradications of established s.c. NS0-derived tumors that were dependent on IFN-gamma, natural killer cells, and CD8(+) T lymphocytes. Natural killer cells accumulated in tumor draining lymph nodes and showed increased IFN-gamma production.
18974390	Colorectal Carcinoma	UBXN11	Promote immunity	Colon antigen-1 (COA-1) was recently identified as a novel antigen of colorectal cancer encoded by the UBXD5 gene. COA-1-specific T cells could also be isolated by in vitro stimulation of peripheral blood mononuclear cells with autologous dendritic cells loaded with tumor lysate, suggesting that this antigen can generate a dominant immunologic response against colorectal cancer cells. Notably, we could identify also COA-1-derived epitopes binding to HLA-A*0201 molecules that elicited antigen- and tumor-specific CD8+ T-cell-mediated responses in colorectal cancer patients.
18974151	Breast Carcinoma	SPARC	Inhibit immunity	Gene expression profiles associate SPARC to malignant progression. Using reciprocal bone marrow chimeras between SPARC knockout and wild-type mice, we show that SPARC produced by inflammatory cells is necessary for spontaneous, but not experimental, i.v. metastasis. Macrophage-derived SPARC induces cancer cell migration and enhances their migration to other ECM proteins at least through alpha(v)beta(5) integrin.
18974133	Melanoma	MFGE8	Inhibit immunity	Milk fat globule EGF-8 promotes melanoma progression through coordinated Akt and twist signaling in the tumor microenvironment. In human melanoma cells, MFG-E8 knockdown attenuated Akt and Twist signaling and thereby compromised tumor cell survival, EMT, and invasive ability. MFG-E8-deficient human melanoma cells also showed increased sensitivity to small molecule inhibitors of insulin-like growth factor I receptor and c-Met.
18974110	Fibrosarcoma	IL4	Inhibit immunity	Endogenous interleukin-4 promotes tumor development by increasing tumor cell resistance to apoptosis. Nonetheless, IL-4 up-regulates antiapoptotic gene expression in tumor cells and reduces apoptosis of tumor cells in vivo, as evidenced by real-time PCR, immunoblotting, and TUNEL staining.
18971421	Nasopharyngeal Carcinoma	PTPRC	Inhibit immunity; Resistant to immunotherapy	Eight patients with recurrent NPC received CD45 mAbs followed by escalating doses of autologous EBV-specific CTL. Infusion of CD45 mAbs resulted in transient lymphopenia in all patients and an increase in interleukin-15 (IL-15) levels in 6 out 8 patients. All patients had an increase in their peripheral blood frequency of EBV-specific T cells after CTL infusion.
18958887	Melanoma	IL4	Inhibit immunity (infiltration)	IL-4 inhibits VLA-4 expression on Tc1 cells resulting in poor tumor infiltration and reduced therapy benefit. We now show that IL-4 treatment of committed Tc1 cells promotes the selective loss in the expression of very-late antigen (VLA)-4, without impacting the Tc1 cytokine production profile, cytotoxic activity, or expression of alternate cell surface markers. Tc1IL-4 (but not Tc1 control) cells adhere poorly to plate-bound VCAM-1-Fc fusion protein and fail to be co-stimulated by VCAM-1 in vitro. They were also markedly impaired in their ability to traffic into intracranial melanoma lesions after adoptive transfer, yielding inferior therapeutic benefit to tumor-bearing mice.
18952840	Skin Papilloma	IDO1	Inhibit immunity	The induced IDO-mediated inhibitory activity in this subset of pDCs was potent, dominantly suppressing the T cell stimulatory activity of other DCs that comprise the major fraction of dLN DCs. Consistent with the hypothesis that T cell suppressive, IDO(+) pDCs elicited by PMA exposure create local immune privilege that favors tumor development, IDO-deficient mice exhibited a robust tumor-resistant phenotype in the standard DMBA/PMA 2-stage carcinogenesis model of skin papilloma formation.
18922917	Lymphoma; Melanoma	IFNG	Promote immunity (infiltration)	Natural killer cell accumulation in tumors is dependent on IFN-gamma and CXCR3 ligands. Exogenous application of IFN-gamma in the tumor augmented levels of ligands of the chemokine receptor CXCR3, increased NK cell accumulation, and prolonged survival. Our results identify IFN-gamma and the expression of CXCR3 on NK cells as prerequisites for NK cell infiltration into tumors.
18922917	Lymphoma; Melanoma	CXCR3	Promote immunity (infiltration)	Accordingly, significantly lower numbers of tumor-infiltrating NK cells were detected in CXCR3(-/-) mice, and the capacity of adoptively transferred CXCR3(-/-) NK cells to accumulate in the tumor was severely impaired. Our results identify IFN-gamma and the expression of CXCR3 on NK cells as prerequisites for NK cell infiltration into tumors.
18922917	Lymphoma; Melanoma	CXCL10	Promote immunity (infiltration)	Natural killer cell accumulation in tumors is dependent on IFN-gamma and CXCR3 ligands. Finally, exogenous application of the CXCR3 ligand CXCL10 in the tumor or ectopic expression of CXCL10 by tumor cells increased the numbers of NK cells in the tumors and prolonged NK cell-dependent survival.
18922895	Renal Cell Carcinoma	SPAG9	Inhibit immunity	Sperm-associated antigen 9 is associated with tumor growth, migration, and invasion in renal cell carcinoma. Consistent with the clinical findings, knockdown of SPAG9 expression in RCC cells with specific siRNA significantly reduced cell growth and colony formation. In conclusion, SPAG9 expression is associated with clinicopathologic features of tumors, suggesting that SPAG9 could contribute to the early spread of cancer.
18850006	Breast Carcinoma; Prostate Carcinoma	CD274	Inhibit immunity	B7-H1-mediated immunoresistance can be attenuated by inhibitors of the PI(3) kinase pathway, and is dependent on S6K1-mediated translational regulation of B7-H1 protein. Breast and prostate carcinoma cells with activated PI(3) kinase lose the immunoresistant phenotype after treatment with B7-H1 siRNA. Conversely, breast and prostate carcinoma cells with minimal PI(3) kinase activation adopt an immunoresistant phenotype when engineered to overexpress B7-H1 protein.
18830416	Colon Carcinoma	TNFSF10	Promote immunity	CD4+CD25+ Tregs control the TRAIL-dependent cytotoxicity of tumor-infiltrating DCs in rodent models of colon cancer. Here we have shown, in 2 rodent models of colon cancer, that CD4(+)CD25(+) Tregs inhibit the ability of CD11b(+) TIDCs to mediate TNF-related apoptosis-inducing ligand-induced (TRAIL-induced) tumor cell death.
18829567	Prostate Carcinoma; Melanoma	HDAC9	Promote immunity	Presentation of telomerase reverse transcriptase, a self-tumor antigen, is down-regulated by histone deacetylase inhibition. We found that HDAC inhibition with trichostatin A wa s associated with a decreased presentation and diminished killing of tumor cells by CTLs. Using gene array analysis, we found that HDAC inhibition resulted in a decrease of genes coding for proteasome catalytic proteins and for tapasin, an endoplasmic reticulum resident protein involved in the MHC class I pathway of endogenous antigen presentation.
18829562	Rhabdomyosarcoma	IGF1R	Inhibit immunity; Immunotherapy target	Addiction to elevated insulin-like growth factor I receptor and initial modulation of the AKT pathway define the responsiveness of rhabdomyosarcoma to the targeting antibody. Insulin-like growth factor I receptor (IGF-IR) and its ligands are overexpressed by tumors, mediating proliferation and protecting against stress-induced apoptosis.
18829539	Medulloblastoma	SHH	Inhibit immunity	Hepatocyte growth factor and sonic Hedgehog expression in cerebellar neural progenitor cells costimulate medulloblastoma initiation and growth. In genetically engineered mice, activation of Sonic Hedgehog (Shh) signaling in neural stem cells in the developing cerebellum induces medulloblastomas.
18829539	Medulloblastoma	HGF	Inhibit immunity	Hepatocyte growth factor and sonic Hedgehog expression in cerebellar neural progenitor cells costimulate medulloblastoma initiation and growth. HGF is neuroprotective for cerebellar granule cells and promotes growth of human medulloblastoma cells in culture and in murine xenografts. Systemic administration of a monoclonal antibody against HGF prolonged survival of mice bearing Shh + HGF-induced medulloblastomas by stimulating apoptosis.
18829492	Metastatic Malignant Neoplasm in the Lung	IL18	Inhibit immunity; Immunotherapy target	Interleukin (IL)-18 plays important roles in cancer progression and metastasis. IL-18bp-Fc had high and specific accumulation in the fLuc-4T1 lung metastasis tumor as evidenced by both PET and biodistribution studies. IL-18bp-Fc therapy can inhibit 4T1 breast cancer experimental lung metastasis.
18820666	Breast Carcinoma	FOXP3	Inhibit immunity	Higher average numbers of FoxP3-positive cells present significantly correlated with higher Nottingham grade status (P=0.000229). Higher average numbers of FoxP3-positive cells were also significantly associated with larger tumor size (>2.0 cm; P=0.012824) and trended toward an association with estrogen receptor negativity.
18820130	Leukemia	AURKA	Immunotherapy target	Aurora-A kinase: a novel target of cellular immunotherapy for leukemia. Aur-A-specific CTLs were able to lyse human leukemia cell lines and freshly isolated leukemia cells, but not normal cells, in an HLA-A*0201-restricted manner.
18802069	Breast Carcinoma	S100A8	Inhibit immunity	S100A8/A9 proteins bind to carboxylated N-glycans expressed on the receptor for advanced glycation end-products and other cell surface glycoprotein receptors on MDSC, signal through the NF-kappaB pathway, and promote MDSC migration.
18794336	Squamous Cell Carcinoma	SELE	Promote immunity	Human squamous cell carcinomas evade the immune response by down-regulation of vascular E-selectin and recruitment of regulatory T cells. We found that blood vessels in SCCs did not express E-selectin, and tumors contained few cutaneous lymphocyte antigen (CLA)(+) T cells, the cell type thought to provide cutaneous immunosurveillance.
18794336	Squamous Cell Carcinoma	TLR7	Promote immunity	Tumors treated with the Toll-like receptor (TLR)7 agonist imiquimod before excision showed induction of E-selectin on tumor vessels, recruitment of CLA(+) CD8(+) T cells, and histological evidence of tumor regression. Treatment of T reg cells in vitro with imiquimod inhibited their suppressive activity and reduced FOXP3, CD39, CD73, IL-10, and TGF-beta by indirect mechanisms.
18770863	Squamous Cell Carcinoma	IFNA1	Promote immunity	The expression of IFN-regulated genes correlated with the extent of the lesional immune-cell infiltrate. Immunohistological examinations confirmed the expression of IFN-regulated genes in association with a CXCR3+ cytotoxic inflammatory infiltrate on the protein level. Collectively, our findings support the concept that IFN-associated host responses play an important role in tumor immunosurveillance in the skin.
18768900	Brain Neoplasm	IFNG	Promote immunity	Finally, we show that production of IFN-gamma, but not perforin or TNF-alpha, by the donor lymphocytes is critical for control of autochthonous brain tumors.
18760855	Colon Carcinoma	CD1D	Promote immunity	Surgical subcutaneous tumor mass reduction resulted in the reduction of serum TGF-beta, the recovery of CD1d expressions on liver DCs and the improvement of antitumor effect of alpha-GalCer against metastatic liver tumor. These results suggested that tumor burden reduces CD1d expressions on liver DCs, thus impeding alpha-GalCer-mediated NK cell activation and antitumor activity in the liver.
18759930	Thymoma	CBLB	Inhibit immunity (T cell function)	Inactivation of Cbl-b also renders mice resistant to both transplanted and spontaneous tumors due to an enhanced anti-tumor immunity of CD8(+) T cells.
18757439	Melanoma; Colon Carcinoma	LGALS3	Inhibit immunity	T-cell activation induced by Gal-3 resulted in T-cell apoptosis. We showed that a high level of expression of Gal-3 promoted tumor growth in vitro and in vivo. Using a mouse tumor model, we showed that delivery of high doses of Gal-3 inhibited tumor-reactive T cells and promoted tumor growth in mice receiving tumor-reactive CD8(+) T cells.
18757430	Gastric Carcinoma	LRRC3B	Promote immunity	LRRC3B, encoding a leucine-rich repeat-containing protein, is a putative tumor suppressor gene in gastric cancer. Pyrosequencing analysis of the promoter region revealed that LRRC3B was significantly hypermethylated in gastric tumors. Stable transfection of LRRC3B in SNU-601 cells, a gastric cancer cell line, inhibited anchorage-dependent and anchorage-independent colony formation, and LRRC3B expression suppressed tumorigenesis in nude mice. Microarray analysis of LRRC3B-expressing xenograft tumors showed induction of immune response-related genes and IFN signaling genes. We suggest that LRRC3B is a putative tumor suppressor gene that is silenced in gastric cancers by epigenetic mechanisms and that LRRC3B silencing in cancer may play an important role in tumor escape from immune surveillance.
18713982	Pancreatic Adenocarcinoma	MUC1	Inhibit immunity	MUC1 enhances tumor progression and contributes toward immunosuppression in a mouse model of spontaneous pancreatic adenocarcinoma. MUC1, a membrane tethered mucin glycoprotein, is overexpressed and aberrantly glycosylated in >80% of human ductal pancreatic adenocarcinoma. Data shows that during pancreatic cancer progression, MUC1-mediated mechanisms enhance the onset and progression of the disease, which in turn regulate the immune responses.
18713980	Breast Carcinoma	CXCL16	Promote immunity (infiltration)	Radiation-induced CXCL16 release by breast cancer cells attracts effector T cells. CXCR6-deficient mice showed reduced infiltration of tumors by activated CD8 T cells and impaired tumor regression following treatment with local IR to the tumor and Abs blocking the negative regulator of T cell activation, CTLA-4.
18713947	B Acute Lymphoblastic Leukemia	IRF4	Promote immunity	IRF-4 functions as a tumor suppressor in early B-cell development. We further found that IRF-4 deficiency enhances BCR/ABL transformation of B-lymphoid progenitors in vitro and accelerates disease progression of BCR/ABL-induced acute B-lymphoblastic leukemia (B-ALL) in mice, whereas forced expression of IRF-4 potently suppresses BCR/ABL transformation of B-lymphoid progenitors in vitro and BCR/ABL-induced B-ALL in vivo. Further analysis showed that IRF-4 inhibits growth of BCR/ABL+ B lymphoblasts primarily through negative regulation of cell-cycle progression.
18708628	Chronic Lymphocytic Leukemia	FCMR	Promote immunity	Overexpression of TOSO in CLL is triggered by B-cell receptor signaling and associated with progressive disease. High levels of TOSO expression in CLL correlated with high leukocyte count, advanced Binet stage, previous need for chemotherapy, and unmutated IgV(H) status. In summary, we show that the antiapoptotic factor TOSO is associated with progressive disease and enhanced in the proliferative CD38(+) CLL subset.
17675511	Lymphoma	TLR9	Essential for immunotherapy	Lymphoma immunotherapy with CpG oligodeoxynucleotides requires TLR9 either in the host or in the tumor itself. These results indicate that activation of Ag presentation by cells within the tumor via TLR9 stimulation can be an effective form of immunotherapy.
17675472	Melanoma	IFNB1	Promote immunity	IFN-beta (but neither IFN-alpha nor IFN-gamma) augmented both protein and mRNA expression of melanocytic TAA in 15 melanoma lines (irrespective of initial Ag-expression levels). Treatment of low Ag melanoma lines with IFN-beta increased expression of melanocyte-lineage Ags, inducing susceptibility to lysis by specific CTLs. Treatment with IFN-beta also enhances expression of class I HLA molecules, thereby inducing both nominal TAA and the presenting HLA molecule. Data from fluorescent cellular reporter systems demonstrated that IFN-beta triggers promoter activation, resulting in augmentation of Ag expression.
17675324	Pancreatic Adenocarcinoma	CD40LG	Promote immunity	Transfection with CD40L induces tumour suppression by dendritic cell activation in an orthotopic mouse model of pancreatic adenocarcinoma. Using intravital microscopy it was possible to show a significant induction of leukocytes sticking to the tumour endothelium after CD40L treatment. Adoptive cell transfer experiments have revealed that tumour-derived dendritic cells and CD8 cells from CD40L-treated donor mice either harbour anti-tumour activity or induce it in the recipients.
17671219	Ovarian Carcinoma	IL2	Inhibit immunity	We show that administration of IL-2 induces the proliferation of existent Treg cells in patients with ovarian cancer. Furthermore, IL-2 treatment stimulates chemokine receptor CXCR4 expression on Treg cells, enables Treg cell migration toward chemokine CXCL12 in the tumor microenvironment, and may enforce Treg cell tumor accumulation.
17671212	Ovarian Carcinoma	CD55	Resistant to immunotherapy	Combined yeast {beta}-glucan and antitumor monoclonal antibody therapy requires C5a-mediated neutrophil chemotaxis via regulation of decay-accelerating factor CD55. Blockade of CD55 in vitro led to enhanced deposition of C activation product C3b and increased cytotoxicity mediated by beta-glucan-primed neutrophils. We conclude that CD55 suppresses tumor killing by antitumor mAb plus beta-glucan therapy (and, perhaps, in other circumstances).
17671159	Non-Small Cell Lung Carcinoma	MUC1	Immunotherapy target	L-BLP25 is a peptide vaccine strategy that targets the exposed core peptide of MUC1. In preclinical studies, L-BLP25 induced a cellular immune response characterized by T-cell proliferation in response to MUC1 and production of IFN-gamma.
17670934	Hodgkin Lymphoma	LGALS1	Inhibit immunity	The AP1-dependent secretion of galectin-1 by Reed Sternberg cells fosters immune privilege in classical Hodgkin lymphoma. In cocultures of activated T cells and Hodgkin cell lines, RNAi-mediated blockade of RS cell Gal1 increased T cell viability and restored the Th1/Th2 balance. In contrast, Gal1 treatment of activated T cells favored the secretion of Th2 cytokines and the expansion of CD4+CD25high FOXP3+ Treg cells. These data directly implicate RS cell Gal1 in the development and maintenance of an immunosuppressive Th2/Treg-skewed microenvironment in cHL and provide the molecular basis for selective Gal1 expression in RS cells.
17644739	Hodgkin Lymphoma	TGFB1	Inhibit immunity	RNA fingerprints provide direct evidence for the inhibitory role of TGFbeta and PD-1 on CD4+ T cells in Hodgkin lymphoma. Applying these specific fingerprints, we directly demonstrate that CD4+ T cells in HL--but not in follicular lymphoma (FL)--are under the inhibitory influence of both TGFbeta and PD-1 in vivo.
17644739	Hodgkin Lymphoma	PDCD1	Inhibit immunity	RNA fingerprints provide direct evidence for the inhibitory role of TGFbeta and PD-1 on CD4+ T cells in Hodgkin lymphoma. Applying these specific fingerprints, we directly demonstrate that CD4+ T cells in HL--but not in follicular lymphoma (FL)--are under the inhibitory influence of both TGFbeta and PD-1 in vivo.
17638917	Lymphoma	CD40LG	Promote immunity	Some tumor cells in the injected sites expressed the CD40L transgene and had increased expression of the CD80 and CD86 costimulatory molecules.
17621629	Colon Carcinoma	CCL17	Promote immunity (infiltration)	In addition, CCL17 gene transduction induced significant increases in the number of infiltrating macrophages and CD8+ T cells in CT26 tumors, and changed the tumor microenvironment to an immunologic activation state in which there was enhanced expression of lymphocyte activation markers and cell adhesion molecules.
17617571	Colon Carcinoma	NOS2	Promote immunity	BMDC-mediated tumor cell killing requires cell-cell contact and depends on NO production, but not on perforin/granzyme or on death receptors. Thus, intratumoral LPS injections induce an increase of inducible NO synthase expression in tumor-infiltrating DCs associated with a significant arrest of tumor growth.
17616704	Neuroblastoma	HLA-G	Inhibit immunity	Human neuroblastoma cells trigger an immunosuppressive program in monocytes by stimulating soluble HLA-G release. Neuroblastoma patient sera selected according to high sHLA-G concentrations inhibited natural killer (NK) cell and CTL-mediated neuroblastoma cell lysis. Such lysis was partially restored by serum depletion of sHLA-G.
17616653	Renal Cell Carcinoma	VCAM1	Inhibit immunity	One recent study has shown that tumor cells can escape T-cell immunity by overexpressing the endothelial cell adhesion molecule vascular cell adhesion molecule-1 (VCAM-1), which normally mediates leukocyte extravasion to sites of tissue inflammation. Renal cell carcinoma (RCC) was identified as one tumor type where VCAM-1 is commonly highly overexpressed. Together, our findings suggest that RCCs might exploit VCAM-1 overexpression for immune escape.
17595664	Neuroblastoma	IL2	Promote immunity	We conclude that syngeneic fibroblasts cotransfected with IL-2 and IL-12 mediate therapeutic effects against established disease, and are capable of generating immunological memory.
17582604	Glioma	IL21	Promote immunity	Most notably 100% of the animals receiving a primary implant of IL-21-transduced cells rejected the implant, and 76% of these animals survived to a subsequent rechallenge with GL261 parental cells. More importantly, IL-21-secreting GL D2-60 cells or 1 microg of rIL-21 protein stereotactically injected into established GL D2-60 tumors were able to trigger glioblastoma rejection in 90 and 77% of mice, respectively.
17579057	Malignant Skin Neoplasm	IL10	Inhibit immunity	IL-10 has been shown to be a key mediator of UV-induced immunosuppression. IL-10(+/+) and IL-10(+/-) mice developed skin cancer to similar extents, whereas IL-10(-/-) mice were protected against the induction of skin malignancies by UV. Together, these findings indicate that IL-10 is critically involved in antitumoral immunity during photocarcinogenesis.
17567706	Hepatocellular Carcinoma	CCL21	Promote immunity (infiltration)	As a result, rAAV-SLC induced a significant delay of tumor progression, which was paralleled by a profound infiltration of DCs and activated CD4(+) T cells and CD8(+) T cells (CD3(+) CD69(+) cells) into the tumor site. In addition, rAAV-SLC treatment was also found to reduce tumor growth in nude mice, most likely due to inhibition of neoangiogenesis.
17565341	Cutaneous Melanoma	TGFB2	Inhibit immunity	Our results indicate that tolerogenic DCs and suppressor T lymphocytes are present in melanoma at all stages of disease progression. In primary melanoma, TGFbeta2 is likely to render peripheral DCs tolerogenic, while in lymph nodes IDO and TGFbeta1 may have a major effect.
17565341	Cutaneous Melanoma	IDO1	Inhibit immunity	Our results indicate that tolerogenic DCs and suppressor T lymphocytes are present in melanoma at all stages of disease progression. In primary melanoma, TGFbeta2 is likely to render peripheral DCs tolerogenic, while in lymph nodes IDO and TGFbeta1 may have a major effect.
17565341	Cutaneous Melanoma	TGFB1	Inhibit immunity	Our results indicate that tolerogenic DCs and suppressor T lymphocytes are present in melanoma at all stages of disease progression. In primary melanoma, TGFbeta2 is likely to render peripheral DCs tolerogenic, while in lymph nodes IDO and TGFbeta1 may have a major effect.
17565340	Fibrosarcoma	FOXP3	Inhibit immunity	We surmised that immune surveillance would be hampered by the inhibitory effect of naturally occurring FoxP3(+) regulatory T cells, a population of T cells shown to be present at an increased frequency in a variety of human tumours. These fibrosarcomas were strikingly infiltrated with FoxP3(+) regulatory T cells implying that these cells impinge upon immune-mediated rejection of the tumour. This was confirmed by partial ablation of FoxP3(+) regulatory T-cell activity, which resulted in a marked reduction in tumour incidence.
17548592	Fibrosarcoma	IL23A	Promote immunity	The IL-23 treatment was associated with significant suppression of the growth of pre-existing MCA205 fibrosarcoma and prolongation of the survival of treated mice without significant toxicity when compared with those of the mice treated with EGFP.
17545627	Breast Adenocarcinoma	PRF1	Promote immunity	Interestingly, perforin significantly delayed the onset of mammary tumorigenesis and reduced the number of mammary tumors without improving survival. This data suggests that perforin may mediate some suppression of epithelial carcinogenesis by intervening early in the tumor development process.
17541610	Astrocytoma	PSMB9	Promote immunity	Among human WHO grade II-IV astrocytomas, downregulation of LMP2, TAP1 and beta2m correlated with grade of malignancy. Our results support the hypothesis that coordinated downregulation or impaired upregulation of certain HLA class I APM components may serve as a mechanism for astrocytoma cells to evade the host's immune response, even if HLA class I antigen surface expression is not altered.
17541610	Astrocytoma	TAP1	Promote immunity	Among human WHO grade II-IV astrocytomas, downregulation of LMP2, TAP1 and beta2m correlated with grade of malignancy. Our results support the hypothesis that coordinated downregulation or impaired upregulation of certain HLA class I APM components may serve as a mechanism for astrocytoma cells to evade the host's immune response, even if HLA class I antigen surface expression is not altered.
17541610	Astrocytoma	B2M	Promote immunity	Among human WHO grade II-IV astrocytomas, downregulation of LMP2, TAP1 and beta2m correlated with grade of malignancy. Our results support the hypothesis that coordinated downregulation or impaired upregulation of certain HLA class I APM components may serve as a mechanism for astrocytoma cells to evade the host's immune response, even if HLA class I antigen surface expression is not altered.
17538933	Hepatocellular Carcinoma	TP53	Promote immunity	We show that even brief reactivation of endogenous p53 in p53-deficient tumours can produce complete tumour regressions. The primary response to p53 was not apoptosis, but instead involved the induction of a cellular senescence program that was associated with differentiation and the upregulation of inflammatory cytokines. This program, although producing only cell cycle arrest in vitro, also triggered an innate immune response that targeted the tumour cells in vivo, thereby contributing to tumour clearance.
17535975	Skin Basal Cell Carcinoma	TLR7	Promote immunity	Tumoricidal activity of TLR7/8-activated inflammatory dendritic cells. The biological relevance of this observation can be deduced from our further findings that peripheral blood-derived CD11c(+) mDCs acquired antiperforin and anti-granzyme B reactivity upon TLR7/8 stimulation and could use these molecules to effectively lyse major histocompatibility complex (MHC) class I(lo) cancer cell lines.
17535975	Skin Basal Cell Carcinoma	TLR8	Promote immunity	Tumoricidal activity of TLR7/8-activated inflammatory dendritic cells. The biological relevance of this observation can be deduced from our further findings that peripheral blood-derived CD11c(+) mDCs acquired antiperforin and anti-granzyme B reactivity upon TLR7/8 stimulation and could use these molecules to effectively lyse major histocompatibility complex (MHC) class I(lo) cancer cell lines.
17530024	Lymphoma	CD22	Promote immunity	Epratuzumab is a humanized anti-CD22 monoclonal, which has undergone preclinical and phase I/II clinical evaluation in patients with indolent or aggressive lymphoma. Data suggest that this agent is well tolerated, and can induce tumor regressions.
17530018	Chronic Lymphocytic Leukemia	CD52	Inhibit immunity	Alemtuzumab (Campath-1H) is a humanized IgG1 monoclonal antibody that targets the human CD52 antigen. Importantly, alemtuzumab is effective in patients with high-risk del(17p13.1) and del(11q22.3) CLL.
17530017	Breast Carcinoma	ERBB2	Inhibit immunity; Immunotherapy target	The human epidermal growth factor receptor 2 (HER2) tyrosine kinase receptor is overexpressed in approximately 20-30% of human breast cancers, and is associated with reduced survival. The humanized monoclonal antibody trastuzumab (Herceptin) was the first HER2-targeted agent approved for clinical use in breast cancer patients.
17530016	B-Cell Non-Hodgkin Lymphoma	MS4A1	Promote immunity	Rituximab (chimeric anti-CD20 monoclonal antibody) is the first Food and Drug Administration approved antitumor antibody and is used in the treatment of B-non-Hodgkin's lymphoma (B-NHL). Rituximab has been shown to inhibit the p38 mitogen-activated protein kinase, nuclear factor-kappaB (NF-kappaB), extracellular signal-regulated kinase 1/2 (ERK 1/2) and AKT antiapoptotic survival pathways, all of which result in upregulation of phosphatase and tensin homolog deleted on chromosome ten and Raf kinase inhibitor protein and in the downregulation of antiapoptotic gene products (particularly Bcl-2, Bcl-(xL) and Mcl-1), and resulting in chemo/immunosensitization. Further, rituximab treatment inhibits the overexpressed transcription repressor Yin Yang 1 (YY1), which negatively regulates Fas and DR5 expression and its inhibition leads to sensitization to Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis.
17530015	B-Cell Non-Hodgkin Lymphoma	MS4A1	Promote immunity	Radioimmunotherapy for B-cell lymphoma: Y90 ibritumomab tiuxetan and I(131) tositumomab. Radioimmunotherapy, targeting the CD20 antigen, in B-cell lymphoma has clearly demonstrated efficacy and tolerability over the preceding 15 years. Both demonstrate high-response rates and durability of remission in the relapsed/refractory disease setting.
17515574	Hodgkin Lymphoma	TNFRSF8	Inhibit immunity	Phase I/II study of an anti-CD30 monoclonal antibody (MDX-060) in Hodgkin's lymphoma and anaplastic large-cell lymphoma. MDX-060 is a human anti-CD30 immunoglobulin (Ig) G1kappa monoclonal antibody that inhibits growth of CD30-expressing tumor cells in preclinical models.
17513794	Colorectal Carcinoma; Pancreatic Carcinoma; Melanoma	LILRB4	Inhibit immunity	Furthermore, we found that patients with melanoma, and carcinomas of the colon, rectum, and pancreas produce the soluble ILT3 protein, which induces the differentiation of CD8(+) T suppressor cells and impairs T cell responses in MLC. These responses are restored by anti-ILT3 mAb or by depletion of soluble ILT3 from the serum.
17513560	Renal Cell Carcinoma	COL18A1	Promote immunity	Anti-tumor effect of endostatin mediated by retroviral gene transfer in mice bearing renal cell carcinoma. In conclusion, retroviral endostatin gene transfer led to secretion of functional endostatin that was sufficiently active to inhibit tumor angiogenesis and tumor growth.
17510431	Melanoma	MSR1	Inhibit immunity; Resistant to immunotherapy	Scavenger receptor-A negatively regulates antitumor immunity. The lack of SR-A significantly enhances HSP- or lipopolysaccharide-mediated vaccine activities against poorly immunogenic tumors, indicating that SR-A is able to attenuate immunostimulatory effects of adjuvants or "danger" molecules. The improved antitumor response in SR-A knockout mice is correlated with an increased antigen-specific T-cell response. Moreover, SR-A-deficient dendritic cells are more responsive to inflammatory stimuli and display a more effective antigen-presenting capability compared with wild-type cells.
17510409	Adenoma	FASLG	Promote immunity (infiltration)	Loss of functional Fas ligand enhances intestinal tumorigenesis in the Min mouse model. Comparison of FasL-deficient versus proficient Min mice revealed a significant increase in polyp number in the gld/gld mice. Although the Fas counterattack hypothesis suggests that the absence of FasL would result in increased immune-mediated tumor elimination, the opposite is true in the Min model with lack of functional FasL associated with reduced neutrophil influx and increased tumor development.
17509674	Endometrioid Adenocarcinoma	VTCN1	Inhibit immunity (infiltration)	B7-H4 (DD-O110) is overexpressed in high risk uterine endometrioid adenocarcinomas and inversely correlated with tumor T-cell infiltration. The proportion of B7-H4 positive tumor cells was inversely related to the number of CD3-positive and CD8-positive tumor-associated lymphocytes (TALs).
17483365	Acute Myeloid Leukemia	SOCS1	Inhibit immunity	Dormant tumor cells develop cross-resistance to apoptosis induced by CTLs or imatinib mesylate via methylation of suppressor of cytokine signaling 1. Dormant tumor cells also show a progressive decrease of suppressor of cytokine signaling 1 (SOCS1) gene expression and a deregulation of the Janus-activated kinase/signal transducers and activators of transcription (JAK/STAT) pathway due to methylation of the SOCS1 gene. Dormant tumor cells were more resistant to apoptosis induced by specific CTLs, but resistance decreased when SOCS1 expression was restored via demethylation or gene transfer. Thus, SOCS1 regulation of the JAK/STAT pathways contributes to the resistance of tumor cells to CTL-mediated killing.
17475896	Renal Cell Carcinoma	TNF	Inhibit immunity	TNF-alpha induction of GM2 expression on renal cell carcinomas promotes T cell dysfunction. In this study, we report that TNF-alpha secreted by infiltrating inflammatory cells and/or genetically modified tumors augments tumor-associated GM2 levels, which leads to T cell death and immune dysfunction. TNF-alpha increases GM2 ganglioside expression by enhancing the mRNA levels encoding its synthetic enzyme, GM2 synthase, as demonstrated by both RT-PCR and Southern analysis.
17473183	Metastatic Melanoma	SELE	Promote immunity (infiltration)	Results show that the majority of metastatic melanoma samples examined do not express the vascular adhesion receptors E-selectin (CD62E), P-selectin (CD62P), and intercellular adhesion molecule-1 (CD54) on vessels within the tumor boundaries. This results in a block to recruitment of activated tumor-specific CTL to melanoma metastases and is a likely factor limiting the effectiveness of current immunotherapy protocols.
17473183	Metastatic Melanoma	SELP	Promote immunity (infiltration)	Results show that the majority of metastatic melanoma samples examined do not express the vascular adhesion receptors E-selectin (CD62E), P-selectin (CD62P), and intercellular adhesion molecule-1 (CD54) on vessels within the tumor boundaries. This results in a block to recruitment of activated tumor-specific CTL to melanoma metastases and is a likely factor limiting the effectiveness of current immunotherapy protocols.
17473183	Metastatic Melanoma	ICAM1	Promote immunity (infiltration)	Results show that the majority of metastatic melanoma samples examined do not express the vascular adhesion receptors E-selectin (CD62E), P-selectin (CD62P), and intercellular adhesion molecule-1 (CD54) on vessels within the tumor boundaries. This results in a block to recruitment of activated tumor-specific CTL to melanoma metastases and is a likely factor limiting the effectiveness of current immunotherapy protocols.
16299253	Melanoma	CA2	Inhibit immunity	Carbonic anhydrase II is a tumor vessel endothelium-associated antigen targeted by dendritic cell therapy. These findings suggest that CA-II is a tumor vessel endothelium-associated antigen in melanoma and other cancers, and elicitation of serum anti-CA-II antibody by dendritic cell therapy may be associated with good clinical outcome including tumor reduction.
16293616	Colorectal Carcinoma	NR4A2	Inhibit immunity	Finally, functional studies reveal that PGE2-mediated protection from apoptosis is completely inhibited by a dominant-negative NR4A2 construct. These most recent data suggest that NR4A2, a member of another family of nuclear receptors can stimulate progression of colorectal cancer downstream from cyclooxygenase 2-derived PGE2.
16288119	Squamous Cell Carcinoma	EGFR	Inhibit immunity	In both cellular cytotoxicity assays, the mimotope-induced antibodies exhibited specific lysis of more than 50%. The induced antibodies caused internalization of the receptor from the cell surface into endocytic vesicles and inhibited growth of EGFR-expressing cells to a similar extent as cetuximab [67% (95% confidence interval {CI} = 55% to 79%) and 69% (95% CI = 55% to 84%), respectively].
16288036	Cervical Carcinoma	KISS1R	Promote immunity	Kisspeptin-10-induced signaling of GPR54 negatively regulates chemotactic responses mediated by CXCR4: a potential mechanism for the metastasis suppressor activity of kisspeptins. The ability of Kp-10 to inhibit signaling and chemotaxis induced by SDF-1 indicates that activation of GPR54 signaling may negatively regulate the role of CXCR4 in programming tumor metastasis.
16286245	Thymoma	TGFB1	Inhibit immunity (T cell function)	We demonstrate that TGF-beta acts on cytotoxic T lymphocytes (CTLs) to specifically inhibit the expression of five cytolytic gene products-namely, perforin, granzyme A, granzyme B, Fas ligand, and interferon gamma-which are collectively responsible for CTL-mediated tumor cytotoxicity. Repression of granzyme B and interferon-gamma involves binding of TGF-beta-activated Smad and ATF1 transcription factors to their promoter regions, indicating direct and selective regulation by the TGF-beta/Smad pathway.
16278417	Burkitt Lymphoma	CD22	Promote immunity	Radioimmunotherapy of CD22-expressing Daudi tumors in nude mice with a 90Y-labeled anti-CD22 monoclonal antibody. These findings indicate that anti-CD22 radioimmunotherapy with Y22 is highly effective in vivo against CD22-expressing malignancies and may be a useful therapy for drug-refractory B cell leukemia patients.
16272366	Melanoma	CD28	Essential for immunotherapy	Expression of the costimulatory molecule CD28 also appeared to be associated with long telomeres and T cell persistence. These results, indicating that the telomere length of transferred lymphocytes correlated with in vivo T cell persistence following adoptive transfer, and coupled with the previous observation that T cell persistence was associated with clinical responses in this adoptive immunotherapy trial, suggest that telomere length and the proliferative potential of the transferred T cells may play a significant role in mediating response to adoptive immunotherapy.
16267003	Colon Carcinoma	FASLG	Inhibit immunity (infiltration)	Addressing the "Fas counterattack" controversy: blocking fas ligand expression suppresses tumor immune evasion of colon cancer in vivo. Down-regulation of FasL expression had no effect on tumor growth in vitro but significantly reduced tumor development in syngeneic immunocompetent mice in vivo. Reduced FasL expression by tumor cells led to increased lymphocyte infiltration.
16249392	Acute Leukemia	CD40LG	Promote immunity	Ten patients (including 7 children) with high-risk acute myeloid (n = 4) or lymphoblastic (n = 6) leukemia in cytologic remission (after allogeneic stem cell transplantation [n = 9] or chemotherapy alone [n = 1]) received up to 6 subcutaneous injections of the IL-2/CD40L vaccine. Immunization produced a 10- to 890-fold increase in the frequencies of major histocompatibility complex (MHC)-restricted T cells reactive against recipient-derived blasts.
16249392	Acute Leukemia	IL2	Promote immunity	Ten patients (including 7 children) with high-risk acute myeloid (n = 4) or lymphoblastic (n = 6) leukemia in cytologic remission (after allogeneic stem cell transplantation [n = 9] or chemotherapy alone [n = 1]) received up to 6 subcutaneous injections of the IL-2/CD40L vaccine. Immunization produced a 10- to 890-fold increase in the frequencies of major histocompatibility complex (MHC)-restricted T cells reactive against recipient-derived blasts.
16243826	Acute Monocytic Leukemia; Breast Carcinoma; Ovarian Carcinoma	MICA	Essential for immunotherapy	MHC class I-related chain A conjugated to antitumor antibodies can sensitize tumor cells to specific lysis by natural killer cells. Importantly, preincubation of the tumor cells with the appropriate Fab-rMICA conjugate resulted in NK cell-mediated tumor cell lysis.
16243821	Prostate Carcinoma	ERBB2	Immunotherapy target	Phase I clinical trial of a HER-2/neu peptide (E75) vaccine for the prevention of prostate-specific antigen recurrence in high-risk prostate cancer patients. The E75 vaccine strategy is safe and effective in eliciting an immune response against the HER-2/neu protein in HRPC patients and may be useful as a preventive strategy against disease recurrence.
16243819	Metastatic Prostate Carcinoma	FOLH1	Promote immunity	Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein primarily expressed on benign and malignant prostatic epithelial cells. J591 is an IgG1 monoclonal antibody that targets the external domain of the PSMA.
16237071	Lung Adenocarcinoma	NCR3	Promote immunity	NK cells infiltrating a MHC class I-deficient lung adenocarcinoma display impaired cytotoxic activity toward autologous tumor cells associated with altered NK cell-triggering receptors. The present study indicates that the MHC-I-deficient lung adenocarcinoma had developed mechanisms of escape from the innate immune response based on down-regulation of NCR and ligands required for target cell recognition.
16237070	Melanoma; Lymphoma	MAPK8	Promote immunity (T cell function)	JNK1 is essential for CD8+ T cell-mediated tumor immune surveillance. JNK1-/- CD8+ T cells have an intrinsic defect in early IFN-gamma gene transcription and production after activation by either anti-CD3/anti-CD28 Abs or dendritic cells loaded with specific Ag in vitro. The impaired IFN-gamma production in JNK1-/- CD8+ T cells is associated with reduced expression of both T-bet and Eomesodermin, indicating that JNK1 regulates the transcription program of CD8+ T cells. Finally, JNK1-/- CD8+ T cells showed reduced perforin expression and impaired CTL function.
16234565	Ovarian Carcinoma	EGFR	Inhibit immunity	We tested a combination regimen consisting of C225, a monoclonal antibody that inhibits the receptor tyrosine kinase activity of EGFR, and benzoporphyrin derivative monoacid A (BPD)-based PDT in a mouse model of human ovarian cancer.
16230414	Prostate Carcinoma	PSCA	Inhibit immunity	PSCA overexpression correlates with a high risk of recurrence after primary therapy for prostate cancer. We have reported previously that anti-PSCA monoclonal antibody (mAb) 1G8 inhibits tumor growth, prevents metastasis, and prolongs the survival of mice inoculated with human prostate cancer cell lines and xenografts.
16227989	Melanoma	IFNG	Promote immunity	Intratumoral release of IFN-gamma had two crucial effects: inhibition of tumor angiogenesis and upregulation of major histocompatibility complex (MHC) class I expression on tumor cells.
16222695	Gestational Trophoblastic Tumor	FTL	Promote immunity	Quantitative RNA analysis confirmed down-regulation of ferritin light polypeptide (FTL) (P = 0.037) and insulin-like growth factor binding protein 1 (IGFBP1) (P = 0.037) in HM that subsequently developed GTN when compared with those HM that regressed. Findings showed that reduced expression of genes related to cell invasion and immunosuppression, especially FTL and IGFBP1, were associated with development of GTN, and this finding may provide a better understanding of the pathogenesis of GTN.
16222695	Gestational Trophoblastic Tumor	IGFBP1	Promote immunity	Quantitative RNA analysis confirmed down-regulation of ferritin light polypeptide (FTL) (P = 0.037) and insulin-like growth factor binding protein 1 (IGFBP1) (P = 0.037) in HM that subsequently developed GTN when compared with those HM that regressed. Immunohistochemical analysis further confirmed reduced IGFBP1 protein (P = 0.03) expression in HM that developed GTN. Findings showed that reduced expression of genes related to cell invasion and immunosuppression, especially FTL and IGFBP1, were associated with development of GTN, and this finding may provide a better understanding of the pathogenesis of GTN.
16222313	Renal Cell Carcinoma	TPBG	Promote immunity	We report here that 5T4 is strongly expressed on the majority of renal cell carcinomas and therefore this population of patients is suitable for trials of 5T4-targeted therapies. In particular, we have shown that T cells from renal cell carcinoma patients can be genetically modified to kill 5T4 expressing renal cancer cell lines by introduction of a chimeric-signalling protein.
16217761	Glioma	CD70	Promote immunity	Immune stimulatory effects of CD70 override CD70-mediated immune cell apoptosis in rodent glioma models and confer long-lasting antiglioma immunity in vivo. In nude mice, CD70 expression in SMA-560 gliomas delays the glioma growth upon subcutaneous (s.c.) or intracerebral (i.c.) inoculation, suggesting a role for CD70/CD27-dependent NK cell activity in tumor surveillance. Similarly, CD70-expressing GL-261 gliomas are rejected in syngeneic C57BL/6 mice, while glioma growth is restored in C57BL/6 CD27(-/-) mice, suggesting that the CD70/CD27 interaction recruits a tumor-specific T-cell repertoire and induces tumor-specific memory.
16210663	Malignant Head and Neck Neoplasm	TGFB1	Inhibit immunity (T cell function)	Inhibition of NK cell activity through TGF-beta 1 by down-regulation of NKG2D in a murine model of head and neck cancer. Incubation of NK cells with tumor homogenate or cultured supernatant of SCC VII/SF cells reduced the expression of NKG2D and CD16. This inhibition appeared to be mediated by TGF-beta1. SCC VII/SF tumors in the oral cavity of the mice secrete high quantities of TGF-beta1, which reduce the expression of NK cell receptor NKG2D as well as CD16 and inhibits biological functions of NK cells.
16208700	Metastatic Renal Cell Cancer	CD274	Inhibit immunity	Patients with high expression of B7-H1 on primary tumor cells and/or lymphocytes were significantly more likely to die of RCC compared with patients with low B7-H1 expression (risk ratio [RR] = 4.17; 95% confidence interval [95% CI], 1.97-8.84; P < 0.001) and this risk persisted in multivariate analysis after adjusting for the Mayo Clinic stage, size, grade, and necrosis score (RR = 2.63; 96% CI, 1.23-5.64; P = 0.013).
16204073	Colon Adenocarcinoma	VANGL1	Inhibit immunity	Suppression of progression and metastasis of established colon tumors in mice by intravenous delivery of short interfering RNA targeting KITENIN, a metastasis-enhancing protein. KITENIN promotes invasion of mouse colon adenocarcinoma (CT-26) cells in vivo.
16204073	Colon Adenocarcinoma	LGALS3BP	Promote immunity	Overexpression of 90K in CT-26/antisense KITENIN cells further delayed tumor growth compared with that of CT-26/antisense KITENIN cells.
16204039	Oral Cavity Squamous Cell Carcinoma	CARD8	Inhibit immunity	A novel isoform of TUCAN is overexpressed in human cancer tissues and suppresses both caspase-8- and caspase-9-mediated apoptosis. Its overexpression inhibited pro-caspase-9 activation, leading to the suppression of the cell death induced by a protein kinase inhibitor, staurosporine, or a chemotherapeutic reagent, etoposide (VP-16). In contrast, specific small interfering RNA-mediated suppression of TUCAN-54 expression in tumor cells increased the VP-16-induced cell death rate, indicating that expression of TUCAN-54 might be associated with chemoresistance of tumor cells. In addition, it inhibited caspase-8 activation as well, thereby suppressing Fas-induced cell death.
16204013	Melanoma	CTLA4	Immunotherapy target	Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) blockade with CP-675,206, a fully human anti-CTLA4 monoclonal antibody, may break peripheral immunologic tolerance leading to effective immune responses to cancer in humans.
16204009	Stage IV Nasopharyngeal Carcinoma AJCC v7	PSMB9	Immunotherapy target	Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-related malignancy expressing EBV antigens that are possible targets of cell therapy, including latent membrane protein 2 (LMP2). Analysis of interferon-gamma-producing cells demonstrated an increased frequency of EBV-specific immunity, with appearance of LMP2-specific responses in four patients, of whom three had clinical benefit.
16203806	Squamous Cell Carcinoma	EGFR	Resistant to immunotherapy	Enhanced efficacy of radioimmunotherapy with 90Y-CHX-A''-DTPA-hu3S193 by inhibition of epidermal growth factor receptor (EGFR) signaling with EGFR tyrosine kinase inhibitor AG1478. The combination of 0.4 mg AG1478 with a single dose of 25 microCi 90Y-CHX-A''-DTPA-hu3S193 resulted in a significant enhancement of efficacy compared with either agent alone.
16203783	Chronic Lymphocytic Leukemia	CD40LG	Promote immunity	CD40 ligand activates the malignant B-cell chronic lymphocytic leukemia cells and enhances their capacity to present tumor antigens. These results suggest that immune responses to B-cell chronic lymphocytic leukemia can be obtained with human CD40 ligand/human interleukin-2-expressing s.c. vaccines but that these responses are transient.
16203783	Chronic Lymphocytic Leukemia	IL2	Promote immunity	CD40 ligand activates the malignant B-cell chronic lymphocytic leukemia cells and enhances their capacity to present tumor antigens. Human interleukin-2 further potentiates the immunogenicity of human CD40 ligand in preclinical murine models. These results suggest that immune responses to B-cell chronic lymphocytic leukemia can be obtained with human CD40 ligand/human interleukin-2-expressing s.c. vaccines but that these responses are transient.
16186187	Rectal Carcinoma; Fibrosarcoma	TNFRSF18	Immunotherapy target	A single administration of agonistic anti-GITR monoclonal antibody (mAb) to tumor-bearing mice intravenously or directly into tumors provoked potent tumor-specific immunity and eradicated established tumors without eliciting overt autoimmune disease. T cell stimulation through GITR attenuates T reg-mediated suppression or enhances tumor-killing by CD4+ and CD8+ effector T cells, including those secreting IFN-gamma, or both.
16186187	Rectal Carcinoma; Fibrosarcoma	IFNG	Essential for immunotherapy	A single administration of agonistic anti-GITR monoclonal antibody (mAb) to tumor-bearing mice intravenously or directly into tumors provoked potent tumor-specific immunity and eradicated established tumors without eliciting overt autoimmune disease. The treatment led to tumor rejection in IFN-gamma-intact mice but not IFN-gamma-deficient mice.
16177085	Sarcoma	IFNG	Promote immunity	IFN-gamma controls the generation/activation of CD4+ CD25+ regulatory T cells in antitumor immune response. In the present study, IFN-gamma was found to abrogate the generation/activation of CD4+ CD25+ regulatory T cells by immunization with SEREX-defined self-Ag. The important role of IFN-gamma produced by CD8+ T cells was shown in experiments demonstrating that CD4+ CD25+ T cells cotransferred with CD8+ T cells from IFN-gamma(-/-) mice, but not from wild-type BALB/c mice, became immunosuppressive and enhanced pulmonary metastasis when recipient animals were subsequently immunized with a SEREX-defined self-Ag and a CTL epitope.
16170184	Colorectal Carcinoma	CEACAM5	Promote immunity	Phase II trial of carcinoembryonic antigen radioimmunotherapy with 131I-labetuzumab after salvage resection of colorectal metastases in the liver: five-year safety and efficacy results. With a median follow-up of 64 months, the median OS time from the first liver resection for RAIT patients was 68.0 months (95% CI, 46.0 months to infinity), and the median DFS time was 18.0 months (95% CI, 11.0 to 31.0 months).
16169855	T-Cell Non-Hodgkin Lymphoma	TYROBP	Promote immunity (T cell function)	T cells gene-engineered with DAP12 mediate effector function in an NKG2D-dependent and major histocompatibility complex-independent manner. T-DAP12 cells were demonstrated to specifically secrete interferon-gamma following receptor ligation and to mediate potent and specific lysis of the NKG2D ligand (NKG2D-L) (Rae-1beta) expressing MHC class I-deficient and class I-sufficient tumors.
16169484	Melanoma	STAT5A	Resistant to immunotherapy	Significantly, the knockdown of STAT5 in interferon-resistant melanoma cells restored the growth-inhibitory response to IFNalpha. The overexpressed STAT5 diminished IFNalpha-triggered STAT1 activation, most evidently through upregulation of the inhibitor of cytokine-signaling CIS. Our data demonstrate that overexpression and activation of STAT5 enable melanoma cells to overcome cytokine-mediated antiproliferative signaling.
16157940	Breast Carcinoma	ERBB2	Immunotherapy target	E75 is an immunogenic peptide from the HER2/neu protein that is highly expressed in breast cancer. All patients have demonstrated clonal expansion of E75-specific CD8+T cells that lysed HER2/neu-expressing tumor cells. This HER2/neu (E75) vaccine is safe and effective in eliciting a peptide-specific immune response in vivo.
16151408	Breast Carcinoma	ERBB2	Inhibit immunity	In addition, the anti-HER2/neu antibody trastuzumab (Herceptin), in combination with standard adjuvant chemotherapy, has been shown to reduce relapses and prolong disease-free and overall survival in high-risk patients after definitive local therapy for breast cancer.
16148096	Thymoma	TNFRSF4	Promote immunity; Essential for immunotherapy	With response to tumor-expressed Ag following adoptive T cell transfer, we show that CD8 effector cells deficient in OX40, a TNFR family member, could not mediate short-term tumor suppression. The first was during CD8 priming in vitro, in which APC-transmitted OX40 signals endowed the ability to survive when adoptively transferred in vivo before tumor Ag encounter. The second was during the in vivo recall response of primed CD8 T cells, the stage in which OX40 contributed to the further survival and accumulation of T cells at the tumor site.
16148096	Thymoma	BCL2L1	Promote immunity	OX40 and Bcl-xL promote the persistence of CD8 T cells to recall tumor-associated antigen. The lack of OX40 costimulation was associated with reduced levels of Bcl-x(L), and retroviral expression of Bcl-x(L) in tumor-reactive CD8 T cells conferred greatly enhanced tumor protection following adoptive transfer.
16144945	Stage III Cutaneous Melanoma AJCC v6; Stage IV Cutaneous Melanoma AJCC v6 and v7	SERPINB9	Resistant to immunotherapy	Expression of PI-9 in metastatic melanoma cells is associated with unfavorable clinical outcome whereas MHC-1 down-regulation is not. Although it cannot be proven that PI-9 expression is directly responsible for failure of immunotherapy, these data suggest that expression of PI-9 could be an important immune escape mechanism and that modulation of this inhibitor may enhance the efficacy of immunotherapy.
16140966	Colon Carcinoma	HSPA4	Promote immunity	Hsp70 induces DC maturation and phagocytosis of cellular debris both in vitro and in vivo, which are conducive to CTL response to chaperoned and nonchaperoned antigens.
16140964	Lung Carcinoma	TAP1	Promote immunity	Fluorescence-activated cell sorting and ELISPOT analysis showed that AdhTAP1 treatment significantly increased dendritic cell cross-presentation and cross-priming of tumor antigens. Furthermore, ex vivo and in vivo AdhTAP1 treatment significantly retarded tumor growth and increased survival of mice bearing CMT.64 tumors. Fluorescence-activated cell sorting analysis and immunohistochemical staining showed a significant increase in CD8+ and CD4+ T cells and CD11c+ dendritic cells infiltrating the tumors.
16126266	Ovarian Neoplasm	MUC16	Inhibit immunity (T cell function)	CA125 was isolated from OVCAR-3 cells and its purity was determined by ELISA and ultra-sensitive mass spectrometric analysis. NK cells incubated with CA125 for 72 h exhibited a 50-70% decrease in the lysis of K562 targets. Inhibition of NK function was observed at CA125 concentrations (10,000-100,000 U/ml) that are expected to be significantly lower than those observed in the tumor microenvironment. CA125 did, however, induce major downregulation of CD16 and minor decrease in expression of CD94/NKG2A.
16112911	Melanoma	DCT	Promote immunity	Enhancement of immunity by a DNA melanoma vaccine against TRP2 with CCL21 as an adjuvant. Induction of anti-TRP2 immunity depended mainly on cell-mediated immunity, which was regulated by timing and route of CCL21 administration with DNA vaccine.
16112911	Melanoma	CCL21	Promote immunity	Enhancement of immunity by a DNA melanoma vaccine against TRP2 with CCL21 as an adjuvant. Induction of anti-TRP2 immunity depended mainly on cell-mediated immunity, which was regulated by timing and route of CCL21 administration with DNA vaccine.
25252915	Lung Carcinoma	MPL	Promote immunity (T cell function)	In the metastatic model of Lewis lung carcinoma, vaccination of the TAA survivin with SA-4-1BBL/MPL yielded superior efficacy against pulmonary metastases. Therapeutic efficacy of SA-4-1BBL/MPL was achieved in the absence of detectable toxicity, correlating with enhanced dendritic cell activation, CD8(+) T-cell function, and an increased intratumoral ratio of CD8(+) T effector cells to CD4(+)FoxP3(+) T regulatory cells.
25248763	lymphoma	IFNG	Promote immunity (T cell function)	Bone marrow chimeras revealed that IFNgammaR1 and Fas expression on immune cells was most critical for rejection, and SPLNX increased the frequency of activated macrophages (Mvarphi) within intraocular tumors in an IFNgamma- and Fas/FasL-dependent manner, suggesting an immune cell target of IFNgamma and Fas. As depletion of Mvarphis limited CD8 T cell-mediated rejection of intraocular tumors in SPLNX mice, our data support a model in which IFNgamma- and Fas/FasL-dependent activation of intratumoral Mvarphis by CD8(+) T cells promotes severe intraocular inflammation that indirectly eliminates intraocular tumors by inducing phthisis, and suggests that immunosuppressive mechanisms that maintain ocular IP interfere with the interaction between CD8(+) T cells and Mvarphis to limit the immunosurveillance of intraocular tumors.
25248763	E.G7-OVA tumors	FAS	Promote immunity (T cell function)	Bone marrow chimeras revealed that IFNgammaR1 and Fas expression on immune cells was most critical for rejection, and SPLNX increased the frequency of activated macrophages (Mvarphi) within intraocular tumors in an IFNgamma- and Fas/FasL-dependent manner, suggesting an immune cell target of IFNgamma and Fas. As depletion of Mvarphis limited CD8 T cell-mediated rejection of intraocular tumors in SPLNX mice, our data support a model in which IFNgamma- and Fas/FasL-dependent activation of intratumoral Mvarphis by CD8(+) T cells promotes severe intraocular inflammation that indirectly eliminates intraocular tumors by inducing phthisis, and suggests that immunosuppressive mechanisms that maintain ocular IP interfere with the interaction between CD8(+) T cells and Mvarphis to limit the immunosurveillance of intraocular tumors.
25248763	lymphoma	FASLG	Promote immunity (T cell function)	Bone marrow chimeras revealed that IFNgammaR1 and Fas expression on immune cells was most critical for rejection, and SPLNX increased the frequency of activated macrophages (Mvarphi) within intraocular tumors in an IFNgamma- and Fas/FasL-dependent manner, suggesting an immune cell target of IFNgamma and Fas. As depletion of Mvarphis limited CD8 T cell-mediated rejection of intraocular tumors in SPLNX mice, our data support a model in which IFNgamma- and Fas/FasL-dependent activation of intratumoral Mvarphis by CD8(+) T cells promotes severe intraocular inflammation that indirectly eliminates intraocular tumors by inducing phthisis, and suggests that immunosuppressive mechanisms that maintain ocular IP interfere with the interaction between CD8(+) T cells and Mvarphis to limit the immunosurveillance of intraocular tumors.
25245536	Lung Carcinoma	TPTE	Promote immunity (T cell function)	First, we confirmed the ectopic expression of TPTE in lung carcinoma tissues by qRT-PCR. Expression of TPTE mRNA was detected in 20% of lung carcinoma tissues analyzed, but not in healthy tissues. From 3 TPTE-seropositive patients with NSCLC, TPTEspecific T cells were isolated and a total of 27 TPTE-specific TCRs were cloned from these cells. Immunologic validation assays revealed multiple HLA class I– and II–restricted epitopes distributed over the entire sequence of the antigen.
25242680	renal cell carcinoma	NFKB1	Inhibit immunity (T cell function)	Most interestingly, our results suggest that the nuclear factor-kappa B signaling pathway might be involved in the impairment of immunological responsiveness and the observed TH-2 deviation
25238097	ovarian carcinoma	FOXP1	Inhibit immunity (T cell function)	Here we have characterized a common mechanism of T cell unresponsiveness in cancer driven by the upregulation of the transcription factor Forkhead box protein P1 (Foxp1), which prevents CD8(+) T cells from proliferating and upregulating Granzyme-B and interferon-gamma in response to tumor antigens.
25238097	ovarian carcinoma	SMAD2	Promote immunity	Mechanistically, Foxp1 interacted with the transcription factors Smad2 and Smad3 in preactivated CD8(+) T cells in response to microenvironmental transforming growth factor-beta (TGF-beta), and was essential for its suppressive activity. Therefore, Smad2 and Smad3-mediated c-Myc repression requires Foxp1 expression in T cells. Furthermore, Foxp1 directly mediated TGF-beta-induced c-Jun transcriptional repression, which abrogated T cell activity.
25238097	ovarian carcinoma	SMAD3	Promote immunity	Mechanistically, Foxp1 interacted with the transcription factors Smad2 and Smad3 in preactivated CD8(+) T cells in response to microenvironmental transforming growth factor-beta (TGF-beta), and was essential for its suppressive activity. Therefore, Smad2 and Smad3-mediated c-Myc repression requires Foxp1 expression in T cells. Furthermore, Foxp1 directly mediated TGF-beta-induced c-Jun transcriptional repression, which abrogated T cell activity.
25238097	ovarian carcinoma	TGFB1	Inhibit immunity (T cell function)	Mechanistically, Foxp1 interacted with the transcription factors Smad2 and Smad3 in preactivated CD8(+) T cells in response to microenvironmental transforming growth factor-beta (TGF-beta), and was essential for its suppressive activity. Therefore, Smad2 and Smad3-mediated c-Myc repression requires Foxp1 expression in T cells. Furthermore, Foxp1 directly mediated TGF-beta-induced c-Jun transcriptional repression, which abrogated T cell activity.
25238096	lung carcinoma; melanoma; colon carcinoma	DDIT3	Inhibit immunity (T cell function)	Here, we show the critical role of the cellular stress sensor C/EBP-homologous protein (Chop) in the accumulation and immune inhibitory activity of tumor-infiltrating myeloid-derived suppressor cells (MDSCs). MDSCs lacking Chop had decreased immune-regulatory functions and showed the ability to prime T cell function and induce antitumor responses.
25238096	lung carcinoma; melanoma; colon carcinoma	CEBPB	Inhibit immunity (T cell function)	Transcription factors CCAAT/enhancer binding protein b (C/EBPb) and phosphorylated signal transducer of activator of transcription 3 (phospho-STAT3) centrally regulate MDSC function and expansion
25238096	lung carcinoma; melanoma; colon carcinoma	IL6	Inhibit immunity (T cell function)	Chop-deficient MDSCs displayed reduced signaling through CCAAT/enhancer-binding protein-beta, leading to a decreased production of interleukin-6 (IL-6) and low expression of phospho-STAT3. IL-6 overexpression restored immune-suppressive activity of Chop-deficient MDSCs.
25238096	lung carcinoma; melanoma; colon carcinoma	STAT3	Inhibit immunity (T cell function)	Transcription factors CCAAT/enhancer binding protein b (C/EBPb) and phosphorylated signal transducer of activator of transcription 3 (phospho-STAT3) centrally regulate MDSC function and expansion
25231413	melanoma; breast carcinoma; ovarian carcinoma; colon carcinoma	TLR8	Promote immunity (T cell function)	Importantly, activation of TLR8 signaling in tumor cells can block the induction and reverse the suppression of senescent naive and tumor-specific T cells in vitro and in vivo, resulting in enhanced anti-tumor immunity.
25229656	Cervical Carcinoma	CD69	Promote immunity (NK cell function)	Indeed, in the presence of HPV-VLPs, DCs further activated NK cells by inducing the upregulation of cell surface activation markers (CD69 and HLADR). The function of NK cells was also improved as shown by an increase in IFN-γ secretion and cytotoxic activity against an HPV+ cell line
25229656	Cervical Carcinoma	HLA-DRA	Promote immunity (NK cell function)	Indeed, in the presence of HPV-VLPs, DCs further activated NK cells by inducing the upregulation of cell surface activation markers (CD69 and HLADR). The function of NK cells was also improved as shown by an increase in IFN-γ secretion and cytotoxic activity against an HPV+ cell line
25229656	Cervical Carcinoma	IL12A	Promote immunity (NK cell function)	IL-12p70 stimulates NK cells to produce IFN-γ [62] and close contacts between NK cells and DCs are necessary to reach the level of concentration allowing NK-cell activation
25229656	Cervical Carcinoma	IL12B	Promote immunity (NK cell function)	IL-12p70 stimulates NK cells to produce IFN-γ [62] and close contacts between NK cells and DCs are necessary to reach the level of concentration allowing NK-cell activation
25229656	Cervical Carcinoma	CD40LG	Promote immunity (NK cell function)	HLA-DR upregulation on DCs in the presence of NK cells and VLPs depends on CD40 engagement at the surface of the DCs (Fig. 1E), additionally NK-cell activation via CD16 is known to induce CD40L expression on NK cells
25228695	Pan-Cancer	HLA-G	Inhibit immunity (NK/T cell function)	miR-152 regulates HLA-G and HLA-C, which act inhibitory to NK and T cells, thereby altering the immunogenicity of tumors. Because HLA-G and HLA-C are both ligands for inhibitory NK cell receptors (9, 10), the miR-148 family is an important regulator of an effective immune response against tumor cells and also against viral infections.
25228695	Pan-Cancer	HLA-C	Inhibit immunity (NK/T cell function)	miR-152 regulates HLA-G and HLA-C, which act inhibitory to NK and T cells, thereby altering the immunogenicity of tumors. Because HLA-G and HLA-C are both ligands for inhibitory NK cell receptors (9, 10), the miR-148 family is an important regulator of an effective immune response against tumor cells and also against viral infections.
25225903	colorectal carcinoma	FOXP3	Inhibit immunity	Moreover, FOXP3 expression has also been seen in tumour cells, which may also provide tumours with direct immunosuppressive powers (Hinz et al, 2007; Ebert et al, 2008)
25225903	colorectal carcinoma	TNF	Promote immunity	We have demonstrated a significant positive correlation between the expression of TNF and IFNG, reiterating the fact that both these cytokines act through TH1 pathways that are associated with immune deviation towards enhanced or suppressed tumour rejection based on their activity
25225903	colorectal carcinoma	IFNG	Promote immunity	We have demonstrated a significant positive correlation between the expression of TNF and IFNG, reiterating the fact that both these cytokines act through TH1 pathways that are associated with immune deviation towards enhanced or suppressed tumour rejection based on their activity; the disease progression in the form of recurrent disease in CRC is likely to be due to the systemic immune suppression as represented by low IFNG expression in PBMC
25225409	lung carcinoma	SIGLEC9	Inhibit immunity	On one hand, engagement of Siglec-9 or Siglec-E by tumor-associated ligands inhibited immunosurveillance and tumor cell killing during establishment of autologous tumors and new metastatic foci
25223833	melanoma	TLR5	Promote immunity	Taken together, our results report a new immunotherapeutic approach based on TLR-5 activation and IFN-gamma production capable to control the metastatic growth of B16F10-Nex2 melanoma, being a promising alternative to be associated with chemotherapeutic drugs for an effective anti-tumor responses.
25223833	melanoma	IFNG	Promote immunity	FliCi was recognizedmainly by TLR5, and the protective response depended on a functionalimmune system and particularly on IFN-γ.
25223704	lung carcinoma	IL10	Inhibit immunity(T cell function)	These results suggest that IL-10 might be involved in the suppression of the immune system by Tregs induced by tumor-secreted miR-214
25223704	lung carcinoma	PTEN	Promote immunity	PTEN is a negative modulator of CD4+CD25highFoxp3+ Treg homeostasis in vivo and expansion ex vivo
25221553	colorectal carcinoma	FCGRT	Promote immunity(T cell function)	Therapeutically targeting the pathway by which FcRn enables T cell activation in response to IgG IC is thus a highly attractive prospect not only for the treatment of diseases that are driven by immune complexes but also for manipulating local immune responses against defined antigens such as those present during infections and cancer.
25220367	Vulvar Intraepithelial Neoplasia	HAVCR2	Inhibit immunity (T cell function)	The immune system prevents uncontrolled inflammation by expression of negative regulatory molecules, including cytotoxic T-lymphocyte antigen-4 (CTLA-4), T cell immunoglobulin mucin 3 (TIM3) and programmed cell death 1 (PD1), suppressing T cell function (reviewed in Refs.
25220367	Vulvar Intraepithelial Neoplasia	KLRD1	Inhibit immunity (T cell function)	Furthermore, activated T cells can express the CD94/ natural killer cell lectin-like receptor A (NKG2A) receptor which upon interaction with its ligand human leukocyte antigen E (HLA-E) inhibit T cell functionality.38,39
19629084	Prostate Adenocarcinoma	KLRK1	Promote immunity (NK and T cell function)	Engagement of NKG2D on NK and T cells could lead to the killing of pathogen-infected target cells as well as tumor cells. For example, in different murine models, rejection of transplanted tumors and a reduced incidence of spontaneous tumors were associated with enhanced NKG2D-mediated cytotoxicity
23878189	colon carcinoma	IFNA1	Promote immunity(T/NK cell function)	Importantly, a recent study demonstrated that engagement of the MEK/Erk pathway is critical for IFNa-induced phosphodiesterase 4 (PDE4) activation and repression ofcAMP in Treg cells (78). This study provided evidence for a novel type I IFN-induced, Erk-mediated, function, involving inhibition of the suppressive effects of Tregs on CD4? T cells and NK cells
23878189	chronic myelogenous leukemia	MAP2K1	Inhibit immunity	Importantly, a recent study demonstrated that engagement of the MEK/Erk pathway is critical for IFNa-induced phosphodiesterase 4 (PDE4) activation and repression ofcAMP in Treg cells (78). This study provided evidence for a novel type I IFN-induced, Erk-mediated, function, involving inhibition of the suppressive effects of Tregs on CD4? T cells and NK cells
23878189	chronic myelogenous leukemia	MAPK1	Promote immunity(T/NK cell function)	Importantly, a recent study demonstrated that engagement of the MEK/Erk pathway is critical for IFNa-induced phosphodiesterase 4 (PDE4) activation and repression ofcAMP in Treg cells (78). This study provided evidence for a novel type I IFN-induced, Erk-mediated, function, involving inhibition of the suppressive effects of Tregs on CD4? T cells and NK cells
25217158	breast carcinoma	KLRK1	Promote immunity(NK cell function)	A prominent additional modulator of NK reactivity is the C-type lectin-like receptor NKG2D that potently induces antitumor immunity after recognition of its ligands (NKG2DL)
21930769	fibrosarcoma	IFNB1	Promote immunity	We recently have reported that targeting low doses of IFN-beta to the tumor microenvironment using tumor-specific mAbs can facilitate antitumor immunity, which could be augmented further with PD-L1/PD-1 blockade
25212604	Anaplastic Thyroid Carcinoma	CXCR3	Promote immunity（NK cell infiltration)	Moreover, ATC cell lines produced high levels of CXCL10 and stimulated migration of expanded NK cells and ATC tumors were enriched for NK cells expressing the cognate chemokine receptor CXCR3.
25212604	Anaplastic thyroid carcinoma	ULBP2	Promote immunity（NK cell function)	We find that ATC cell lines are sensitive to lysis byNKcells correlating with their surface expression of ULBP2/5/6, indicating that ULBP2/5/6 could be used as a predictive marker for NK cell therapy
25212604	Anaplastic thyroid carcinoma	RAET1G	Promote immunity（NK cell function)	We find that ATC cell lines are sensitive to lysis byNKcells correlating with their surface expression of ULBP2/5/6, indicating that ULBP2/5/6 could be used as a predictive marker for NK cell therapy
25212604	Anaplastic thyroid carcinoma	RAET1L	Promote immunity（NK cell function)	We find that ATC cell lines are sensitive to lysis byNKcells correlating with their surface expression of ULBP2/5/6, indicating that ULBP2/5/6 could be used as a predictive marker for NK cell therapy
25209846	Hepatocellular Carcinoma	CD226	Promote immunity（NK cell function)	Here, we demonstrated that activated unfolded protein response (UPR) attenuated the sensitivity of human hepatocellular carcinoma cell (HCC) to NK-cell cytotoxicity by decreasing the expression level of CD226 ligand CD155 in HCC
25209846	Hepatocellular Carcinoma	PVR	Promote immunity（NK cell function)	Here, we demonstrated that activated unfolded protein response (UPR) attenuated the sensitivity of human hepatocellular carcinoma cell (HCC) to NK-cell cytotoxicity by decreasing the expression level of CD226 ligand CD155 in HCC
25209846	Hepatocellular Carcinoma	ATF6	Inhibit immunity	The decreased expression level of CD155 was due to the involvement of the activating transcription factor 6 (ATF6) and inositol-requiring enzyme 1α (IRE1α) pathways.In addition, the IRE1α pathway contributed to the increased expression level of the ER-associated degradation (ERAD)-related molecule HRD1 and facilitated the degradation of CD155
25209846	Hepatocellular Carcinoma	ERN1	Inhibit immunity	The decreased expression level of CD155 was due to the involvement of the activating transcription factor 6 (ATF6) and inositol-requiring enzyme 1α (IRE1α) pathways.In addition, the IRE1α pathway contributed to the increased expression level of the ER-associated degradation (ERAD)-related molecule HRD1 and facilitated the degradation of CD155
25209846	Hepatocellular Carcinoma	SYVN1	Inhibit immunity	The decreased expression level of CD155 was due to the involvement of the activating transcription factor 6 (ATF6) and inositol-requiring enzyme 1α (IRE1α) pathways.In addition, the IRE1α pathway contributed to the increased expression level of the ER-associated degradation (ERAD)-related molecule HRD1 and facilitated the degradation of CD155
25209187	colorectal carcinoma	CD247	Promote immunity	Our initial studies with patients with stage IV colorectal cancer show that before treatment the patients displayed an immunosuppressive status indicated by elevated MDSC levels and the downregulated CD247 expression, which is critical for T-cell and NK cell activities.
25209187	colorectal carcinoma	CASP3	Promote immunity	Detailed analysis of the mechanisms underlying CPT11 and 5FU adverse effects and the affected pathways revealed that in colorectal cancer mice, 5FU reduced MDSC levels, both by inducing their apoptotic death and by enforcing myeloid cell differentiation to mature macrophages and dendritic cells. The former drug effect is associated with elevated levels of cleaved caspase-3 and the latter involves a decreased expression of the proinflammatory S100A8/9 proteins, known to induce MDSC differentiation arrest
25209187	colorectal carcinoma	S100A9	Inhibit immunity	CPT11 also directly affects MDSCs by boosting secretion of proinflammatory cytokines such as TNFa, which is a key MDSC regulator, inducing their differentiation arrest via S100A8/9 and increasing their suppressive activity
25209187	colorectal carcinoma	S100A8	Inhibit immunity	CPT11 also directly affects MDSCs by boosting secretion of proinflammatory cytokines such as TNFa, which is a key MDSC regulator, inducing their differentiation arrest via S100A8/9 and increasing their suppressive activity
25209187	colorectal carcinoma	TNF	Inhibit immunity	CPT11 also directly affects MDSCs by boosting secretion of proinflammatory cytokines such as TNFa, which is a key MDSC regulator, inducing their differentiation arrest via S100A8/9 and increasing their suppressive activity
25205103	lymphoma	HMGN1	Promote immunity (T cell function)	Tumor-bearing Hmgn1 / mice generated fewer OVA-specific CD8 cells in the spleen than EG7-bearing Hmgn1?/? mice, suggesting that HMGN1 supported T cell–mediated antitumor immunity.
25205103	lymphoma	IFNG	Promote immunity	In addition, immunization of mice with an antigen mixed with HMGN1 augmented antigen-specific immune responses with greatly elevated production of IFNg, but not IL4 (25).
25205103	lymphoma	TNF	Promote immunity	Recombinant HMGN1 induced the accumulation and activation of DCs at the site of injection as indicated by upregulation of costimulatory and MHC molecules as well as extracellular secretion of proinflammatory cytokines such as TNFa, IL12 p70, and IL1b
25205103	lymphoma	IL12A	Promote immunity	Recombinant HMGN1 induced the accumulation and activation of DCs at the site of injection as indicated by upregulation of costimulatory and MHC molecules as well as extracellular secretion of proinflammatory cytokines such as TNFa, IL12 p70, and IL1b
25205103	lymphoma	IL12B	Promote immunity	Recombinant HMGN1 induced the accumulation and activation of DCs at the site of injection as indicated by upregulation of costimulatory and MHC molecules as well as extracellular secretion of proinflammatory cytokines such as TNFa, IL12 p70, and IL1b
25205103	lymphoma	IL1B	Promote immunity	Recombinant HMGN1 induced the accumulation and activation of DCs at the site of injection as indicated by upregulation of costimulatory and MHC molecules as well as extracellular secretion of proinflammatory cytokines such as TNFa, IL12 p70, and IL1b
25205101	melanoma	TGFB1	Inhibit immunity	However, current protocols for ex vivo programming of Th17 cells, which include TGFbeta exposure, increase the expression of CD39 and CD73, two cell surface ATP ectonucleotidases that reduce T-cell effector functions and promote immunosuppression
25205101	melanoma	ENTPD1	Inhibit immunity	However, current protocols for ex vivo programming of Th17 cells, which include TGFbeta exposure, increase the expression of CD39 and CD73, two cell surface ATP ectonucleotidases that reduce T-cell effector functions and promote immunosuppression
25205101	melanoma	NT5E	Inhibit immunity	However, current protocols for ex vivo programming of Th17 cells, which include TGFbeta exposure, increase the expression of CD39 and CD73, two cell surface ATP ectonucleotidases that reduce T-cell effector functions and promote immunosuppression
25205101	melanoma	IFNG	Promote immunity	Here, we report that ATP-mediated suppression of IFNgamma production by Th17 cells can be overcome by genetic ablation of CD73 or by using IL1beta instead of TGFbeta to program Th17 cells ex vivo. Th17 cells cultured in IL1beta were also highly polyfunctional, expressing high levels of effector molecules and exhibiting superior short-term control of melanoma in mice, despite reduced stem cell-like properties
25205101	melanoma	IL1B	Promote immunity	Here, we report that ATP-mediated suppression of IFNgamma production by Th17 cells can be overcome by genetic ablation of CD73 or by using IL1beta instead of TGFbeta to program Th17 cells ex vivo. Th17 cells cultured in IL1beta were also highly polyfunctional, expressing high levels of effector molecules and exhibiting superior short-term control of melanoma in mice, despite reduced stem cell-like properties
25200249	melanoma; renal cell carcinoma	IL2	Promote immunity	The infusion of IL-2 at low or high doses for multiple cycles in patients with metastatic melanoma and renal cell carcinoma was the first successful immunotherapy for cancer proving that the immune system could completely eradicate tumor cells under certain conditions.
25200249	melanoma	IL7	Promote immunity	This is consistent with the observations by us and others that IL-21 alone did not drive a large expansion of CD8+ T cells but synergized with IL-7 or IL-15 to promote CD8+ T cell proliferation while curtailing acquisition of a hypo-proliferative terminally-differentiated phenotype [101,102].
25200249	melanoma	IL15	Promote immunity	This is consistent with the observations by us and others that IL-21 alone did not drive a large expansion of CD8+ T cells but synergized with IL-7 or IL-15 to promote CD8+ T cell proliferation while curtailing acquisition of a hypo-proliferative terminally-differentiated phenotype [101,102].
25200249	melanoma	IL21	Promote immunity	This is consistent with the observations by us and others that IL-21 alone did not drive a large expansion of CD8+ T cells but synergized with IL-7 or IL-15 to promote CD8+ T cell proliferation while curtailing acquisition of a hypo-proliferative terminally-differentiated phenotype [101,102].
25193987	renal cell carcinoma	CD274	Inhibit immunity	In non-ccRCC, patients with PD-L1+ tumors appear to have worse clinical outcomes, although only PD-L1 positivity in tumor cells is associated with higher tumor stage and grade
25189484	lung carcinoma; Head and Neck Carcinoma	LGALS1	Inhibit immunity	Radiotherapy-related systemic lymphopenia appeared to be mediated by radiotherapyinduced tumor Gal-1 secretion that could lead to tumor progression through intratumoral immune suppression and enhanced angiogenesis.
25187059	breast carcinoma	IL10	Inhibit immunity (T cell function)	Targeting involution with a neutralizing antibody against the immunosuppressive cytokine IL-10 reduces tumor growth in involution group mice but not in nulliparous mice, implicating the involution microenvironment as the primary target of aIL-10 treatment
25187059	breast carcinoma	FOXP3	Inhibit immunity (T cell function)	Involution breast tissue also contained an elevated number of Foxp31 immune cells that costained for CD4, suggesting the presence of regulatory T cells (Fig. 6b and Supporting Information Fig. S7d).
25185261	lymphoma	PPP3CA	Promote immunity	Our results demonstrate that CNA12-CTL induce regression of EBV-associated tumors in vivo despite ongoing immunosuppression.
25183499	melanoma	BRAF	Inhibit immunity	These findings demonstrate that BRAF inhibition selectively reverses two major mechanisms of immunosuppression in melanoma and liberates host-adaptive antitumor immunity
25183499	melanoma	ITGAM	Inhibit immunity	CD11b(+) myeloid cells from PLX4720-treated tumors also exhibited decreased immunosuppressive function on a per-cell basis.
25183499	melanoma	FOXP3	Inhibit immunity	In the tumor microenvironment, BRAF inhibitor PLX4720 functioned by on-target mechanisms to selectively decrease both the proportions and absolute numbers of CD4(+)Foxp3(+) regulatory T cells (Treg) and CD11b(+)Gr1(+) myeloid-derived suppressor cells (MDSC), while preserving numbers of CD8(+) effector T cells
25178978	melanoma	BRAF	Inhibit immunity	The discovery that BRAF is a driver oncogene in cancer, and complementary improvements in our understanding of the immune system have resulted in new targeted and immune-therapies for metastatic melanoma
25174651	melanoma	BRAF	Inhibit immunity	BRAF mutation-related specific transcripts associate with the poor melanoma phenotype and such association resulted particularly strong in BRAF mutant tumors displaying low expression levels of this gene
25174587	leukemia	CD33	Inhibit immunity	The data from some clinical trials on the efficacy of GO support the conclusion that CD33 is a valid target for some subtypes of AML, mainly in favorable and intermediate risk groups
25170116	breast carcinoma; colon carcinoma	IL6	Inhibit immunity	MDSC and tumor cell cross-talk enhances IL-6 production while IL-16 enhances tumor progression, MDSC suppression and suppressive activity
25170116	breast carcinoma; colon carcinoma	IL10	Inhibit immunity	MDSC and macrophage cross-talk enhances IL-10 production while IL-10 decreases antigen presentation, immune activation, and tumor cell destruction
17617589	breast carcinoma	IL10	Inhibit immunity	Treatment with the chemotherapeutic drug gemcitabine, which reduces MDSC, promotes rejection of established metastatic disease in IL-4Ralpha(-/-) mice that produce M1 macrophages by allowing T cell activation, by maintaining macrophage production of IL-12, and by preventing increased production of IL-10
17617589	breast carcinoma	IL12B	Promote immunity	Treatment with the chemotherapeutic drug gemcitabine, which reduces MDSC, promotes rejection of established metastatic disease in IL-4Ralpha(-/-) mice that produce M1 macrophages by allowing T cell activation, by maintaining macrophage production of IL-12, and by preventing increased production of IL-10
25168392	renal cell carcinoma	MUC1	Promote immunity (T cell infiltration)	This was associated with an early detectable cellular immunity to MUC1 and comparatively more infiltration by CD8? T cells. CD8? T-cell infiltration was observed in various organs, including the kidneys, irrespective of the presence of tumor or the expression of MUC1 by MVA.
25168392	renal cell carcinoma	TLR9	Promote immunity	Coinjection of a Tolllike receptor 9 (TLR9) agonist significantly increased the survival of mice bearing RenCa-MUC1 kidney tumors, which was associated with changes in the pattern of expression of inflammatory genes.
25164013	breast carcinoma; colon carcinoma; melanoma; colon adenocarcinoma; prostate carcinoma	HMGB1	Inhibit immunity	We found that HMGB1 promotes the development of MDSCs from bone marrow progenitor cells, contributing to their ability to suppress antigen-driven activation of CD4(+) and CD8(+) T cells
25164013	breast carcinoma; colon carcinoma; melanoma; colon adenocarcinoma; prostate carcinoma	IL10	Inhibit immunity	Furthermore, HMGB1 increased MDSC-mediated production of IL-10, enhanced crosstalk between MDSCs and macrophages, and facilitated the ability of MDSCs to downregulate expression of the T-cell homing receptor L-selectin
25164013	breast carcinoma; colon carcinoma; melanoma; colon adenocarcinoma; prostate carcinoma	SELL	Promote immunity(T cell function)	Furthermore, HMGB1 increased MDSC-mediated production of IL-10, enhanced crosstalk between MDSCs and macrophages, and facilitated the ability of MDSCs to downregulate expression of the T-cell homing receptor L-selectin
25164008	breast carcinoma	KLRK1	Promote immunity	Primary BCSCs were resistant to cytotoxicity mediated by autologous/allogeneic NK cells due to reduced expression of MICA and MICB, two ligands for the stimulatory NK cell receptor NKG2D. Furthermore, the downregulation of MICA/MICB in BCSCs was mediated by aberrantly expressed oncogenic miR20a, which promoted the resistance of BCSC to NK cell cytotoxicity and resultant lung metastasis.
25164008	breast carcinoma	MICA	Promote immunity	Primary BCSCs were resistant to cytotoxicity mediated by autologous/allogeneic NK cells due to reduced expression of MICA and MICB, two ligands for the stimulatoryNKcell receptor NKG2D. Furthermore, the downregulation of MICA/MICB in BCSCs was mediated by aberrantly expressed oncogenic miR20a, which promoted the resistance of BCSC to NK cell cytotoxicity and resultant lung metastasis.
25164008	breast carcinoma	MICB	Promote immunity	Primary BCSCs were resistant to cytotoxicity mediated by autologous/allogeneic NK cells due to reduced expression of MICA and MICB, two ligands for the stimulatoryNKcell receptor NKG2D. Furthermore, the downregulation of MICA/MICB in BCSCs was mediated by aberrantly expressed oncogenic miR20a, which promoted the resistance of BCSC to NK cell cytotoxicity and resultant lung metastasis.
25136121	breast carcinoma; prostate carcinoma; hepatocellular carcinoma	KLRK1	Inhibit immunity	Together, these findings reveal a previously unidentified immune evasion strategy whereby tumors produce soluble factors that induce NKG2D ligands on myeloid cells, subverting antitumor immune responses
25132599	glioblastoma	FKBP4	Promote immunity	Knockdown of FKBP52 and treatment with the FK-binding immunosuppressant FK506 enhanced TDO expression and activity in glioblastoma cells.
25132599	glioblastoma	TDO2	Inhibit immunity	Accordingly, gene expression profile analyses revealed negative correlation of FKBP52 and TDO in glial and neural tumors and in normal brain. Knockdown of FKBP52 and treatment with the FK-binding immunosuppressant FK506 enhanced TDO expression and activity in glioblastoma cells.
25125657	melanoma	CCDC134	Promote immunity(T cell function)	Here, we show that CCDC134 is differentially expressed on resting and activated immune cells and that it promotes CD8(+) T-cell activation, proliferation, and cytotoxicity by augmenting expression of the T-cell effector molecules IFNγ, TNFα, granzyme B, and perforin
25125657	melanoma	IFNG	Promote immunity(T cell function)	Here, we show that CCDC134 is differentially expressed on resting and activated immune cells and that it promotes CD8(+) T-cell activation, proliferation, and cytotoxicity by augmenting expression of the T-cell effector molecules IFNγ, TNFα, granzyme B, and perforin
25125657	melanoma	TNF	Promote immunity(T cell function)	Here, we show that CCDC134 is differentially expressed on resting and activated immune cells and that it promotes CD8(+) T-cell activation, proliferation, and cytotoxicity by augmenting expression of the T-cell effector molecules IFNγ, TNFα, granzyme B, and perforin
25125657	melanoma	GZMB	Promote immunity(T cell function)	Here, we show that CCDC134 is differentially expressed on resting and activated immune cells and that it promotes CD8(+) T-cell activation, proliferation, and cytotoxicity by augmenting expression of the T-cell effector molecules IFNγ, TNFα, granzyme B, and perforin
25125657	melanoma	PRF1	Promote immunity(T cell function)	Here, we show that CCDC134 is differentially expressed on resting and activated immune cells and that it promotes CD8(+) T-cell activation, proliferation, and cytotoxicity by augmenting expression of the T-cell effector molecules IFNγ, TNFα, granzyme B, and perforin
25125657	melanoma	JAK3	Promote immunity	Mechanistically, in CD8(+) T cells, exposure to CCDC134 promoted cell proliferation through the JAK3-STAT5 pathway, a classic feature of many cytokines of the common gamma-chain (gamma(c)) cytokine receptor family.
25125657	melanoma	STAT5A	Promote immunity	Mechanistically, in CD8(+) T cells, exposure to CCDC134 promoted cell proliferation through the JAK3-STAT5 pathway, a classic feature of many cytokines of the common gamma-chain (gamma(c)) cytokine receptor family.
25116755	breast carcinoma	ERBB2	Inhibit immunity	Adding both cyclophosphamide and the HER2-specific mAb 7.16.4 to vaccination maximized HER2-specific CD8+ T-cell immunity and tumor-free survival in neu transgenic mice
25116754	Merkel cell carcinoma	IFNA1	Promote immunity	Treatment of MCC cell lines with ionizing radiation, etoposide, or IFN resulted in MHC-I upregulation, with IFNs strongly upregulating MHC-I expression in vitro, and in 3 of 3 patients treated with intralesional IFNs.
25100611	melanoma	CD27	Promote immunity	Most importantly, cytotoxic T cells induced by caIKK-transfected DCs combined high CD27 expression, indicating a more memory-like phenotype, and a markedly enhanced secondary expandability with a high lytic capacity.
25100611	melanoma	NFKB1	Promote immunity	Thus, we could show that activation of NF-κB is indeed sufficient to enable the DCs to produce IL-12 and to repetitively stimulate CTLs
25092892	lymphoma	IFNG	Promote immunity	Our data indicate that IFN-gamma beefs up macrophage innate response and cytotoxicity by downregulating miR-3473b to release PTEN from suppression, and then the increase of PTEN contributes to the full activation of IFN-gamma-primed macrophages.
25092892	lymphoma	PTEN	Promote immunity	Our data indicate that IFN-gamma beefs up macrophage innate response and cytotoxicity by downregulating miR-3473b to release PTEN from suppression, and then the increase of PTEN contributes to the full activation of IFN-gamma-primed macrophages.
25092771	colon carcinoma	FASLG	Promote immunity	This combination therapy also increased TILs, including tumor antigen-specific CD8 T cells, and elevated the expression of activation markers FAS-L, CXCL-9, CD31, and CD105 in MDSCs and TAMs, leading to reduced tumor volumes and an increase in the number of tumor-free animals.
25092771	colon carcinoma	CXCL9	Promote immunity	This combination therapy also increased TILs, including tumor antigen-specific CD8 T cells, and elevated the expression of activation markers FAS-L, CXCL-9, CD31, and CD105 in MDSCs and TAMs, leading to reduced tumor volumes and an increase in the number of tumor-free animals.
25092771	colon carcinoma	PECAM1	Promote immunity	This combination therapy also increased TILs, including tumor antigen-specific CD8 T cells, and elevated the expression of activation markers FAS-L, CXCL-9, CD31, and CD105 in MDSCs and TAMs, leading to reduced tumor volumes and an increase in the number of tumor-free animals.
25092771	colon carcinoma	ENG	Promote immunity	This combination therapy also increased TILs, including tumor antigen-specific CD8 T cells, and elevated the expression of activation markers FAS-L, CXCL-9, CD31, and CD105 in MDSCs and TAMs, leading to reduced tumor volumes and an increase in the number of tumor-free animals.
25085111	lung carcinoma	CD80	Promote immunity	Therefore, CD11b+MC may compromise the ability of HBC to promote T cell activation in the setting of LM as a result of diminished expression of CD80
25085111	lung carcinoma	ITGAM	Inhibit immunity	CD11b+MC were responsible for CD80 down-regulation on HBC and resulted in impaired T cell stimulation by HBC. CD80 loss on HBC was dependent on CD11b MC CD11b expression and STAT3 activity.
25085111	lung carcinoma	STAT3	Inhibit immunity	CD80 loss on HBC was dependent on CD11b MC CD11b expression and STAT3 activity.
25084511	Cervical Carcinoma	ARG1	Inhibit immunity	This study indicates that ASE activity and L-Arg degradation mechanisms of immunosuppression are present in cervical cancer.
25082897	Childhood Brain Germinoma	TGFB1	Inhibit immunity	In this report, we show that blockade of T-cell TGF-β signaling directs expansion and activation of CTLs against MB. Specifically, blockade of this signaling pathway during MB malignancy promotes memory T-cell formation, conferring antitumor immunity
25082815	pancreatic carcinoma	CSF1	Inhibit immunity	CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models
25082815	pancreatic carcinoma	CSF1R	Inhibit immunity	CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models
25080445	Melanoma; Colon Carcinoma; Lymphoma	AKT1	Inhibit immunity	Furthermore, these PI3K-Akt inhibitors led to a significant therapeutic antitumor effect, which was shown to be Treg dependent. Here, we report the use of PI3K-Akt pathway inhibitors as potent agents for the selective depletion of suppressive Tregs. We found that PI3K-Akt pathway inhibitors selectively inhibit Tregs with minimal effect on conventional T cells
25080445	Melanoma; Colon Carcinoma; Lymphoma	PIK3CD	Inhibit immunity	Furthermore, these PI3K-Akt inhibitors led to a significant therapeutic antitumor effect, which was shown to be Treg dependent. Here, we report the use of PI3K-Akt pathway inhibitors as potent agents for the selective depletion of suppressive Tregs. We found that PI3K-Akt pathway inhibitors selectively inhibit Tregs with minimal effect on conventional T cells
25074939	Breast Carcinoma	MERTK	Inhibit immunity	Finally, through MERTK, apoptotic cells induced PD-L1 expression, an immune checkpoint blockade, suggesting that cancer cells may adopt MERTK-driven efferocytosis as an immune suppression mechanism for their advantage.
25070854	lymphoma	BCL2L1	Promote immunity	We found that overexpression or induction of Bcl-xL led to increased Ag presentation to NKT cells. Conversely, the inhibition or knockdown of Bcl-xL led to decreased NKT cell activation.
25070854	lymphoma	CD1D	Promote immunity	Furthermore, knockdown of Bcl-xL resulted in the loss of CD1d trafficking to lysosome-associated membrane protein 1(+) compartments.
25063873	Breast Carcinoma	STAT3	Inhibit immunity	These results demonstrate a STAT3/NF-κB/IDO pathway in breast cancer-derived MDSCs, which provides insight into understanding immunosuppressive mechanisms of MDSCs in breast cancer. We have identified a poorly differentiated MDSC subset in breast cancer-suppressing T cell function through STAT3-dependent IDO upregulation
25063873	Breast Carcinoma	NFKB1	Inhibit immunity	These results demonstrate a STAT3/NF-κB/IDO pathway in breast cancer-derived MDSCs, which provides insight into understanding immunosuppressive mechanisms of MDSCs in breast cancer. We have identified a poorly differentiated MDSC subset in breast cancer-suppressing T cell function through STAT3-dependent IDO upregulation
25060519	Neuroblastoma	CCL5	Promote immunity	When used in combination, Ad5Δ24 directly accelerated the caspase pathways in tumor cells exposed to CAR-T cells, whereas the intratumoral release of both RANTES and IL15 attracted CAR-T cells and promoted their local survival, respectively, increasing the overall survival of tumor-bearing mice.
25060519	Neuroblastoma	IL15	Promote immunity	When used in combination, Ad5Δ24 directly accelerated the caspase pathways in tumor cells exposed to CAR-T cells, whereas the intratumoral release of both RANTES and IL15 attracted CAR-T cells and promoted their local survival, respectively, increasing the overall survival of tumor-bearing mice.
23386060	Breast Carcinoma; Cervical Carcinoma	CNOT8	Inhibit immunity	we show that hCAF1/CNOT7 regulates class I and II IFN pathways at different crucial steps.Since abnormal and unbalanced JAK/STAT activation is associated with immune disorders and cancer, hCAF1 could play a major role in innate immunity and oncogenesis, contributing to tumour escape
23386060	Breast Carcinoma; Cervical Carcinoma	STAT1	Promote immunity	we show that hCAF1/CNOT7 regulates class I and II IFN pathways at different crucial steps.Since abnormal and unbalanced JAK/STAT activation is associated with immune disorders and cancer, hCAF1 could play a major role in innate immunity and oncogenesis, contributing to tumour escape
23386060	Breast Carcinoma; Cervical Carcinoma	IFNA1	Promote immunity	we show that hCAF1/CNOT7 regulates class I and II IFN pathways at different crucial steps.Since abnormal and unbalanced JAK/STAT activation is associated with immune disorders and cancer, hCAF1 could play a major role in innate immunity and oncogenesis, contributing to tumour escape
23386060	Breast Carcinoma; Cervical Carcinoma	JAK1	Promote immunity	we show that hCAF1/CNOT7 regulates class I and II IFN pathways at different crucial steps.Since abnormal and unbalanced JAK/STAT activation is associated with immune disorders and cancer, hCAF1 could play a major role in innate immunity and oncogenesis, contributing to tumour escape
23384943	Pan-Cancer	IL21	Inhibit immunity	Our findings show for the first time that IL-21 induces GrB(+) human Bregs. They also establish the existence of human B cells with a regulatory phenotype in solid tumor infiltrates, where they may contribute to the suppression of antitumor immune responses.
23384943	Pan-Cancer	IL10	Inhibit immunity	Mechanistic investigations into how IL-21 induced GrB expression in B cells to confer Breg function revealed a CD19?CD38?CD1d?IgM?CD147? expression signature, along with expression of additional key regulatory molecules including IL-10, CD25, and indoleamine-2,3-dioxygenase
23384943	Pan-Cancer	IDO1	Inhibit immunity	Mechanistic investigations into how IL-21 induced GrB expression in B cells to confer Breg function revealed a CD19?CD38?CD1d?IgM?CD147? expression signature, along with expression of additional key regulatory molecules including IL-10, CD25, and indoleamine-2,3-dioxygenase
23378296	Breast Carcinoma	FOXP3	Promote immunity	In a related biochemical assay, the rs2294021C allele was found to significantly enhance transcription activity, leading to higher mRNA levels of FOXP3 compared with T allele. Moreover, the number of Tregs and its corresponding interleukin-10 (IL-10) secretion were elevated whereas the proliferation of antitumor T cells was decreased in the C-allele carriers.
23373542	Breast Carcinoma; Osteosarcoma; Pancreatic Adenocarcinoma	SPHK1	Promote immunity	Mechanistically, PhotoImmunoNanoTherapy induced a sphingosine kinase 2-dependent increase in sphingosine-1-phosphate and dihydrosphingosine-1-phosphate. Furthermore, dihydrosphingosine-1-phosphate was shown to selectively abrogate myeloid lineage cells while concomitantly allowing the expansion of lymphocytes that exerted an antitumor effect.
23373542	Breast Carcinoma; Osteosarcoma; Pancreatic Adenocarcinoma	SPHK2	Promote immunity	these findings revealed that PhotoImmunoNanoTherapy, utilizing the novel nontoxic theranostic agent ICG-CPSNP, can decrease tumor-associated inflammation and immature myeloid cells in a sphingosine kinase 2-dependent manner.
23370329	Melanoma	TYRP1	Promote immunity	In this study, we show that Aire deficiency decreases thymic expression of TRP-1 (TYRP1), which is a self-antigen in melanocytes and a cancer antigen in melanomas. Aire deficiency resulted in defective negative selection of TRP-1-specific T cells without affecting thymic numbers of regulatory T cells.
23370329	Melanoma	AIRE	Inhibit immunity	In this study, we show that Aire deficiency decreases thymic expression of TRP-1 (TYRP1), which is a self-antigen in melanocytes and a cancer antigen in melanomas. Aire deficiency resulted in defective negative selection of TRP-1-specific T cells without affecting thymic numbers of regulatory T cells.
23365136	Melanoma; Breast Carcinoma; Colon Carcinoma	GZMB	Promote immunity	Mechanistic investigations suggested that CpG-ODN upregulates low surface levels of 4-1BBL on tBregs to elicit granzyme B-expressing cytolytic CD8(+) T cells, offering some explanative power for the effect. These findings underscore the immunotherapeutic importance of tBreg inactivation as a strategy to enhance cancer therapy by targeting both the regulatory and activating arms of the immune system in vivo.
23363817	Breast Carcinoma	CD4	Promote immunity	Furthermore, intratumoral depletion of CD4(+) T cells or blockade of the activating cell-surface protein CD40L inhibits the antitumor response.
23363817	Breast Carcinoma	CD40LG	Promote immunity	Furthermore, intratumoral depletion of CD4(+) T cells or blockade of the activating cell-surface protein CD40L inhibits the antitumor response.
23363816	Head and Neck Carcinoma	PTPN11	Inhibit immunity	These findings suggest for the first time an important role for SHP2 in APM-mediated escape of HNC cells from CTL recognition. Targeting SHP2 could enhance T-cell-based cancer immunotherapy.
23363816	Head and Neck Carcinoma	STAT1	Promote immunity	In HNC cells, SHP2 depletion significantly upregulated expression of pSTAT1 and HLA class I APM components. Overexpression of SHP2 in nonmalignant keratinocytes inhibited IFN-gamma-mediated STAT1 phosphorylation, and SHP2 depletion in STAT1(-/-) tumor cells did not significantly induce IFN-gamma-mediated APM component expression, verifying STAT1 dependence of SHP2 activity
23363816	Head and Neck Carcinoma	IFNG	Promote immunity	In HNC cells, SHP2 depletion significantly upregulated expression of pSTAT1 and HLA class I APM components. Overexpression of SHP2 in nonmalignant keratinocytes inhibited IFN-gamma-mediated STAT1 phosphorylation, and SHP2 depletion in STAT1(-/-) tumor cells did not significantly induce IFN-gamma-mediated APM component expression, verifying STAT1 dependence of SHP2 activity
23363815	Bladder Carcinoma; Renal cell Carcinoma	CCL1	Inhibit immunity	Elevated secretion of CCL1 by tumors and increased presence of CCR8(+) myeloid cells in peripheral blood and cancer tissues indicate that CCL1/CCR8 axis is a component of cancer-related inflammation and may contribute to immune evasion.
23363815	Bladder Carcinoma; Renal cell Carcinoma	CCR8	Inhibit immunity	Elevated secretion of CCL1 by tumors and increased presence of CCR8(+) myeloid cells in peripheral blood and cancer tissues indicate that CCL1/CCR8 axis is a component of cancer-related inflammation and may contribute to immune evasion.
23355732	Breast Carcinoma	TLR8	Promote immunity	We found that gammadelta Treg cells induced immunosenescence in the targeted naive and effector T cells, as well as dendritic cells (DCs). Furthermore, senescent T cells and DCs induced by gammadelta Treg cells had altered phenotypes and impaired functions and developed potent suppressive activities, further amplifying the immunosuppression mediated by gammadelta Treg cells.
23349395	Hepatocellular Carcinoma	PVR	Promote immunity	Here, we show that DNA damage response–induced expression of the DNAM-1 ligand CD155 in tumor cells leads to spontaneous rejection of tumor cells from the blood of young Em-myc mice
23341634	fibrosarcoma; Melanoma	IFNG	Promote immunity	Complete tumor rejection required IFNgamma-regulated Fas by the tumor stroma. Therefore, T(E) cells lacking IFNgamma or FasL cannot prevent progression of antigenic cancer because the tumor stroma escapes destruction if its Fas expression is down-regulated.
23341634	fibrosarcoma; Melanoma	FASLG	Promote immunity	Complete tumor rejection required IFNgamma-regulated Fas by the tumor stroma. Therefore, T(E) cells lacking IFNgamma or FasL cannot prevent progression of antigenic cancer because the tumor stroma escapes destruction if its Fas expression is down-regulated.
23341634	fibrosarcoma; Melanoma	FAS	Promote immunity	Complete tumor rejection required IFNgamma-regulated Fas by the tumor stroma. Therefore, T(E) cells lacking IFNgamma or FasL cannot prevent progression of antigenic cancer because the tumor stroma escapes destruction if its Fas expression is down-regulated.
23333935	Prostate Carcinoma; Colon Carcinoma	IFNG	Promote immunity	Antibody neutralization assays show that IL-12 and IFN-γ are essential for the Flagrp170-elicited antitumor response, which also involves CD8(+) T cells and natural killer cells.
23333935	Prostate Carcinoma; Colon Carcinoma	IL12A	Promote immunity	The enhanced tumor destruction is accompanied with significantly increased tumor infiltration by CD8(+) cells as well as elevation of IFN-gamma and interleukin (IL)-12 levels in the tumor sites.
23333712	pancreatic carcinoma	ENO1	Promote immunity	In a genetic model of pancreatic carcinoma, vaccination with ENO1 DNA elicits humoral and cellular immune responses against tumors, delays tumor progression, and significantly extends survival
23325833	leukemia	ITGB2	Promote immunity	Our report identifies a novel cancer immune evasion mechanism whereby tumor cells induce Rho GTPase signaling defects in T cells that prevent appropriate LFA-1 activation and motility.
23325833	leukemia	RHOA	Promote immunity	We show that following the coculture of previously healthy T cells with CLL cells, subsequent LFA-1 engagement leads to altered Rho GTPase activation signaling by downregulating RhoA and Rac1, while upregulating Cdc42
23325833	leukemia	RAC1	Promote immunity	We show that following the coculture of previously healthy T cells with CLL cells, subsequent LFA-1 engagement leads to altered Rho GTPase activation signaling by downregulating RhoA and Rac1, while upregulating Cdc42
23324210	Melanoma	IGF2R	Promote immunity	We found that chemotherapy enhanced the levels of insulin-like growth factor 2 receptor/cation-independent mannose-6-phosphate receptor (IGF2R) on the surface of tumor cells, which leads to better tumor targeting by cytotoxic T cells (CTLs)
23319800	Melanoma	TP53	Promote immunity	Trp53 inactivation in the tumor microenvironment promotes tumor progression by expanding the immunosuppressive lymphoid-like stromal network.
23319800	Melanoma	FOXP3	Inhibit immunity	Interestingly, tumor growth in p53(null) mice was greatly accelerated, correlating with marked increases in CD11b(+)Gr-1(+) myeloid-derived suppressor cells (MDSC), FoxP3(+) regulatory T cells, and a loss of effector function, compared with those in WT mice.
23319306	Breast Carcinoma; Melanoma	IL12B	Promote immunity	Upon reaching the bronchoalveolar space, aerosolized CpG-ODN activated a local immune response, as indicated by production of IL-12p40, IFN-gamma and IL-1beta and by recruitment and maturation of DC cells in bronchoalveolar lavage fluid of mice.
23319306	Breast Carcinoma; Melanoma	IFNG	Promote immunity	Upon reaching the bronchoalveolar space, aerosolized CpG-ODN activated a local immune response, as indicated by production of IL-12p40, IFN-gamma and IL-1beta and by recruitment and maturation of DC cells in bronchoalveolar lavage fluid of mice.
23319306	Breast Carcinoma; Melanoma	IL1B	Promote immunity	Upon reaching the bronchoalveolar space, aerosolized CpG-ODN activated a local immune response, as indicated by production of IL-12p40, IFN-gamma and IL-1beta and by recruitment and maturation of DC cells in bronchoalveolar lavage fluid of mice.
23319273	Prostate Carcinoma	DUSP1	Inhibit immunity	Studies revealed that the levels of expression of genes responsible for T-cell proliferation (C-FOS, C-JUN and DUSP1) and cellular migration (RGS1) were greater in Tregs from mCRPC patients as compared to values observed in healthy donors.
23319273	Prostate Carcinoma	RGS1	Inhibit immunity	Studies revealed that the levels of expression of genes responsible for T-cell proliferation (C-FOS, C-JUN and DUSP1) and cellular migration (RGS1) were greater in Tregs from mCRPC patients as compared to values observed in healthy donors.
23319273	Prostate Carcinoma	FOS	Inhibit immunity	Studies revealed that the levels of expression of genes responsible for T-cell proliferation (C-FOS, C-JUN and DUSP1) and cellular migration (RGS1) were greater in Tregs from mCRPC patients as compared to values observed in healthy donors.
23319273	Prostate Carcinoma	JUN	Inhibit immunity	Studies revealed that the levels of expression of genes responsible for T-cell proliferation (C-FOS, C-JUN and DUSP1) and cellular migration (RGS1) were greater in Tregs from mCRPC patients as compared to values observed in healthy donors.
23315072	Melanoma	IFNG	Promote immunity	Nevertheless, IFN-γ played a critical role by creating a microenvironment that promoted Tc17-mediated antitumor activity
23312906	Glioma; Mesothelioma	CTAG1B	Promote immunity	In two non epithelial cancers (glioma and mesothelioma), we found that the epigenetic regulation of the NY-ESO1 gene requires the sequential recruitment of the HDAC1-mSin3a-NCOR, Dnmt3b-HDAC1-Egr1 and Dnmt1-PCNA-UHRF1-G9a complexes.The NY-ESO1 gene is a cancer/testis antigen considered to be suitable target for the immunotherapy of human malignancies.
23312906	Glioma; Mesothelioma	HDAC1	Promote immunity	In two non epithelial cancers (glioma and mesothelioma), we found that the epigenetic regulation of the NY-ESO1 gene requires the sequential recruitment of the HDAC1-mSin3a-NCOR, Dnmt3b-HDAC1-Egr1 and Dnmt1-PCNA-UHRF1-G9a complexes.The NY-ESO1 gene is a cancer/testis antigen considered to be suitable target for the immunotherapy of human malignancies.
23312906	Glioma; Mesothelioma	DNMT1	Promote immunity	In two non epithelial cancers (glioma and mesothelioma), we found that the epigenetic regulation of the NY-ESO1 gene requires the sequential recruitment of the HDAC1-mSin3a-NCOR, Dnmt3b-HDAC1-Egr1 and Dnmt1-PCNA-UHRF1-G9a complexes.The NY-ESO1 gene is a cancer/testis antigen considered to be suitable target for the immunotherapy of human malignancies.
23312906	Glioma; Mesothelioma	DNMT3B	Promote immunity	In two non epithelial cancers (glioma and mesothelioma), we found that the epigenetic regulation of the NY-ESO1 gene requires the sequential recruitment of the HDAC1-mSin3a-NCOR, Dnmt3b-HDAC1-Egr1 and Dnmt1-PCNA-UHRF1-G9a complexes.The NY-ESO1 gene is a cancer/testis antigen considered to be suitable target for the immunotherapy of human malignancies.
23312906	Glioma; Mesothelioma	EHMT2	Promote immunity	In two non epithelial cancers (glioma and mesothelioma), we found that the epigenetic regulation of the NY-ESO1 gene requires the sequential recruitment of the HDAC1-mSin3a-NCOR, Dnmt3b-HDAC1-Egr1 and Dnmt1-PCNA-UHRF1-G9a complexes.The NY-ESO1 gene is a cancer/testis antigen considered to be suitable target for the immunotherapy of human malignancies.
23312906	Glioma; Mesothelioma	NCOR1	Promote immunity	In two non epithelial cancers (glioma and mesothelioma), we found that the epigenetic regulation of the NY-ESO1 gene requires the sequential recruitment of the HDAC1-mSin3a-NCOR, Dnmt3b-HDAC1-Egr1 and Dnmt1-PCNA-UHRF1-G9a complexes.The NY-ESO1 gene is a cancer/testis antigen considered to be suitable target for the immunotherapy of human malignancies.
23312906	Glioma; Mesothelioma	EGR1	Promote immunity	In two non epithelial cancers (glioma and mesothelioma), we found that the epigenetic regulation of the NY-ESO1 gene requires the sequential recruitment of the HDAC1-mSin3a-NCOR, Dnmt3b-HDAC1-Egr1 and Dnmt1-PCNA-UHRF1-G9a complexes.The NY-ESO1 gene is a cancer/testis antigen considered to be suitable target for the immunotherapy of human malignancies.
23312906	Glioma; Mesothelioma	PCNA	Inhibit immunity	In two non epithelial cancers (glioma and mesothelioma), we found that the epigenetic regulation of the NY-ESO1 gene requires the sequential recruitment of the HDAC1-mSin3a-NCOR, Dnmt3b-HDAC1-Egr1 and Dnmt1-PCNA-UHRF1-G9a complexes.The NY-ESO1 gene is a cancer/testis antigen considered to be suitable target for the immunotherapy of human malignancies.
23312906	Glioma; Mesothelioma	UHRF1	Promote immunity	In two non epithelial cancers (glioma and mesothelioma), we found that the epigenetic regulation of the NY-ESO1 gene requires the sequential recruitment of the HDAC1-mSin3a-NCOR, Dnmt3b-HDAC1-Egr1 and Dnmt1-PCNA-UHRF1-G9a complexes.The NY-ESO1 gene is a cancer/testis antigen considered to be suitable target for the immunotherapy of human malignancies.
23307859	Melanoma	BRAF	Inhibit immunity	Together, these data suggest that treatment with BRAF inhibition enhances melanoma antigen expression and facilitates T-cell cytotoxicity and a more favorable tumor microenvironment, providing support for potential synergy of BRAF-targeted therapy and immunotherapy.
23305737	Hepatocellular Carcinoma	CSF2	Inhibit immunity	Regardless of the model, tumors produced interleukin-6 and vascular endothelial growth factor but not granulocyte macrophage–colony-stimulating factor (GM-CSF) and induced iMC (CD11b(+)Gr-1(int)) that suppressed CTL responses in vitro. Nonetheless, iMC became competent MDSC in vivo following adoptive transfer when exposed to granulocyte macrophage–colony-stimulating factor (GM-CSF).
23300177	leukemia	PDCD1	Inhibit immunity	Within chronic lymphocytic leukemia proliferation centers in the lymph node, CD4(+)/PD-1(+) T lymphocytes were found to be in close contact with PD-L1(+) chronic lymphocytic leukemia cells. Lastly, functional experiments using recombinant soluble PD-L1 and blocking antibodies indicated that this axis contributes to the inhibition of IFN-γ production by CD8(+) T cells.
23300177	leukemia	CD274	Inhibit immunity	Within chronic lymphocytic leukemia proliferation centers in the lymph node, CD4(+)/PD-1(+) T lymphocytes were found to be in close contact with PD-L1(+) chronic lymphocytic leukemia cells. Lastly, functional experiments using recombinant soluble PD-L1 and blocking antibodies indicated that this axis contributes to the inhibition of IFN-γ production by CD8(+) T cells.
23300177	leukemia	IFNG	Promote immunity	Within chronic lymphocytic leukemia proliferation centers in the lymph node, CD4(+)/PD-1(+) T lymphocytes were found to be in close contact with PD-L1(+) chronic lymphocytic leukemia cells. Lastly, functional experiments using recombinant soluble PD-L1 and blocking antibodies indicated that this axis contributes to the inhibition of IFN-γ production by CD8(+) T cells.
23296706	colon carcinoma	IL2	Promote immunity	Mechanistically, poly-G ODN directly induced the phosphorylation of Lck (an essential element of the T cell-signaling pathway), thereby enhancing the production of IL-2 and CD8 T cell proliferation
23296706	colon carcinoma	TLR9	Promote immunity	Mechanistically, poly-G ODN directly induced the phosphorylation of Lck (an essential element of the T cell-signaling pathway), thereby enhancing the production of IL-2 and CD8 T cell proliferation
23296706	colon carcinoma	LCK	Promote immunity	Mechanistically, poly-G ODN directly induced the phosphorylation of Lck (an essential element of the T cell-signaling pathway), thereby enhancing the production of IL-2 and CD8 T cell proliferation
23295947	Melanoma	HDAC9	Inhibit immunity	HDAC inhibition suppresses primary immune responses, enhances secondary immune responses, and abrogates autoimmunity during tumor immunotherapy. Our data indicate that immunomodulation by HDACi occurs at multiple levels and their therapeutic benefit depends on the context and timing.
23295945	leukemia	TRG	Promote immunity	CD19(+) leukemia xenografts in mice were reduced with CAR(+)γδ T cells compared with control mice. Polyclonal CAR(+)γδ T cells were functional when TCRγδ and CAR were stimulated and displayed enhanced killing of CD19(+) tumor cell lines compared with CAR(neg)γδ T cells.
23295945	leukemia	TRD	Promote immunity	CD19(+) leukemia xenografts in mice were reduced with CAR(+)γδ T cells compared with control mice. Polyclonal CAR(+)γδ T cells were functional when TCRγδ and CAR were stimulated and displayed enhanced killing of CD19(+) tumor cell lines compared with CAR(neg)γδ T cells.
23293080	Melanoma	FCGR1A	Promote immunity	The high-affinity human IgG receptor FcγRI (CD64) promotes IgG-mediated inflammation, anaphylaxis, and antitumor immunotherapy. Finally, hFcgammaRI was capable of mediating antibody-induced immunotherapy of metastatic melanoma. Our results unravel novel capabilities of human FcgammaRI that confirm the role of high-affinity IgG receptors in vivo.
23292955	Head and Neck Squamous Cell Carcinoma	CD47	Inhibit immunity	Finally, decreasing tumor cell CD47 in combination with standard radiation and chemotherapy results in improved immune-mediated tumor clearance in vivo.
23292955	Head and Neck Squamous Cell Carcinoma	IFNG	Promote immunity	Furthermore, reduction of tumor cell CD47 increases phagocytosis of these cells by dendritic cells and leads to increased interferon gamma and granzyme production from mixed lymphocytes.
23288508	Head and Neck Squamous Cell Carcinoma	IFNG	Inhibit immunity	Significant levels of mRNA for IFN-gamma, a major cytokine inducer of PD-L1 expression, were found in HPV+ PD-L1(+) tumors.
23284053	lymphoma	IFNG	Promote immunity	With respect to CD8(+) T cell responses, the coNS5A gene primed more potent IFN-γ-producing and lytic cytotoxic T cells in wt mice compared with NS5A-Tg mice.
23281444	Colon adenocarcinoma	IL2	Inhibit immunity	Here, it was initially verified that cytokine (interleukin (IL)2) or chemokine (CCL5) expression from a systemically delivered oncolytic virus resulted in reduced oncolytic activity and suboptimal immune activation, while IL2 also resulted in increased toxicity
23280601	colon carcinoma	CLEC7A	Promote immunity	The therapeutic response of orally administered MD-Fraction was associated with (i) induced systemic tumor-antigen specific T cell response via dectin-1-dependent activation of DCs, (ii) increased infiltration of the activated T cells into the tumor and (iii) decreased number of tumor-caused immunosuppressive cells such as regulatory T cells and myeloid-derived suppressor cells
23271806	Lung Carcinoma; Mesothelioma	MRC1	Inhibit immunity	Recurrent tumors and draining lymph nodes are infiltrated with M2 (CD11b+F4/80hiCD206hi and CD11b+F4/80hiCD124hi) macrophages and CD4+Foxp3+ regulatory T cells. This complex network of immunosuppression in the surrounding tumor microenvironment explains the resistance of tumor recurrences to conventional cancer vaccines despite small tumor size, an intact antitumor immune response, and unaltered cancer cells.
23271806	Lung Carcinoma; Mesothelioma	IL4R	Inhibit immunity	Recurrent tumors and draining lymph nodes are infiltrated with M2 (CD11b+F4/80hiCD206hi and CD11b+F4/80hiCD124hi) macrophages and CD4+Foxp3+ regulatory T cells. This complex network of immunosuppression in the surrounding tumor microenvironment explains the resistance of tumor recurrences to conventional cancer vaccines despite small tumor size, an intact antitumor immune response, and unaltered cancer cells.
23269246	Pancreatic ductal adenocarcinoma	CCL22	Inhibit immunity	KCR mice also maintained a significantly less suppressive milieu evidenced by marked decreases in CCL22 in relation to CXCL10 and diminished serum levels of IL-6.
23269246	Pancreatic ductal adenocarcinoma	IL6	Inhibit immunity	To study the role of RAGE expression in the setting of mutant Ras-promoted pancreatic carcinogenesis (KC), a triple-transgenic model of spontaneous murine PDA in a RAGE-null background (KCR) was generated. KCR mice also maintained a significantly less suppressive milieu evidenced by marked decreases in CCL22 in relation to CXCL10 and diminished serum levels of IL-6.
23269246	Pancreatic ductal adenocarcinoma	AGER	Inhibit immunity	To study the role of RAGE expression in the setting of mutant Ras-promoted pancreatic carcinogenesis (KC), a triple-transgenic model of spontaneous murine PDA in a RAGE-null background (KCR) was generated. KCR mice also maintained a significantly less suppressive milieu evidenced by marked decreases in CCL22 in relation to CXCL10 and diminished serum levels of IL-6.
23266888	Breast Carcinoma	CCL5	Inhibit immunity	Because of the apparent dispensable nature of this molecule in normal physiology, CCL5 may represent an excellent therapeutic target in immunotherapy for breast cancer as well as a broad range of solid tumors that have significant amounts of MDSC infiltration. CCL5 also helps maintain the immunosuppressive capacity of human MDSCs.
23266392	Bladder Carcinoma	PSCA	Promote immunity	The study suggests that anti-PSCA immunotherapy might be beneficial for bladder cancer patients with high tumor PSCA expression, which is statistically significantly associated with the presence of CT and TT genotypes of a common genetic variant, rs2294008.
23262246	Hepatocellular Carcinoma	TGFB1	Inhibit immunity	The functional impairment of HCC-infiltrating γδ T cells, partially mediated by regulatory T cells in a TGFβ- and IL-10-dependent manner.
23262246	Hepatocellular Carcinoma	IL10	Inhibit immunity	The functional impairment of HCC-infiltrating γδ T cells, partially mediated by regulatory T cells in a TGFβ- and IL-10-dependent manner.
23262246	Hepatocellular Carcinoma	IFNG	Promote immunity	Moreover, isolated HCC-infiltrating CD4(+)CD25(+) regulatory T cells (Treg cells) directly suppressed the cytotoxic function and IFN-γ secretion of γδ T cells in a TGFβ- and IL-10-dependent manner
23251005	Melanoma	IFNG	Promote immunity	When small metastatic melanoma foci were formed in the lungs, systemic administration of IL-12-conjugated HVJ-E significantly reduced the number of metastatic foci by inducing local production of IFN-γ in the lungs and generating large numbers of melanoma-specific CTLs.
23251000	Melanoma	BRAF	Inhibit immunity	Combining the BRAF inhibitors with immunotherapy may prolong the response, but will acquisition of resistance to BRAF inhibitors also make melanoma cells resistant to immunotherapy
23248262	Gastric Carcinoma	S100A8	Inhibit immunity	S100A8/A9 has been identified as a potential target to modulate antitumor immunity by reversing MDSC-mediated immunosuppression. The ability of MDSCs to suppress T lymphocyte response and the effect of S100A8/A9 and RAGE blocking were tested in vitro by (autologous) MLR. GC patients had significantly more MDSCs than healthy individuals. These MDSCs suppressed both T lymphocyte proliferation and IFN-gamma production and had high arginase-I expression.
23248262	Gastric Carcinoma	S100A9	Inhibit immunity	S100A8/A9 has been identified as a potential target to modulate antitumor immunity by reversing MDSC-mediated immunosuppression. The ability of MDSCs to suppress T lymphocyte response and the effect of S100A8/A9 and RAGE blocking were tested in vitro by (autologous) MLR. GC patients had significantly more MDSCs than healthy individuals. These MDSCs suppressed both T lymphocyte proliferation and IFN-gamma production and had high arginase-I expression.
23248262	Gastric Carcinoma	IFNG	Promote immunity	S100A8/A9 has been identified as a potential target to modulate antitumor immunity by reversing MDSC-mediated immunosuppression. The ability of MDSCs to suppress T lymphocyte response and the effect of S100A8/A9 and RAGE blocking were tested in vitro by (autologous) MLR. GC patients had significantly more MDSCs than healthy individuals. These MDSCs suppressed both T lymphocyte proliferation and IFN-gamma production and had high arginase-I expression.
23241877	fibrosarcoma	IFNG	Inhibit immunity	To our knowledge, these studies report for the first time that IFN-γ-mediated stress leads to the loss of specific chemokine expression by tumor cells, which in turn promotes tumor growth and evasion of the immune response.
23241877	fibrosarcoma	CXCL9	Promote immunity	Remarkably, the ability of Mig-deficient tumor cells to express another CXCR3 ligand, CXCL10/IFN-gamma-inducible protein, does not compensate for the absent antitumor functions of Mig, suggesting a nonredundant role for this chemokine in the suppression of tumor growth.
23241743	colon carcinoma	RORC	Inhibit immunity	Indeed, ablation of the RORgammat gene in Foxp3(+) cells in polyp-prone mice stabilized T(reg) anti-inflammatory functions, suppressed inflammation, improved polyp-specific immune surveillance, and severely attenuated polyposis.
23225218	Hepatocellular Carcinoma	TNF	Promote immunity	However, in patients with advanced-stage HCC, NK cells were significantly decreased in number with impaired tumor necrosis factor alpha (TNF-alpha) and interferon-gamma (IFN-gamma) production.Further kinetic experiments revealed that soon after exposure to tumor-derived monocytes, NK cells underwent a rapid, transient activation, but then they became exhausted, and eventually died.
23225218	Hepatocellular Carcinoma	IFNG	Promote immunity	However, in patients with advanced-stage HCC, NK cells were significantly decreased in number with impaired tumor necrosis factor alpha (TNF-alpha) and interferon-gamma (IFN-gamma) production.Further kinetic experiments revealed that soon after exposure to tumor-derived monocytes, NK cells underwent a rapid, transient activation, but then they became exhausted, and eventually died.
23225218	Hepatocellular Carcinoma	CD48	Inhibit immunity	The monocytes from HCC tissues, but not from nontumoral liver, strongly express CD48 proteins; and such monocyte-induced NK cell dysfunction was markedly attenuated by blocking CD48 receptor 2B4 on NK cells, but not by blockade of NKG2D and NKp30.
23225218	Hepatocellular Carcinoma	CD244	Inhibit immunity	The monocytes from HCC tissues, but not from nontumoral liver, strongly express CD48 proteins; and such monocyte-induced NK cell dysfunction was markedly attenuated by blocking CD48 receptor 2B4 on NK cells, but not by blockade of NKG2D and NKp30.
23225163	plasmacytoma	IL27	Promote immunity	While STAT3 activation and the CTL survival-enhancing effects can be independent of CTL IL-10 production, we show here that IL-27-induced CTL IL-10 production contributes to memory precursor cell phenotype induction, CTL memory, and tumor rejection.
23225163	plasmacytoma	IL10	Promote immunity	While STAT3 activation and the CTL survival-enhancing effects can be independent of CTL IL-10 production, we show here that IL-27-induced CTL IL-10 production contributes to memory precursor cell phenotype induction, CTL memory, and tumor rejection.
23222714	Prostate Carcinoma	GPR68	Inhibit immunity	In summary, the expression of OGR1 in myeloid-derived cells, especially in DP cells, was required for PCa tumor cell-induced immunosuppression.
23221383	pancreatic carcinoma	CCR2	Inhibit immunity	Targeting CCR2 or CSF1R improves chemotherapeutic efficacy, inhibits metastasis, and increases antitumor T-cell responses.
23221383	pancreatic carcinoma	CSF1R	Inhibit immunity	Targeting CCR2 or CSF1R improves chemotherapeutic efficacy, inhibits metastasis, and increases antitumor T-cell responses.
23209317	lymphoma	IL12A	Promote immunity	IL-12/15/18-preactivated NK cells expressed high levels of IL-2Ralpha (CD25), and their rapid in vivo proliferation depended on IL-2 produced by CD4+ T cells. IL-12/15/18-preactivated NK cells accumulated in the tumor tissue and persisted at high cell numbers with potent effector function that required the presence of CD4+ T cells.
23209317	lymphoma	IL15	Promote immunity	IL-12/15/18-preactivated NK cells expressed high levels of IL-2Ralpha (CD25), and their rapid in vivo proliferation depended on IL-2 produced by CD4+ T cells. IL-12/15/18-preactivated NK cells accumulated in the tumor tissue and persisted at high cell numbers with potent effector function that required the presence of CD4+ T cells.
23209317	lymphoma	IL18	Promote immunity	IL-12/15/18-preactivated NK cells expressed high levels of IL-2Ralpha (CD25), and their rapid in vivo proliferation depended on IL-2 produced by CD4+ T cells. IL-12/15/18-preactivated NK cells accumulated in the tumor tissue and persisted at high cell numbers with potent effector function that required the presence of CD4+ T cells.
23209317	lymphoma	IL2	Promote immunity	IL-12/15/18-preactivated NK cells expressed high levels of IL-2Ralpha (CD25), and their rapid in vivo proliferation depended on IL-2 produced by CD4+ T cells. IL-12/15/18-preactivated NK cells accumulated in the tumor tissue and persisted at high cell numbers with potent effector function that required the presence of CD4+ T cells.
23209317	lymphoma	CD4	Promote immunity	IL-12/15/18-preactivated NK cells expressed high levels of IL-2Ralpha (CD25), and their rapid in vivo proliferation depended on IL-2 produced by CD4+ T cells. IL-12/15/18-preactivated NK cells accumulated in the tumor tissue and persisted at high cell numbers with potent effector function that required the presence of CD4+ T cells.
23204239	Melanoma	IFNG	Promote immunity	IFN-γ expression by TCR(hi) T cells was critical for upregulation of MHC-I on tumor cells and control of tumor growth.
23204230	Breast Carcinoma	LGALS1	Inhibit immunity	Taken together, our results offer a preclinical proof of concept that therapeutic targeting of Gal1 can overcome breast cancer-associated immunosuppression and can prevent metastatic disease.
23204227	lymphoma	TNFSF9	Promote immunity	Our results reveal a new regulatory mechanism for CD137L expression that mediates immune escape by HRS cells, and they identify CD137 as a candidate target for immunotherapy of Hodgkin lymphoma. Disappearance of CD137L from the surface of HRS and antigen-presenting cells led to reduced costimulation of T cells through CD137, reducing IFN-gamma release and proliferation.
23204227	lymphoma	TNFRSF9	Promote immunity	Our results reveal a new regulatory mechanism for CD137L expression that mediates immune escape by HRS cells, and they identify CD137 as a candidate target for immunotherapy of Hodgkin lymphoma. Disappearance of CD137L from the surface of HRS and antigen-presenting cells led to reduced costimulation of T cells through CD137, reducing IFN-gamma release and proliferation.
22006996	Prostate Carcinoma; Breast Carcinoma	HIF1A	Promote immunity	Indeed, our findings show a mechanistic link between hypoxia-induced accumulation of the α-subunit of HIF-1 (HIF-1α), increased expression of ADAM10, and decreased surface MICA levels leading to tumor cell resistance to lysis mediated by innate immune effectors.
22006996	Prostate Carcinoma; Breast Carcinoma	ADAM10	Inhibit immunity (NK cell function)	Indeed, our findings show a mechanistic link between hypoxia-induced accumulation of the α-subunit of HIF-1 (HIF-1α), increased expression of ADAM10, and decreased surface MICA levels leading to tumor cell resistance to lysis mediated by innate immune effectors.
21998209	lymphoma	STAT4	Promote immunity	Treatment with the proteasome inhibitor bortezomib reversed chemotherapy-induced STAT4 deficiency and defective IFN-gamma production. We conclude that acquired STAT4 deficiency in lymphoma patients is a consequence of treatment with chemotherapy, results that have important implications for the design of optimal immunotherapy for lymphoma. Furthermore, treatment of control PBMC cultures or a natural killer cell line with chemotherapy drugs in vitro also resulted in reduced STAT4 protein and diminished, IL-12-induced IFN-gamma production.
21987790	Lung Carcinoma	CD1D	Promote immunity	These findings suggest that CD1d-phenyl glycolipid complexes may interact with the same population of iNKT cells but with higher avidity and stability to drive Th1 polarization. Thus, this study provides a key to the rational design of Th1 biased CD1d reactive glycolipids in the future.
21984704	Lung Carcinoma	EGFR	Inhibit immunity	This is the first report, to our knowledge, of a tumor-specific CTL response generated by Ab-mediated EGFR inhibition, suggesting an important contribution of immunogenic apoptosis to this effect.
21982044	Endometrial Carcinoma	CD276	Inhibit immunity(infiltration)	B7-H3 is overexpressed on cancer cells and in the endothelium of tumor-associated vasculature in high grade tumors (G3) and type II carcinomas. B7-H3 expression on cancer cells is correlated with the number of T cells infiltrating the tumor.
21972293	ovarian carcinoma	PTGER4	Inhibit immunity	The disruption of COX2-PGE(2) feedback using COX2 inhibitors or EP2 and EP4 antagonists suppresses the production of MDSC-associated suppressive factors and the CTL-inhibitory function of fully developed MDSCs from cancer patients.
21972293	ovarian carcinoma	PTGER2	Inhibit immunity	The disruption of COX2-PGE(2) feedback using COX2 inhibitors or EP2 and EP4 antagonists suppresses the production of MDSC-associated suppressive factors and the CTL-inhibitory function of fully developed MDSCs from cancer patients.
21972293	ovarian carcinoma	PTGS2	Inhibit immunity	The disruption of COX2-PGE(2) feedback using COX2 inhibitors or EP2 and EP4 antagonists suppresses the production of MDSC-associated suppressive factors and the CTL-inhibitory function of fully developed MDSCs from cancer patients.
21972292	Melanoma	PTEN	Inhibit immunity	Mechanistically, we identified Pten (phosphatase and tensin homolog) as the functionally important target of miR-19b, whereas the function of miR-17 is mediated by TGFβRII and the novel target CREB1.In the present study, we showed that Pten is the dominant functionally relevant target of miR-19b in CD4 T cells. The ability of Pten to suppress T-cell proliferation and survival through its antagonizing effect on the PI3K-Akt pathway is well documented
21972292	Melanoma	TGFBR2	Inhibit immunity	In accordance with previous findings,44,45 we found that miR-17 inhibits TGF- signaling through targeting TGF RII. Biochemically, the reduction of either CREB1 or TGF RII is not dramatic, but the impacts from these moderate adjustments on T-cell function are not negligible.
21972292	Melanoma	CREB1	Inhibit immunity	In accordance with previous findings,44,45 we found that miR-17 inhibits TGF- signaling through targeting TGF RII. Biochemically, the reduction of either CREB1 or TGF RII is not dramatic, but the impacts from these moderate adjustments on T-cell function are not negligible.
21971567	Neuroblastoma	IL2	Promote immunity	Thus, the one proven beneficial immunotherapy for patients with high-risk neuroblastoma uses a chimeric anti-GD2 mAb combined with IL-2 and GM-CSF to treat patients after they have received intensive cyto-reductive chemotherapy, irradiation, and surgery
21971567	Neuroblastoma	CSF2	Promote immunity	Thus, the one proven beneficial immunotherapy for patients with high-risk neuroblastoma uses a chimeric anti-GD2 mAb combined with IL-2 and GM-CSF to treat patients after they have received intensive cyto-reductive chemotherapy, irradiation, and surgery
21969559	Melanoma	IL1B	Inhibit immunity	Indeed, upon manipulation of the melanoma microenvironment with the phosphodiesterase-5 inhibitor sildenafil, we observed reduced levels of numerous inflammatory mediators (e.g., IL-1β, IL-6, VEGF, S100A9) in association with decreased MDSC amounts and immunosuppressive function, indicating an antiinflammatory effect of sildenafil
21969559	Melanoma	IL6	Inhibit immunity	Indeed, upon manipulation of the melanoma microenvironment with the phosphodiesterase-5 inhibitor sildenafil, we observed reduced levels of numerous inflammatory mediators (e.g., IL-1β, IL-6, VEGF, S100A9) in association with decreased MDSC amounts and immunosuppressive function, indicating an antiinflammatory effect of sildenafil
21969559	Melanoma	VEGFA	Inhibit immunity	Indeed, upon manipulation of the melanoma microenvironment with the phosphodiesterase-5 inhibitor sildenafil, we observed reduced levels of numerous inflammatory mediators (e.g., IL-1β, IL-6, VEGF, S100A9) in association with decreased MDSC amounts and immunosuppressive function, indicating an antiinflammatory effect of sildenafil
21969559	Melanoma	S100A9	Inhibit immunity	Indeed, upon manipulation of the melanoma microenvironment with the phosphodiesterase-5 inhibitor sildenafil, we observed reduced levels of numerous inflammatory mediators (e.g., IL-1β, IL-6, VEGF, S100A9) in association with decreased MDSC amounts and immunosuppressive function, indicating an antiinflammatory effect of sildenafil
21964766	Melanoma	STAT1	Promote immunity	Whole genome transcriptional analysis clearly indicate that regression of melanoma metastases is due to an acute immune rejection mediated by the upregulation of genes involved in antigen presentation and interferon mediated response (STAT-1/IRF-1) in all the regressing metastases from both patients.
21964766	Melanoma	IRF1	Promote immunity	Whole genome transcriptional analysis clearly indicate that regression of melanoma metastases is due to an acute immune rejection mediated by the upregulation of genes involved in antigen presentation and interferon mediated response (STAT-1/IRF-1) in all the regressing metastases from both patients.
21953582	colorectal carcinoma	KLRC1	Inhibit immunity	A mechanism of tumor immune escape might involve expression of the human leucocyte antigen (HLA)-E/beta2m on tumor cells. The inhibitory effect of HLA-E/beta2m on CD8+ cytotoxic T lymphocytes and natural killer (NK) cells is mediated by the main HLA-E receptor CD94/NKG2A.
21949133	Lung Carcinoma	TLR4	Promote immunity	Activation of Toll-like receptor 4 (TLR4) triggers the innate immune response and leads to the induction of adaptive immunity. TLR4 agonists are known to function as immunostimulants and exhibit promising therapeutic potential for cancer immunotherapy.
21949133	Lung Carcinoma	CXCL9	Promote immunity	Increased apoptosis, the induction of cytokines (IFN-γ and IL-12) and chemokines (CXCL9 and CXCL10), and the elevation of leukocyte markers (CD11b, CD11c, CD4, and CD8) were detected at tumor sites in C3H/HeN mice but not in C3H/HeJ mice
21949133	Lung Carcinoma	CXCL10	Promote immunity	Increased apoptosis, the induction of cytokines (IFN-γ and IL-12) and chemokines (CXCL9 and CXCL10), and the elevation of leukocyte markers (CD11b, CD11c, CD4, and CD8) were detected at tumor sites in C3H/HeN mice but not in C3H/HeJ mice
21949133	Lung Carcinoma	IFNG	Promote immunity	Increased apoptosis, the induction of cytokines (IFN-γ and IL-12) and chemokines (CXCL9 and CXCL10), and the elevation of leukocyte markers (CD11b, CD11c, CD4, and CD8) were detected at tumor sites in C3H/HeN mice but not in C3H/HeJ mice
21949133	Lung Carcinoma	IL12A	Promote immunity	Increased apoptosis, the induction of cytokines (IFN-γ and IL-12) and chemokines (CXCL9 and CXCL10), and the elevation of leukocyte markers (CD11b, CD11c, CD4, and CD8) were detected at tumor sites in C3H/HeN mice but not in C3H/HeJ mice
21948231	glioblastoma	ARG1	Inhibit immunity	These data indicate that peripheral cellular immunosuppression in patients with GBM is associated with neutrophil degranulation and elevated levels of circulating ArgI, and that T-cell function can be restored in these individuals by targeting ArgI.
21937679	Breast Carcinoma	KLRK1	Promote immunity	Functional experiments in breast cancer subtypes expressing various levels of NK cell ligands showed that NK-mediated cytotoxicity is mainly HLA, NKG2D, and DNAM dependent
21937679	Breast Carcinoma	CD226	Promote immunity	Functional experiments in breast cancer subtypes expressing various levels of NK cell ligands showed that NK-mediated cytotoxicity is mainly HLA, NKG2D, and DNAM dependent
21937679	Breast Carcinoma	HLA-C	Promote immunity	Functional experiments in breast cancer subtypes expressing various levels of NK cell ligands showed that NK-mediated cytotoxicity is mainly HLA, NKG2D, and DNAM dependent
21937447	Melanoma	MLANA	Promote immunity	Here we investigated the MART-1(27-35) tumor antigen, for which anchor modification (replacement of the position two alanine with leucine) dramatically reduces or ablates antigenicity with a wide range of T cell clones despite significantly improving peptide binding to MHC.
21930770	colon carcinoma	CCL2	Inhibit immunity	Intratumoral RNS production induces CCL2 chemokine nitration and hinders T cell infiltration, resulting in the trapping of tumor-specific T cells in the stroma that surrounds cancer cells. Preconditioning of the tumor microenvironment with novel drugs that inhibit CCL2 modification facilitates CTL invasion of the tumor, suggesting that these drugs may be effective in cancer immunotherapy
21930769	Fibrosarcoma	IFNA1	Promote immunity	Herein, we show that type I IFN is required to initiate the antitumor response and that its actions are temporally distinct from IFN-γ during cancer immunoediting.
21930769	Fibrosarcoma	IFNB1	Promote immunity	Herein, we show that type I IFN is required to initiate the antitumor response and that its actions are temporally distinct from IFN-γ during cancer immunoediting.
21930769	Fibrosarcoma	IFNAR1	Promote immunity	We further show that mice lacking IFNAR1 (IFN-α/β receptor 1) in dendritic cells (DCs; Itgax-Cre(+)Ifnar1(f/f) mice) cannot reject highly immunogenic tumor cells and that CD8α(+) DCs from these mice display defects in antigen cross-presentation to CD8(+) T cells
21926464	Melanoma	IL6	Promote immunity (infiltration)	Inflammatory cytokines such as IL-6 exert tumor-promoting activities by driving growth and survival of neoplastic cells. Mechanistically, IL-6 produced by nonhematopoietic stromal cells acted cooperatively with soluble IL-6 receptor-α and thermally induced gp130 to promote E/P-selectin- and ICAM-1-dependent extravasation of cytotoxic T cells in tumors.
21926464	Melanoma	IL6R	Promote immunity (infiltration)	Inflammatory cytokines such as IL-6 exert tumor-promoting activities by driving growth and survival of neoplastic cells. Mechanistically, IL-6 produced by nonhematopoietic stromal cells acted cooperatively with soluble IL-6 receptor-α and thermally induced gp130 to promote E/P-selectin- and ICAM-1-dependent extravasation of cytotoxic T cells in tumors.
21926464	Melanoma	SELE	Promote immunity (infiltration)	Inflammatory cytokines such as IL-6 exert tumor-promoting activities by driving growth and survival of neoplastic cells. Mechanistically, IL-6 produced by nonhematopoietic stromal cells acted cooperatively with soluble IL-6 receptor-α and thermally induced gp130 to promote E/P-selectin- and ICAM-1-dependent extravasation of cytotoxic T cells in tumors.
21926464	Melanoma	SELP	Promote immunity (infiltration)	Inflammatory cytokines such as IL-6 exert tumor-promoting activities by driving growth and survival of neoplastic cells. Mechanistically, IL-6 produced by nonhematopoietic stromal cells acted cooperatively with soluble IL-6 receptor-α and thermally induced gp130 to promote E/P-selectin- and ICAM-1-dependent extravasation of cytotoxic T cells in tumors.
21926464	Melanoma	IL6ST	Promote immunity (infiltration)	Inflammatory cytokines such as IL-6 exert tumor-promoting activities by driving growth and survival of neoplastic cells. Mechanistically, IL-6 produced by nonhematopoietic stromal cells acted cooperatively with soluble IL-6 receptor-α and thermally induced gp130 to promote E/P-selectin- and ICAM-1-dependent extravasation of cytotoxic T cells in tumors.
21926464	Melanoma	ICAM1	Promote immunity (infiltration)	Inflammatory cytokines such as IL-6 exert tumor-promoting activities by driving growth and survival of neoplastic cells. Mechanistically, IL-6 produced by nonhematopoietic stromal cells acted cooperatively with soluble IL-6 receptor-α and thermally induced gp130 to promote E/P-selectin- and ICAM-1-dependent extravasation of cytotoxic T cells in tumors.
21918960	cervical squamous cell carcinoma	IFNG	Promote immunity	E7(61-69) (CDSTLRLCV) and E7(67-76) (LCVQSTHVDI) induced significantly greater IFN-γ production as well as increased in vitro cytotoxicity against SiHa cells compared with those of other peptides and the negative control (P < .01), and the antitumor effects of these peptide-sensitized PBMCs were induced by CD8(+) CTLs.
21918960	cervical squamous cell carcinoma	HLA-A	Promote immunity	E7(61-69) (CDSTLRLCV) and E7(67-76) (LCVQSTHVDI) induced significantly greater IFN-γ production as well as increased in vitro cytotoxicity against SiHa cells compared with those of other peptides and the negative control (P < .01), and the antitumor effects of these peptide-sensitized PBMCs were induced by CD8(+) CTLs.
21914786	Melanoma	MSR1	Inhibit immunity	Our studies establish that downregulating SRA/CD204 strongly enhances DC-mediated antitumor immunity. Using SRA/CD204-silenced DCs to generate antigen-targeted vaccines, we documented a marked increase in the level of antitumor immunity achieved against established B16 tumors and metastases.
21908738	Myeloma	HLA-A	Promote immunity	MHC class I expression on myeloma cells and contact with T cells were required for CD8(+) T cell divisions and DP-T cell development. DP-T cells present in myeloma-infiltrated bones contained a higher proportion of cells expressing cytotoxic mediators IFN-gamma and/or perforin compared with single-positive CD8(+) T cells, acquired the capacity to degranulate as measured by CD107 expression, and contributed to an elevated perforin level seen in the myeloma-infiltrated bones.
21908738	Myeloma	HLA-B	Promote immunity	MHC class I expression on myeloma cells and contact with T cells were required for CD8(+) T cell divisions and DP-T cell development. DP-T cells present in myeloma-infiltrated bones contained a higher proportion of cells expressing cytotoxic mediators IFN-gamma and/or perforin compared with single-positive CD8(+) T cells, acquired the capacity to degranulate as measured by CD107 expression, and contributed to an elevated perforin level seen in the myeloma-infiltrated bones.
21908738	Myeloma	HLA-C	Promote immunity	MHC class I expression on myeloma cells and contact with T cells were required for CD8(+) T cell divisions and DP-T cell development. DP-T cells present in myeloma-infiltrated bones contained a higher proportion of cells expressing cytotoxic mediators IFN-gamma and/or perforin compared with single-positive CD8(+) T cells, acquired the capacity to degranulate as measured by CD107 expression, and contributed to an elevated perforin level seen in the myeloma-infiltrated bones.
21908738	Myeloma	IFNG	Promote immunity	MHC class I expression on myeloma cells and contact with T cells were required for CD8(+) T cell divisions and DP-T cell development. DP-T cells present in myeloma-infiltrated bones contained a higher proportion of cells expressing cytotoxic mediators IFN-gamma and/or perforin compared with single-positive CD8(+) T cells, acquired the capacity to degranulate as measured by CD107 expression, and contributed to an elevated perforin level seen in the myeloma-infiltrated bones.
21908738	Myeloma	PRF1	Promote immunity	MHC class I expression on myeloma cells and contact with T cells were required for CD8(+) T cell divisions and DP-T cell development. DP-T cells present in myeloma-infiltrated bones contained a higher proportion of cells expressing cytotoxic mediators IFN-gamma and/or perforin compared with single-positive CD8(+) T cells, acquired the capacity to degranulate as measured by CD107 expression, and contributed to an elevated perforin level seen in the myeloma-infiltrated bones.
21908736	Breast Carcinoma	IL12A	Promote immunity	Intratumoral delivery of IL-12 and GM-CSF induces local and systemic antitumor CD8(+) T cell activation and tumor kill.
21908736	Breast Carcinoma	CSF2	Promote immunity	Intratumoral delivery of IL-12 and GM-CSF induces local and systemic antitumor CD8(+) T cell activation and tumor kill.
21908576	Merkel cell carcinoma	IFNG	Promote immunity	Intracellular cytokine cytometry, IFN-γ enzyme-linked immunospot (ELISPOT) assay, and a novel HLA-A*2402-restricted MCPyV tetramer were used to identify and characterize T-cell responses against MCPyV oncoproteins in tumors and blood of MCC patients and control subjects. Although tetramer-positive CD8 T cells were detected in the blood of 2 of 5 HLA-matched MCC patients, these cells failed to produce IFN-g when challenged ex vivo with peptide.
21900395	colon carcinoma	IRF1	Promote immunity	Mechanistic investigations revealed that IRF-1-induced NK cell cytotoxicity was independent of perforin and granzyme B but dependent on the NK cell activating receptor DNAM-1. Taken together, our findings establish IRF-1 as an essential mediator of the cross-talk between tumor cells and NK cells that mediate immune surveillance in the metastatic niche
21900395	colon carcinoma	CD226	Promote immunity	Mechanistic investigations revealed that IRF-1-induced NK cell cytotoxicity was independent of perforin and granzyme B but dependent on the NK cell activating receptor DNAM-1. Taken together, our findings establish IRF-1 as an essential mediator of the cross-talk between tumor cells and NK cells that mediate immune surveillance in the metastatic niche
21900394	renal cell carcinoma	ALOX15B	Inhibit immunity	we show that TAMs isolated from human RCC produce substantial amounts of the proinflammatory chemokine CCL2 and immunosuppressive cytokine IL-10, in addition to enhanced eicosanoid production via an activated 15-lipoxygenase-2 (15-LOX2) pathway.
21900394	renal cell carcinoma	CCL2	Inhibit immunity	Inhibition of lipoxygenase activity significantly reduced production of CCL2 and IL-10 by RCC TAMs. In addition, TAMs isolated from RCC were capable of inducing in T lymphocytes, the pivotal T regulatory cell transcription factor forkhead box P3 (FOXP3), and the inhibitory cytotoxic T-lymphocyte antigen 4 (CTLA-4) coreceptor.
21900394	renal cell carcinoma	IL10	Inhibit immunity	Inhibition of lipoxygenase activity significantly reduced production of CCL2 and IL-10 by RCC TAMs. In addition, TAMs isolated from RCC were capable of inducing in T lymphocytes, the pivotal T regulatory cell transcription factor forkhead box P3 (FOXP3), and the inhibitory cytotoxic T-lymphocyte antigen 4 (CTLA-4) coreceptor.
21898502	Hepatocellular Carcinoma	STAT3	Inhibit immunity	In addition, sunitinib treatment of tumor-bearing mice was associated with suppression of STAT3 and a block in T-cell tolerance. These findings indicate that sunitinib inhibits HCC tumor growth directly through the STAT3 pathway and prevents tumor antigen-specific CD8(+) T-cell tolerance, thus defining a synergistic chemoimmunotherapeutic approach for HCC.
21898484	cholangiocarcinoma	ASPH	Promote immunity	These findings suggest that immunization with ASPH-loaded DCs may constitute a novel therapeutic approach for intrahepatic cholangiocarcinoma, because this protein also appears to be highly conserved and expressed on human hepatobiliary tumors. Immunization with ASPH-loaded DCs generated cytotoxicity against cholangiocarcinoma cells in vitro and significantly suppressed intrahepatic tumor growth and metastasis, and was associated with increased CD3+ lymphocyte infiltration into the tumors.
21896488	Glioma	TIMD4	Inhibit immunity	We conclude that macrophage-derived TIM4 plays an important role in the induction of Tregs in gliomas, which may play an important role in tumor tolerance.
21880588	Prostate Carcinoma	SSX2	Inhibit immunity	We found that SSX2 was expressed most frequently in prostate cell lines, but that SSX1 and SSX5 were also expressed after treatment with the DNA demethylating agent 5-aza-2'-deoxycytidine. Humoral and cell-mediated immune responses to the SSX family member SSX2 can arise spontaneously in prostate cancer patients. Thus, SSX2 and other proteins of the SSX family may offer useful targets for tumor immunotherapy.
21873989	gastrointestinal stromal tumor	IDO1	Inhibit immunity	Imatinib therapy activated CD8(+) T cells and induced regulatory T cell (T(reg) cell) apoptosis within the tumor by reducing tumor-cell expression of the immunosuppressive enzyme indoleamine 2,3-dioxygenase (Ido).
21856769	Breast Carcinoma; Head and Neck Cell Carcinoma; Pancreas Carcinoma	ALDH1A1	Promote immunity	Adoptive therapy with ALDH1A1-specific CD8(+) T cells eliminated ALDH(bright) cells, inhibited tumor growth and metastases, or prolonged survival of xenograft-bearing immunodeficient mice.
21852502	lymphoma	CD40	Promote immunity	. Direct comparison of mAbs to CD40 enhanced for activating FcgammaR binding, hence capable of cytotoxicity, or for inhibitory FcgammaRIIB binding, revealed that enhancing FcgammaRIIB binding conferred immunostimulatory activity and considerably greater anti-tumor responses.
21852386	Breast Carcinoma	CCL22	Inhibit immunity	Taken together, our results show a dialogue between NK and tumor cells leading to IFN-γ secretion, which in turn associates with monocyte-derived IL-1β and TNF-α to drive production of CCL22 by tumor cells and subsequent recruitment of T(reg) to evade this early antitumor immune response.
21852386	Breast Carcinoma	IL1B	Inhibit immunity	Taken together, our results show a dialogue between NK and tumor cells leading to IFN-γ secretion, which in turn associates with monocyte-derived IL-1β and TNF-α to drive production of CCL22 by tumor cells and subsequent recruitment of T(reg) to evade this early antitumor immune response.
21852386	Breast Carcinoma	TNF	Inhibit immunity	Taken together, our results show a dialogue between NK and tumor cells leading to IFN-γ secretion, which in turn associates with monocyte-derived IL-1β and TNF-α to drive production of CCL22 by tumor cells and subsequent recruitment of T(reg) to evade this early antitumor immune response.
21852386	Breast Carcinoma	IFNG	Inhibit immunity	In this study, we showed that breast tumor cell recognition by NK cells leads to their activation and IFN-g secretion, which in turn triggers CCL22 production by tumor cells through cooperation with monocyte-derived IL-1b and TNF-a.
21844012	Melanoma	KLRK1	Promote immunity	However, the persistent NK cells in the circulation expressed significantly lower levels of the key activating receptor NKG2D and could not lyse tumor cell targets in vitro unless reactivated with IL-2.
21844012	Melanoma	IL2	Promote immunity	However, the persistent NK cells in the circulation expressed significantly lower levels of the key activating receptor NKG2D and could not lyse tumor cell targets in vitro unless reactivated with IL-2.
21841316	Breast Carcinoma	NCR3	Promote immunity	With disease progression, we found that expression of activating NK cell receptors (such as NKp30, NKG2D, DNAM-1, and CD16) decreased while expression of inhibitory receptors (such as NKG2A) increased and that this correlated with decreased NK cell function, most notably cytotoxicity
21841316	Breast Carcinoma	KLRK1	Promote immunity	With disease progression, we found that expression of activating NK cell receptors (such as NKp30, NKG2D, DNAM-1, and CD16) decreased while expression of inhibitory receptors (such as NKG2A) increased and that this correlated with decreased NK cell function, most notably cytotoxicity
21841316	Breast Carcinoma	CD226	Promote immunity	With disease progression, we found that expression of activating NK cell receptors (such as NKp30, NKG2D, DNAM-1, and CD16) decreased while expression of inhibitory receptors (such as NKG2A) increased and that this correlated with decreased NK cell function, most notably cytotoxicity
21841316	Breast Carcinoma	KLRC1	Inhibit immunity	With disease progression, we found that expression of activating NK cell receptors (such as NKp30, NKG2D, DNAM-1, and CD16) decreased while expression of inhibitory receptors (such as NKG2A) increased and that this correlated with decreased NK cell function, most notably cytotoxicity
21841316	Breast Carcinoma	TGFB1	Inhibit immunity	Importantly, Ti-NK cells had more pronounced impairment of their cytotoxic potential than p-NK cells. We also identified several stroma-derived factors, including TGF-beta1, involved in tumor-induced reduction of normal NK cell function.
21829171	colon carcinoma	FOLH1	Promote immunity	Tumor inhibition was dependent on homing to PSMA-expressing tumor cells and 4-1BB costimulation. Aptamer targeted costimulation is a broadly applicable and clinically feasible approach to enhance the costimulatory environment of disseminated tumor lesions
21825014	Lung Carcinoma	DLL1	Promote immunity	Here, we report a novel mechanism of escape from T-cell immunity that is caused by reduction in levels of the Delta family Notch ligands DLL1 and DLL4 in hematopoietic microenvironments. An important mediator of this effect was an elevation in the levels of circulating VEGF. Selective activation of the DLL1-Notch signaling pathway in bone marrow precursors enhanced T-cell activation and inhibited tumor growth.
21825014	Lung Carcinoma	DLL4	Promote immunity	Here, we report a novel mechanism of escape from T-cell immunity that is caused by reduction in levels of the Delta family Notch ligands DLL1 and DLL4 in hematopoietic microenvironments. An important mediator of this effect was an elevation in the levels of circulating VEGF. Selective activation of the DLL1-Notch signaling pathway in bone marrow precursors enhanced T-cell activation and inhibited tumor growth.
21825014	Lung Carcinoma	VEGFA	Inhibit immunity	Here, we report a novel mechanism of escape from T-cell immunity that is caused by reduction in levels of the Delta family Notch ligands DLL1 and DLL4 in hematopoietic microenvironments. An important mediator of this effect was an elevation in the levels of circulating VEGF. Selective activation of the DLL1-Notch signaling pathway in bone marrow precursors enhanced T-cell activation and inhibited tumor growth.
21805477	Hepatocellular Carcinoma	CALR	Promote immunity (infiltration)	Calreticulin (CRT), a chaperone protein mainly located in the endoplasmic reticulum, has been shown to exert anti-angiogenic activity and inhibit tumor growth. Here, we demonstrate that in addition to inhibiting angiogenesis, CRT also enhances the expression of both ICAM-1 and VCAM-1 on tumor endothelial cells. This expression results in enhanced leukocyte-endothelial cell interactions and increased lymphocyte infiltration into tumors.
21805477	Hepatocellular Carcinoma	ICAM1	Promote immunity (infiltration)	Calreticulin (CRT), a chaperone protein mainly located in the endoplasmic reticulum, has been shown to exert anti-angiogenic activity and inhibit tumor growth. Here, we demonstrate that in addition to inhibiting angiogenesis, CRT also enhances the expression of both ICAM-1 and VCAM-1 on tumor endothelial cells. This expression results in enhanced leukocyte-endothelial cell interactions and increased lymphocyte infiltration into tumors.
21805477	Hepatocellular Carcinoma	VCAM1	Promote immunity (infiltration)	Calreticulin (CRT), a chaperone protein mainly located in the endoplasmic reticulum, has been shown to exert anti-angiogenic activity and inhibit tumor growth. Here, we demonstrate that in addition to inhibiting angiogenesis, CRT also enhances the expression of both ICAM-1 and VCAM-1 on tumor endothelial cells. This expression results in enhanced leukocyte-endothelial cell interactions and increased lymphocyte infiltration into tumors.
21804019	lymphoma; lung carcinoma; colon carcinoma	TLR5	Promote immunity	We demonstrate that human monocyte-derived DCs are endowed with significant cytotoxic activity against tumor cells following activation with LPS. The mechanism of DC-mediated tumor cell killing primarily involves peroxynitrites. This observed cytotoxic activity is restricted to immature DCs. Additionally, after killing, these cytotoxic DCs are able to activate tumor Ag-specific T cells
21796616	Melanoma	IFNG	Promote immunity	The production of multiple cytokines (IFNgamma, TNFalpha, IL-2) and upregulation of LAMP-1 (CD107a) by tumor (Melan-A/MART-1) specific T-cells was comparable to virus (EBV-BMLF1) specific CD8 T-cells. Furthermore, phosphorylation of STAT1, STAT5 and ERK1/2, and expression of CD3 zeta chain were similar in tumor- and virus-specific T-cells, demonstrating functional signaling pathways.
21796616	Melanoma	TNF	Promote immunity	The production of multiple cytokines (IFNgamma, TNFalpha, IL-2) and upregulation of LAMP-1 (CD107a) by tumor (Melan-A/MART-1) specific T-cells was comparable to virus (EBV-BMLF1) specific CD8 T-cells. Furthermore, phosphorylation of STAT1, STAT5 and ERK1/2, and expression of CD3 zeta chain were similar in tumor- and virus-specific T-cells, demonstrating functional signaling pathways.
21796616	Melanoma	IL2	Promote immunity	The production of multiple cytokines (IFNgamma, TNFalpha, IL-2) and upregulation of LAMP-1 (CD107a) by tumor (Melan-A/MART-1) specific T-cells was comparable to virus (EBV-BMLF1) specific CD8 T-cells. Furthermore, phosphorylation of STAT1, STAT5 and ERK1/2, and expression of CD3 zeta chain were similar in tumor- and virus-specific T-cells, demonstrating functional signaling pathways.
21796616	Melanoma	LAMP1	Promote immunity	The production of multiple cytokines (IFNgamma, TNFalpha, IL-2) and upregulation of LAMP-1 (CD107a) by tumor (Melan-A/MART-1) specific T-cells was comparable to virus (EBV-BMLF1) specific CD8 T-cells. Furthermore, phosphorylation of STAT1, STAT5 and ERK1/2, and expression of CD3 zeta chain were similar in tumor- and virus-specific T-cells, demonstrating functional signaling pathways.
21796616	Melanoma	STAT1	Promote immunity	The production of multiple cytokines (IFNgamma, TNFalpha, IL-2) and upregulation of LAMP-1 (CD107a) by tumor (Melan-A/MART-1) specific T-cells was comparable to virus (EBV-BMLF1) specific CD8 T-cells. Furthermore, phosphorylation of STAT1, STAT5 and ERK1/2, and expression of CD3 zeta chain were similar in tumor- and virus-specific T-cells, demonstrating functional signaling pathways.
21796616	Melanoma	STAT5A	Promote immunity	The production of multiple cytokines (IFNgamma, TNFalpha, IL-2) and upregulation of LAMP-1 (CD107a) by tumor (Melan-A/MART-1) specific T-cells was comparable to virus (EBV-BMLF1) specific CD8 T-cells. Furthermore, phosphorylation of STAT1, STAT5 and ERK1/2, and expression of CD3 zeta chain were similar in tumor- and virus-specific T-cells, demonstrating functional signaling pathways.
21796616	Melanoma	MAPK1	Promote immunity	The production of multiple cytokines (IFNgamma, TNFalpha, IL-2) and upregulation of LAMP-1 (CD107a) by tumor (Melan-A/MART-1) specific T-cells was comparable to virus (EBV-BMLF1) specific CD8 T-cells. Furthermore, phosphorylation of STAT1, STAT5 and ERK1/2, and expression of CD3 zeta chain were similar in tumor- and virus-specific T-cells, demonstrating functional signaling pathways.
21796616	Melanoma	MAPK3	Promote immunity	The production of multiple cytokines (IFNgamma, TNFalpha, IL-2) and upregulation of LAMP-1 (CD107a) by tumor (Melan-A/MART-1) specific T-cells was comparable to virus (EBV-BMLF1) specific CD8 T-cells. Furthermore, phosphorylation of STAT1, STAT5 and ERK1/2, and expression of CD3 zeta chain were similar in tumor- and virus-specific T-cells, demonstrating functional signaling pathways.
21795744	lymphoma	CD37	Inhibit immunity	Finally, a surrogate Fc-engineered Ab to macaque CD37, with in vitro proapoptotic and ADCC activities very similar to those of mAb 37.1, induced dose-dependent, reversible B-cell depletion in cynomolgus monkeys.
21792901	renal cell carcinoma; melanoma; colon carcinoma	IFNG	Promote immunity (T cell function)	The CD8 tumor-infiltrating T lymphocytes in 6-gingerol-treated mice strongly expressed IFN-γ, a marker of activation of cytotoxic T lymphocytes (CTL) CD107a and chemokine receptors that are expressed on T(H) 1 cells, such as CXCR3 and CCR5.
21792901	renal cell carcinoma; melanoma; colon carcinoma	LAMP1	Promote immunity (T cell function)	The CD8 tumor-infiltrating T lymphocytes in 6-gingerol-treated mice strongly expressed IFN-γ, a marker of activation of cytotoxic T lymphocytes (CTL) CD107a and chemokine receptors that are expressed on T(H) 1 cells, such as CXCR3 and CCR5.
21792901	renal cell carcinoma; melanoma; colon carcinoma	CXCR3	Promote immunity (T cell function)	The CD8 tumor-infiltrating T lymphocytes in 6-gingerol-treated mice strongly expressed IFN-γ, a marker of activation of cytotoxic T lymphocytes (CTL) CD107a and chemokine receptors that are expressed on T(H) 1 cells, such as CXCR3 and CCR5.
21792901	renal cell carcinoma; melanoma; colon carcinoma	CCR5	Promote immunity (T cell function)	The CD8 tumor-infiltrating T lymphocytes in 6-gingerol-treated mice strongly expressed IFN-γ, a marker of activation of cytotoxic T lymphocytes (CTL) CD107a and chemokine receptors that are expressed on T(H) 1 cells, such as CXCR3 and CCR5.
21788345	Melanoma	TLR9	Promote immunity	By transferring wild-type pDCs into TLR9-deficient mice, we finally showed that TLR9 expression in pDCs is sufficient to benefit from CpG as an adjuvant. These studies indicate that the efficacy of CpG in cancer immunotherapy is dependent on cross-talk between pDCs and specific subsets of cDCs.
21784871	Breast Carcinoma	CSF2	Promote immunity	Furthermore, we showed that treatment with these NPs resulted in priming of the immune TME, characterized by increased IFN-gamma, p-STAT-1, GM-CSF, IL-2, IL-15, and IL-12b and reduced TGF-beta, IL-6, and IL-10 protein expression. In addition, we found significantly increased tumor infiltration by activated CD8(+) T cells, M1 macrophages, and dendritic cells.
21784871	Breast Carcinoma	IFNG	Promote immunity	Furthermore, we showed that treatment with these NPs resulted in priming of the immune TME, characterized by increased IFN-gamma, p-STAT-1, GM-CSF, IL-2, IL-15, and IL-12b and reduced TGF-beta, IL-6, and IL-10 protein expression. In addition, we found significantly increased tumor infiltration by activated CD8(+) T cells, M1 macrophages, and dendritic cells.
21784871	Breast Carcinoma	STAT1	Promote immunity	Furthermore, we showed that treatment with these NPs resulted in priming of the immune TME, characterized by increased IFN-gamma, p-STAT-1, GM-CSF, IL-2, IL-15, and IL-12b and reduced TGF-beta, IL-6, and IL-10 protein expression. In addition, we found significantly increased tumor infiltration by activated CD8(+) T cells, M1 macrophages, and dendritic cells.
21784871	Breast Carcinoma	IL2	Promote immunity	Furthermore, we showed that treatment with these NPs resulted in priming of the immune TME, characterized by increased IFN-gamma, p-STAT-1, GM-CSF, IL-2, IL-15, and IL-12b and reduced TGF-beta, IL-6, and IL-10 protein expression. In addition, we found significantly increased tumor infiltration by activated CD8(+) T cells, M1 macrophages, and dendritic cells.
21784871	Breast Carcinoma	IL15	Promote immunity	Furthermore, we showed that treatment with these NPs resulted in priming of the immune TME, characterized by increased IFN-gamma, p-STAT-1, GM-CSF, IL-2, IL-15, and IL-12b and reduced TGF-beta, IL-6, and IL-10 protein expression. In addition, we found significantly increased tumor infiltration by activated CD8(+) T cells, M1 macrophages, and dendritic cells.
21784871	Breast Carcinoma	IL12B	Promote immunity	Furthermore, we showed that treatment with these NPs resulted in priming of the immune TME, characterized by increased IFN-gamma, p-STAT-1, GM-CSF, IL-2, IL-15, and IL-12b and reduced TGF-beta, IL-6, and IL-10 protein expression. In addition, we found significantly increased tumor infiltration by activated CD8(+) T cells, M1 macrophages, and dendritic cells.
21784871	Breast Carcinoma	TGFB1	Inhibit immunity	Furthermore, we showed that treatment with these NPs resulted in priming of the immune TME, characterized by increased IFN-gamma, p-STAT-1, GM-CSF, IL-2, IL-15, and IL-12b and reduced TGF-beta, IL-6, and IL-10 protein expression. In addition, we found significantly increased tumor infiltration by activated CD8(+) T cells, M1 macrophages, and dendritic cells.
21784871	Breast Carcinoma	IL6	Inhibit immunity	Furthermore, we showed that treatment with these NPs resulted in priming of the immune TME, characterized by increased IFN-gamma, p-STAT-1, GM-CSF, IL-2, IL-15, and IL-12b and reduced TGF-beta, IL-6, and IL-10 protein expression. In addition, we found significantly increased tumor infiltration by activated CD8(+) T cells, M1 macrophages, and dendritic cells.
21784871	Breast Carcinoma	IL10	Inhibit immunity	Furthermore, we showed that treatment with these NPs resulted in priming of the immune TME, characterized by increased IFN-gamma, p-STAT-1, GM-CSF, IL-2, IL-15, and IL-12b and reduced TGF-beta, IL-6, and IL-10 protein expression. In addition, we found significantly increased tumor infiltration by activated CD8(+) T cells, M1 macrophages, and dendritic cells.
21782419	pancreatic carcinoma	LGALS1	Inhibit immunity	PSCs that overexpressed Galectin-1 induced apoptosis of CD4(+) T cells (p < 0.01) and CD8(+) T cells (p < 0.05) significantly, compared to normal PSCs. Knockdown of Galectin-1 in PSCs increased CD4(+) T cell (p < 0.01) and CD8(+) T cell viability (p < 0.05). Supernatants from T cells cocultured with PSCs that overexpressed Galectin-1 contained significantly increased levels of Th2 cytokines (IL-4 and IL-5, p < 0.01) and decreased Th1 cytokines (IL-2 and INF-gamma, p < 0.01).
21782419	pancreatic carcinoma	IL4	Inhibit immunity	PSCs that overexpressed Galectin-1 induced apoptosis of CD4(+) T cells (p < 0.01) and CD8(+) T cells (p < 0.05) significantly, compared to normal PSCs. Knockdown of Galectin-1 in PSCs increased CD4(+) T cell (p < 0.01) and CD8(+) T cell viability (p < 0.05). Supernatants from T cells cocultured with PSCs that overexpressed Galectin-1 contained significantly increased levels of Th2 cytokines (IL-4 and IL-5, p < 0.01) and decreased Th1 cytokines (IL-2 and INF-gamma, p < 0.01).
21782419	pancreatic carcinoma	IL2	Promote immunity	PSCs that overexpressed Galectin-1 induced apoptosis of CD4(+) T cells (p < 0.01) and CD8(+) T cells (p < 0.05) significantly, compared to normal PSCs. Knockdown of Galectin-1 in PSCs increased CD4(+) T cell (p < 0.01) and CD8(+) T cell viability (p < 0.05). Supernatants from T cells cocultured with PSCs that overexpressed Galectin-1 contained significantly increased levels of Th2 cytokines (IL-4 and IL-5, p < 0.01) and decreased Th1 cytokines (IL-2 and INF-gamma, p < 0.01).
21782419	pancreatic carcinoma	IFNG	Promote immunity	PSCs that overexpressed Galectin-1 induced apoptosis of CD4(+) T cells (p < 0.01) and CD8(+) T cells (p < 0.05) significantly, compared to normal PSCs. Knockdown of Galectin-1 in PSCs increased CD4(+) T cell (p < 0.01) and CD8(+) T cell viability (p < 0.05). Supernatants from T cells cocultured with PSCs that overexpressed Galectin-1 contained significantly increased levels of Th2 cytokines (IL-4 and IL-5, p < 0.01) and decreased Th1 cytokines (IL-2 and INF-gamma, p < 0.01).
17016559	colon carcinoma	IFNG	Inhibit immunity	CD11b+IL-4Ralpha+ cells produced IL-13 and IFN-gamma and integrated the downstream signals of these cytokines to trigger the molecular pathways suppressing antigen-activated CD8+ T lymphocytes. Analogous immunosuppressive circuits were active in CD11b+ cells present within the tumor microenvironment.
17016559	colon carcinoma	IL13	Inhibit immunity	CD11b+IL-4Ralpha+ cells produced IL-13 and IFN-gamma and integrated the downstream signals of these cytokines to trigger the molecular pathways suppressing antigen-activated CD8+ T lymphocytes. Analogous immunosuppressive circuits were active in CD11b+ cells present within the tumor microenvironment.
17015756	colon carcinoma	PRF1	Promote immunity	Notably, redirected CD4+ T cells mediate cytolysis of CEA+ tumor cells with high efficiencies. Lysis by redirected CD4+ T cells is independent of death receptor signaling via TNF-alpha or Fas, but mediated by perforin and granzyme because cytolysis is inhibited by blocking the release of cytotoxic granules, but not by blocking of Fas ligand or TNF-alpha.
17015756	colon carcinoma	GZMB	Promote immunity	Notably, redirected CD4+ T cells mediate cytolysis of CEA+ tumor cells with high efficiencies. Lysis by redirected CD4+ T cells is independent of death receptor signaling via TNF-alpha or Fas, but mediated by perforin and granzyme because cytolysis is inhibited by blocking the release of cytotoxic granules, but not by blocking of Fas ligand or TNF-alpha.
17015756	colon carcinoma	GZMA	Promote immunity	Notably, redirected CD4+ T cells mediate cytolysis of CEA+ tumor cells with high efficiencies. Lysis by redirected CD4+ T cells is independent of death receptor signaling via TNF-alpha or Fas, but mediated by perforin and granzyme because cytolysis is inhibited by blocking the release of cytotoxic granules, but not by blocking of Fas ligand or TNF-alpha.
17000687	Melanoma	PMEL	Promote immunity	DNAs encoding cytokines that affect T cells [interleukin (IL)-2, IL-12, IL-15, IL-18, IL-21, and the chemokine CCL21] and antigen-presenting cells [granulocyte macrophage colony-stimulating factor (GM-CSF)] were compared in mouse models as adjuvants to enhance CD8+ T-cell responses and tumor immunity. We found that (a) cytokine DNAs generally increased CD8+ T-cell responses against gp100; (b) ligation to Fc domains further enhanced T-cell responses
17000676	pancreatic carcinoma	CD4	Inhibit immunity	CD4+CD25+ regulatory T cells (TR) play a central role in self-tolerance and suppress effective antitumor immune responses. The prevalence of TR was significantly increased in the ductal adenocarcinomas compared with that in the stroma of nonneoplastic inflammation (P<0.0001). T(R) play a role in controlling the immune response against pancreatic ductal carcinoma from the premalignant stage to established cancer. In pancreatic ductal carcinoma, a high prevalence of TR seems to be a marker of poor prognosis.
17000676	pancreatic carcinoma	IL2RA	Inhibit immunity	CD4+CD25+ regulatory T cells (TR) play a central role in self-tolerance and suppress effective antitumor immune responses. The prevalence of TR was significantly increased in the ductal adenocarcinomas compared with that in the stroma of nonneoplastic inflammation (P<0.0001). T(R) play a role in controlling the immune response against pancreatic ductal carcinoma from the premalignant stage to established cancer. In pancreatic ductal carcinoma, a high prevalence of TR seems to be a marker of poor prognosis.
16998881	Hepatocellular Carcinoma	GZMB	Promote immunity	Cytotoxic T lymphocyte (CTL) activity after WT p53 peptide-specific stimulation was assessed by analysis of granzyme B and interferon-gamma mRNA transcription, using a quantitative real-time polymerase chain reaction assay.
16998881	Hepatocellular Carcinoma	IFNG	Promote immunity	Cytotoxic T lymphocyte (CTL) activity after WT p53 peptide-specific stimulation was assessed by analysis of granzyme B and interferon-gamma mRNA transcription, using a quantitative real-time polymerase chain reaction assay.
16998881	Hepatocellular Carcinoma	TP53	Promote immunity	Our results indicate the existence of natural immunosurveillance and tumor immune evasion, involving a T cell response against WT p53 tumor antigen in patients with HCC.
16998790	Melanoma	IL18	Promote immunity	Here, we show that B16 melanoma cells actively modulate the interaction between DCs derived from bone marrow precursors and NK/LAK cells propagated from the spleen of C57BL/6 mice. DCs increased in a dose-dependent manner the ability of NK/LAK cells to kill melanoma cells and to produce cytokines. This activatory cross-talk entailed the production of IL-18 by DCs and of IFN-gamma by NK/LAK cells. Melanoma cells were not a passive target of NK activity; they regulated the outcome of the interaction between DCs and NK/LAK cells, inhibiting the in vitro production of cytokines as effectively as the genetic deletion of IL-18 or IFN-gamma.
16998790	Melanoma	IFNG	Promote immunity	Here, we show that B16 melanoma cells actively modulate the interaction between DCs derived from bone marrow precursors and NK/LAK cells propagated from the spleen of C57BL/6 mice. DCs increased in a dose-dependent manner the ability of NK/LAK cells to kill melanoma cells and to produce cytokines. This activatory cross-talk entailed the production of IL-18 by DCs and of IFN-gamma by NK/LAK cells. Melanoma cells were not a passive target of NK activity; they regulated the outcome of the interaction between DCs and NK/LAK cells, inhibiting the in vitro production of cytokines as effectively as the genetic deletion of IL-18 or IFN-gamma.
16997859	mastocytoma	KLRD1	Inhibit immunity	All NK clones analyzed (n 50) were CD3–, CD94 , CD56 (90% bright, 10% dim), whereas 50% were NKvSF1 . Using a classical, redirected killing assay [9], we found that CD94 was expressed in the activatory form by 25% and in the inhibitory form by 75% of the clones. Among NKvSF1 clones, the ratio was inverted (25% expressed the inhibitory form and 75% the activatory form of the receptor).
29632540	Burkitt’s lymphoma; acute myeloid leukemia	KIR2DL3	Inhibit immunity	We found that DAC upregulated KIR2DL2/3 expression in KIR2DL2/3-negative γδ T cells by inhibiting KIR2DL2/3 promoter methylation, which enhances the binding of KIR2DL2/3 promoter to Sp-1 and activates KIR2DL2/3 gene expression.
16990779	leukemia	WT1	Promote immunity	Importantly, T cells stimulated with the new analogs crossreacted with the native WT1 peptide sequence and were able to kill HLA-matched chronic myeloid leukemia cell lines. In conclusion, analog heteroclitic WT1 peptides with increased immunogenicity can be synthesized and are potential cancer vaccine candidates.
16990769	leukemia	CD40LG	Promote immunity	In conclusion, stimulation of T cells with CD40L+BCP-ALL cells-loaded DC not only elicited the generation of potent and specific anti-leukemic cytotoxic effectors, but also the differentiation of specific and functional Th-1 CD4 lymphocytes. These effectors are fully equipped to reach leukemia-infiltrated tissues and have characteristics to support and orchestrate the anti-tumor immune-response.
16990769	leukemia	IFNG	Promote immunity	After 21-day co-culture with DC pulsed with CD40L+ apoptotic BCP-ALL blasts, T cells presented with both effector and central memory phenotype, and showed high and specific cytotoxic activity against leukemic cells (average lysis = 77%), mostly mediated by CD8+ T cells. Noticeably, growth of CD4 T cells was maintained (45% of total cells), which actively produced Th1 cytokines (IFN-gamma, TNF-alpha, IL-2), but not IL-4, IL-5 and IL-10.
16990769	leukemia	TNF	Promote immunity	After 21-day co-culture with DC pulsed with CD40L+ apoptotic BCP-ALL blasts, T cells presented with both effector and central memory phenotype, and showed high and specific cytotoxic activity against leukemic cells (average lysis = 77%), mostly mediated by CD8+ T cells. Noticeably, growth of CD4 T cells was maintained (45% of total cells), which actively produced Th1 cytokines (IFN-gamma, TNF-alpha, IL-2), but not IL-4, IL-5 and IL-10.
16990769	leukemia	IL2	Promote immunity	After 21-day co-culture with DC pulsed with CD40L+ apoptotic BCP-ALL blasts, T cells presented with both effector and central memory phenotype, and showed high and specific cytotoxic activity against leukemic cells (average lysis = 77%), mostly mediated by CD8+ T cells. Noticeably, growth of CD4 T cells was maintained (45% of total cells), which actively produced Th1 cytokines (IFN-gamma, TNF-alpha, IL-2), but not IL-4, IL-5 and IL-10.
16990769	leukemia	CXCR4	Promote immunity(infiltration)	Anti-BCP-ALL T cells expressed CD49d and CXCR4 (implicated in the recruitment to bone marrow), and CD62L and CCR7 (involved in the migration to lymphoid organs). In accordance with this profile, T cells significantly migrated in response to the chemokines CXCL12 and CCL19.
16990769	leukemia	CXCL12	Promote immunity(infiltration)	Anti-BCP-ALL T cells expressed CD49d and CXCR4 (implicated in the recruitment to bone marrow), and CD62L and CCR7 (involved in the migration to lymphoid organs). In accordance with this profile, T cells significantly migrated in response to the chemokines CXCL12 and CCL19.
16990769	leukemia	CCL19	Promote immunity(infiltration)	Anti-BCP-ALL T cells expressed CD49d and CXCR4 (implicated in the recruitment to bone marrow), and CD62L and CCR7 (involved in the migration to lymphoid organs). In accordance with this profile, T cells significantly migrated in response to the chemokines CXCL12 and CCL19.
16990769	leukemia	CCR7	Promote immunity(infiltration)	Anti-BCP-ALL T cells expressed CD49d and CXCR4 (implicated in the recruitment to bone marrow), and CD62L and CCR7 (involved in the migration to lymphoid organs). In accordance with this profile, T cells significantly migrated in response to the chemokines CXCL12 and CCL19.
16985173	lymphoma	LTA	Inhibit immunity	Our findings strongly suggest that secondary lymphoid organs contain MSCs able to give rise to adipocytes, chondrocytes, osteoblasts, as well as fully functional B-cell supportive FRCs. In vitro, bone marrow-derived MSCs acquire a complete FRC phenotype in response to a combination of tumor necrosis factor-alpha and lymphotoxin-alpha1beta2. Moreover, MSCs recruit primary FL cells that, in turn, trigger their differentiation into FRCs, making them able to support malignant B-cell survival.
16982933	leukemia	LUZP6	Promote immunity	Furthermore, the MPD6-IRES-mediated translation, but not myotrophin-MPD6 transcription, was significantly up-regulated in response to IFN-alpha stimulation. The eliciting antitumor immune response against unconventional Ag MPD6 in patients with myeloproliferative diseases suggests MPD6 as a potential target of novel immunotherapy.
16982933	leukemia	IFNA1	Promote immunity	Furthermore, the MPD6-IRES-mediated translation, but not myotrophin-MPD6 transcription, was significantly up-regulated in response to IFN-alpha stimulation. The eliciting antitumor immune response against unconventional Ag MPD6 in patients with myeloproliferative diseases suggests MPD6 as a potential target of novel immunotherapy.
16982932	lymphoma	IL2	Promote immunity	A single stimulation of CD8+ T cells from healthy virus carriers, and patients with HL with this adenoviral construct in combination with IL-2, was sufficient to reverse the functional T cell impairment and restored both IFN-gamma production and cytolytic function.
16982932	lymphoma	IFNG	Promote immunity	A single stimulation of CD8+ T cells from healthy virus carriers, and patients with HL with this adenoviral construct in combination with IL-2, was sufficient to reverse the functional T cell impairment and restored both IFN-gamma production and cytolytic function.
16982889	mastocytoma	RAG2	Inhibit immunity	An adoptive transfer model was developed in which tumor-specific 2C/RAG2(-/-) TCR transgenic CD8+ T cells were introduced either into the lymphopenic environment of RAG2(-/-) mice or into P14/RAG2(-/-) mice containing an irrelevant CD8+ TCR transgenic population. RAG2(-/-), but not P14/RAG2(-/-) recipients supported homeostatic proliferation of transferred T cells as well as tumor rejection.
16982889	mastocytoma	IFNG	Promote immunity	However, these cells showed poor IFN-gamma and IL-2 production upon restimulation, consistent with T cell anergy and similar to the hyporesponsiveness induced by administration of soluble peptide Ag.
16982889	mastocytoma	IL2	Promote immunity	However, these cells showed poor IFN-gamma and IL-2 production upon restimulation, consistent with T cell anergy and similar to the hyporesponsiveness induced by administration of soluble peptide Ag.
16982863	Melanoma	RRAD	Promote immunity	In the s.c. injected B16h5T4 melanoma model, early local but not systemic i.v. administration of syngeneic h5T4-specific CR T cells significantly increased mice survival. This improvement was further enhanced when combined with immunization with Rad.h5T4, followed by post-CR T cell treatment with BMDC in the active therapy model, possibly through mechanisms of enhancing Ag-specific cellular immune responses
16982775	Renal cell carcinoma	IL2	Inhibit immunity	During the IL-2 treatment, the ATRA effect was completely eliminated. To assess the role of IL-2, specimens from 15 patients with metastatic renal cell carcinoma who had been treated with i.v. IL-2 alone were analyzed. In this group also, IL-2 significantly reduced the number and function of dendritic cells as well as T-cell function.
16982774	Melanoma	TGFB1	Inhibit immunity	Here, we report the first evidence that tumor-released microvesicles alter myeloid cell function by impairing monocyte differentiation into dendritic cells and promoting the generation of a myeloid immunosuppressive cell subset. These phenotypic changes were paralleled by a significant release of different cytokines, including IL-6, tumor necrosis factor-alpha, and transforming growth factor-beta (TGF-beta), and a dose-dependent suppressive activity on activated T-cell-proliferation and cytolytic functions, which could be reversed by anti-TGF-beta-neutralizing antibodies.
16982774	Melanoma	IL6	Inhibit immunity	CD14+ monocytes isolated from healthy donors and differentiated with interleukin (IL)-4 and granulocyte macrophage colony-stimulating factor in the presence of tumor-derived microvesicles turned into HLA-DR(-/low) cells, retaining CD14 expression and failing to up-regulate costimulatory molecules, such as CD80 and CD86.These phenotypic changes were paralleled by a significant release of different cytokines, including IL-6, tumor necrosis factor-alpha, and transforming growth factor-beta (TGF-beta), and a dose-dependent suppressive activity on activated T-cell-proliferation and cytolytic functions, which could be reversed by anti-TGF-beta-neutralizing antibodies.
16982774	Melanoma	TNF	Inhibit immunity	CD14+ monocytes isolated from healthy donors and differentiated with interleukin (IL)-4 and granulocyte macrophage colony-stimulating factor in the presence of tumor-derived microvesicles turned into HLA-DR(-/low) cells, retaining CD14 expression and failing to up-regulate costimulatory molecules, such as CD80 and CD86.These phenotypic changes were paralleled by a significant release of different cytokines, including IL-6, tumor necrosis factor-alpha, and transforming growth factor-beta (TGF-beta), and a dose-dependent suppressive activity on activated T-cell-proliferation and cytolytic functions, which could be reversed by anti-TGF-beta-neutralizing antibodies.
16980511	Breast Carcinoma	CXCL10	Promote immunity (infiltration)	Mechanical analysis showed that targeted expression of IP-10 in 4T1 tumor cells markedly enhanced the infiltration of tumor-specific T cells into the 4T1-IP-10 tumor. These tumor infiltrating T lymphocytes (TILs) recruited by IP-10 were potent cytolytic killers against 4T1 tumor cells and were able to proliferate and produce high levels of IFN-gamma in response to 4T1 cells. In vivo administration of IP-10-recruited TILs induced vigorous proliferation of these TILs in situ in the 4T1-IP-10 tumor but not in the 4T1-pcDNA3 and parental 4T1 tumors.
16980511	Breast Carcinoma	IFNG	Promote immunity	Mechanical analysis showed that targeted expression of IP-10 in 4T1 tumor cells markedly enhanced the infiltration of tumor-specific T cells into the 4T1-IP-10 tumor. These tumor infiltrating T lymphocytes (TILs) recruited by IP-10 were potent cytolytic killers against 4T1 tumor cells and were able to proliferate and produce high levels of IFN-gamma in response to 4T1 cells. In vivo administration of IP-10-recruited TILs induced vigorous proliferation of these TILs in situ in the 4T1-IP-10 tumor but not in the 4T1-pcDNA3 and parental 4T1 tumors.
16968820	Melanoma	HMGB1	Promote immunity	HMGB1, along with other intracellular factors released from tumor cells induced by cytolysis, may be important components of the disordered tumor microenvironment.
16968820	Melanoma	IL2	Promote immunity	We examined HMGB1 release from tumor cells following coincubation with NK cells with enhanced lymphokine-activated killing (LAK) activity, induced by IL-2 exposure or mediated by melanoma-specific CTL
11875499	colon carcinoma	TNF	Promote immunity	CTL and NK cells promote tumor cell apoptosis with delivery of perforin and granzymes directly into cells or through the extrinsic pathway, inducing apoptotic death by triggering death receptors by the TNF family of molecules, including TRAIL, TNF- , Fas ligand (FasL), and lymphotoxin (LT), thereby inducing apoptosis in cells.
11875499	colon carcinoma	TNFSF10	Promote immunity	CTL and NK cells promote tumor cell apoptosis with delivery of perforin and granzymes directly into cells or through the extrinsic pathway, inducing apoptotic death by triggering death receptors by the TNF family of molecules, including TRAIL, TNF- , Fas ligand (FasL), and lymphotoxin (LT), thereby inducing apoptosis in cells.
11875499	colon carcinoma	FASLG	Promote immunity	CTL and NK cells promote tumor cell apoptosis with delivery of perforin and granzymes directly into cells or through the extrinsic pathway, inducing apoptotic death by triggering death receptors by the TNF family of molecules, including TRAIL, TNF- , Fas ligand (FasL), and lymphotoxin (LT), thereby inducing apoptosis in cells.
11875499	colon carcinoma	LTA	Promote immunity	CTL and NK cells promote tumor cell apoptosis with delivery of perforin and granzymes directly into cells or through the extrinsic pathway, inducing apoptotic death by triggering death receptors by the TNF family of molecules, including TRAIL, TNF- , Fas ligand (FasL), and lymphotoxin (LT), thereby inducing apoptosis in cells.
16953240	Melanoma	IFNG	Promote immunity	Finally, we show that in situ tumour ablation can be efficiently combined with immune modulation by anti-CTLA-4 antibodies or regulatory T-cell depletion. These combination treatments protected mice from the outgrowth of tumour challenges, and led to in vivo enhancement of tumour-specific T-cell numbers, which produced more IFN-gamma upon activation.
16953240	Melanoma	CTLA4	Inhibit immunity	Finally, we show that in situ tumour ablation can be efficiently combined with immune modulation by anti-CTLA-4 antibodies or regulatory T-cell depletion. These combination treatments protected mice from the outgrowth of tumour challenges, and led to in vivo enhancement of tumour-specific T-cell numbers, which produced more IFN-gamma upon activation.
16951315	Melanoma	IFNB1	Promote immunity	Even though the expression of surface markers for DC activation ex vivo did not always reach the level attained by an optimized amount of LPS, superior antitumor effects to B16F1 melanoma, namely tumor elimination and survival, were obtained with use of SeV-GFP/DC as compared with those seen with LPS/DC in vivo, and the effect was enhanced by SeV/DC-expressing IFN-beta (SeV-murine IFN-beta (mIFN-beta)/DC).
16951314	PAN-Cancer	IFNG	Promote immunity	Experiments with ERK-1/2 inhibitors demonstrated that bryostatin-1 induction of IFN- gamma and T-bet was ERK-dependent and IL-12-independent. Similar results were obtained from both normal donors and cancer patients. In summary, our results suggest that bryostatin-1-induced IFN-gamma expression is T-bet independent. They also suggest for the first time that IFN- gamma and T-bet can be induced in human DC through an ERK-dependent pathway. Bryostatin-1-induced IFN- gamma may play a crucial role in the initiation of the immune response, before specific recognition by T cells that could be beneficial in the treatment of cancer.
16951314	PAN-Cancer	MAPK3	Promote immunity	Experiments with ERK-1/2 inhibitors demonstrated that bryostatin-1 induction of IFN- gamma and T-bet was ERK-dependent and IL-12-independent. Similar results were obtained from both normal donors and cancer patients. In summary, our results suggest that bryostatin-1-induced IFN-gamma expression is T-bet independent. They also suggest for the first time that IFN- gamma and T-bet can be induced in human DC through an ERK-dependent pathway. Bryostatin-1-induced IFN- gamma may play a crucial role in the initiation of the immune response, before specific recognition by T cells that could be beneficial in the treatment of cancer.
16951314	PAN-Cancer	MAPK1	Promote immunity	Experiments with ERK-1/2 inhibitors demonstrated that bryostatin-1 induction of IFN- gamma and T-bet was ERK-dependent and IL-12-independent. Similar results were obtained from both normal donors and cancer patients. In summary, our results suggest that bryostatin-1-induced IFN-gamma expression is T-bet independent. They also suggest for the first time that IFN- gamma and T-bet can be induced in human DC through an ERK-dependent pathway. Bryostatin-1-induced IFN- gamma may play a crucial role in the initiation of the immune response, before specific recognition by T cells that could be beneficial in the treatment of cancer.
16931630	leukemia	HMMR	Promote immunity	Specific T-cell responses were detected in 8 (47%) of 17 patients with AML in complete remission for RHAMM/HMMR-R3 peptide, in 7 (70%) of 10 for PRAME-P3 peptide, and in 6 (60%) of 10 for newly characterized G250/CA9-G2 peptide, a significant increased immune response compared with patients with AML patients who had refractory disease. In conclusion, expression of the TAAs RHAMM/HMMR, PRAME, and G250/CA9 can induce strong antileukemic immune responses, possibly enabling MRD control.
16931630	leukemia	PRAME	Promote immunity	Specific T-cell responses were detected in 8 (47%) of 17 patients with AML in complete remission for RHAMM/HMMR-R3 peptide, in 7 (70%) of 10 for PRAME-P3 peptide, and in 6 (60%) of 10 for newly characterized G250/CA9-G2 peptide, a significant increased immune response compared with patients with AML patients who had refractory disease. In conclusion, expression of the TAAs RHAMM/HMMR, PRAME, and G250/CA9 can induce strong antileukemic immune responses, possibly enabling MRD control.
16931630	leukemia	CA9	Promote immunity	Specific T-cell responses were detected in 8 (47%) of 17 patients with AML in complete remission for RHAMM/HMMR-R3 peptide, in 7 (70%) of 10 for PRAME-P3 peptide, and in 6 (60%) of 10 for newly characterized G250/CA9-G2 peptide, a significant increased immune response compared with patients with AML patients who had refractory disease. In conclusion, expression of the TAAs RHAMM/HMMR, PRAME, and G250/CA9 can induce strong antileukemic immune responses, possibly enabling MRD control.
16931626	leukemia; renal cell carcinoma	TNFRSF9	Promote immunity	In vitro expansion of tumor-reactive T cells followed by CD137-mediated SAD might enhance the antitumor efficacy of T-cell allografts with lower risk of inducing GVHD
16929491	pancreatic carcinoma	MICA	Inhibit immunity	Our results demonstrate that sMIC impairs NKG2D-mediated immunity against pancreatic carcinoma by directly diminishing cytotoxicity of gammadelta T cells and NK cells. IFN-alpha, which is used in adjuvant treatment of pancreatic carcinoma, might partly act via up-regulation of MIC without induction of sMIC release.
16929491	pancreatic carcinoma	MICB	Inhibit immunity	Our results demonstrate that sMIC impairs NKG2D-mediated immunity against pancreatic carcinoma by directly diminishing cytotoxicity of gammadelta T cells and NK cells. IFN-alpha, which is used in adjuvant treatment of pancreatic carcinoma, might partly act via up-regulation of MIC without induction of sMIC release.
16929491	pancreatic carcinoma	KLRK1	Promote immunity	Our results demonstrate that sMIC impairs NKG2D-mediated immunity against pancreatic carcinoma by directly diminishing cytotoxicity of gammadelta T cells and NK cells. IFN-alpha, which is used in adjuvant treatment of pancreatic carcinoma, might partly act via up-regulation of MIC without induction of sMIC release.
16920991	leukemia	IFNG	Promote immunity	We found that imatinib-treated CML-chronic phase patients showing a complete cytogenetic response had NKT cells capable of producing IFN-gamma, whereas NKT cells from patients who were only partially responsive to imatinib treatment did not produce IFN-gamma
16920987	pancreatic carcinoma	NR3C2	Promote immunity	Medium conditioned by human pancreatic carcinoma cells inhibited iMo-DC proliferation, expression of costimulatory molecules (CD80 and CD40) and of HLA-DR, and functional activity as assessed by MLR and IL-12p70 production. iMo-DC generated from pancreatic carcinoma patients in advanced stages of the disease similarly showed decreased levels of HLA-DR expression and reduced ability to stimulate MLR in response to CD40L and IFN-gamma.
16920987	pancreatic carcinoma	CD80	Promote immunity	Medium conditioned by human pancreatic carcinoma cells inhibited iMo-DC proliferation, expression of costimulatory molecules (CD80 and CD40) and of HLA-DR, and functional activity as assessed by MLR and IL-12p70 production. iMo-DC generated from pancreatic carcinoma patients in advanced stages of the disease similarly showed decreased levels of HLA-DR expression and reduced ability to stimulate MLR in response to CD40L and IFN-gamma.
16920987	pancreatic carcinoma	CD40	Promote immunity	Medium conditioned by human pancreatic carcinoma cells inhibited iMo-DC proliferation, expression of costimulatory molecules (CD80 and CD40) and of HLA-DR, and functional activity as assessed by MLR and IL-12p70 production. iMo-DC generated from pancreatic carcinoma patients in advanced stages of the disease similarly showed decreased levels of HLA-DR expression and reduced ability to stimulate MLR in response to CD40L and IFN-gamma.
16920987	pancreatic carcinoma	IL12B	Promote immunity	Medium conditioned by human pancreatic carcinoma cells inhibited iMo-DC proliferation, expression of costimulatory molecules (CD80 and CD40) and of HLA-DR, and functional activity as assessed by MLR and IL-12p70 production. iMo-DC generated from pancreatic carcinoma patients in advanced stages of the disease similarly showed decreased levels of HLA-DR expression and reduced ability to stimulate MLR in response to CD40L and IFN-gamma.
16920987	pancreatic carcinoma	IL12A	Promote immunity	Medium conditioned by human pancreatic carcinoma cells inhibited iMo-DC proliferation, expression of costimulatory molecules (CD80 and CD40) and of HLA-DR, and functional activity as assessed by MLR and IL-12p70 production. iMo-DC generated from pancreatic carcinoma patients in advanced stages of the disease similarly showed decreased levels of HLA-DR expression and reduced ability to stimulate MLR in response to CD40L and IFN-gamma.
16920987	pancreatic carcinoma	CD40LG	Promote immunity	Medium conditioned by human pancreatic carcinoma cells inhibited iMo-DC proliferation, expression of costimulatory molecules (CD80 and CD40) and of HLA-DR, and functional activity as assessed by MLR and IL-12p70 production. iMo-DC generated from pancreatic carcinoma patients in advanced stages of the disease similarly showed decreased levels of HLA-DR expression and reduced ability to stimulate MLR in response to CD40L and IFN-gamma.
16920987	pancreatic carcinoma	IFNG	Promote immunity	Medium conditioned by human pancreatic carcinoma cells inhibited iMo-DC proliferation, expression of costimulatory molecules (CD80 and CD40) and of HLA-DR, and functional activity as assessed by MLR and IL-12p70 production. iMo-DC generated from pancreatic carcinoma patients in advanced stages of the disease similarly showed decreased levels of HLA-DR expression and reduced ability to stimulate MLR in response to CD40L and IFN-gamma.
16920987	pancreatic carcinoma	HLA-DRB1	Promote immunity	Medium conditioned by human pancreatic carcinoma cells inhibited iMo-DC proliferation, expression of costimulatory molecules (CD80 and CD40) and of HLA-DR, and functional activity as assessed by MLR and IL-12p70 production. iMo-DC generated from pancreatic carcinoma patients in advanced stages of the disease similarly showed decreased levels of HLA-DR expression and reduced ability to stimulate MLR in response to CD40L and IFN-gamma.
16917008	Multiple myeloma(IgA, IgD, IgE, IgM, IgG)	CD1A	Promote immunity	We found that patient-derived MoDCs are phenotypically and functionally defective. Compared with their normal counterparts, patient-derived, mature MoDCs expressed significantly lower levels of CD1a, CD40, CD80, and HLA-DR and were poor at activating alloreactive T cells, presenting recall antigen, and activating autologous antigen- and myeloma-specific T cells.
16917008	Multiple myeloma(IgA, IgD, IgE, IgM, IgG)	CD40	Promote immunity	We found that patient-derived MoDCs are phenotypically and functionally defective. Compared with their normal counterparts, patient-derived, mature MoDCs expressed significantly lower levels of CD1a, CD40, CD80, and HLA-DR and were poor at activating alloreactive T cells, presenting recall antigen, and activating autologous antigen- and myeloma-specific T cells.
16917008	Multiple myeloma(IgA, IgD, IgE, IgM, IgG)	CD80	Promote immunity	We found that patient-derived MoDCs are phenotypically and functionally defective. Compared with their normal counterparts, patient-derived, mature MoDCs expressed significantly lower levels of CD1a, CD40, CD80, and HLA-DR and were poor at activating alloreactive T cells, presenting recall antigen, and activating autologous antigen- and myeloma-specific T cells.
16917008	Multiple myeloma(IgA, IgD, IgE, IgM, IgG)	HLA-DRB1	Promote immunity	We found that patient-derived MoDCs are phenotypically and functionally defective. Compared with their normal counterparts, patient-derived, mature MoDCs expressed significantly lower levels of CD1a, CD40, CD80, and HLA-DR and were poor at activating alloreactive T cells, presenting recall antigen, and activating autologous antigen- and myeloma-specific T cells.
16917008	Multiple myeloma(IgA, IgD, IgE, IgM, IgG)	IL6	Inhibit immunity	These abnormalities may be attributed to elevated production of autocrine cytokines such as IL-6, activated p38 and STAT3, and inhibited MEK/ERK signaling pathways in the progenitor cells. Treatment with neutralizing IL-6-specific antibody and, more importantly, p38 inhibitor, or both, could correct these abnormalities. Treating patient-derived cells with these agents not only significantly increased cell yield but also produced MoDCs that were as functional as their normal counterparts.
16917008	Multiple myeloma(IgA, IgD, IgE, IgM, IgG)	MAPK14	Inhibit immunity	These abnormalities may be attributed to elevated production of autocrine cytokines such as IL-6, activated p38 and STAT3, and inhibited MEK/ERK signaling pathways in the progenitor cells. Treatment with neutralizing IL-6-specific antibody and, more importantly, p38 inhibitor, or both, could correct these abnormalities. Treating patient-derived cells with these agents not only significantly increased cell yield but also produced MoDCs that were as functional as their normal counterparts.
16917008	Multiple myeloma(IgA, IgD, IgE, IgM, IgG)	STAT3	Inhibit immunity	These abnormalities may be attributed to elevated production of autocrine cytokines such as IL-6, activated p38 and STAT3, and inhibited MEK/ERK signaling pathways in the progenitor cells. Treatment with neutralizing IL-6-specific antibody and, more importantly, p38 inhibitor, or both, could correct these abnormalities. Treating patient-derived cells with these agents not only significantly increased cell yield but also produced MoDCs that were as functional as their normal counterparts.
16917008	Multiple myeloma(IgA, IgD, IgE, IgM, IgG)	MAP2K1	Promote immunity	These abnormalities may be attributed to elevated production of autocrine cytokines such as IL-6, activated p38 and STAT3, and inhibited MEK/ERK signaling pathways in the progenitor cells. Treatment with neutralizing IL-6-specific antibody and, more importantly, p38 inhibitor, or both, could correct these abnormalities. Treating patient-derived cells with these agents not only significantly increased cell yield but also produced MoDCs that were as functional as their normal counterparts.
16917008	Multiple myeloma(IgA, IgD, IgE, IgM, IgG)	MAPK1	Promote immunity	These abnormalities may be attributed to elevated production of autocrine cytokines such as IL-6, activated p38 and STAT3, and inhibited MEK/ERK signaling pathways in the progenitor cells. Treatment with neutralizing IL-6-specific antibody and, more importantly, p38 inhibitor, or both, could correct these abnormalities. Treating patient-derived cells with these agents not only significantly increased cell yield but also produced MoDCs that were as functional as their normal counterparts.
16916931	Melanoma	ADORA2A	Inhibit immunity	We hypothesized that A2AR also protects cancerous tissues by inhibiting incoming antitumor T lymphocytes. Here we confirm this hypothesis by showing that genetic deletion of A2AR in the host resulted in rejection of established immunogenic tumors in approximately 60% of A2AR-deficient mice with no rejection observed in control WT mice.
16908932	Breast carcinoma; Ovarian carcinoma	FOLR1	Promote immunity	These findings demonstrate that the FRalpha is a target of the immune system in breast and ovarian cancer patients. Understanding which antigens are targeted by the immune system may be important for prognosis or immune-based therapies.
16906541	Glioma	TLR9	Promote immunity	Our results indicate that TLR9 is overexpressed in human and murine glioma cell lines and CpG stimulation prolongs the survival of mice with experimental brain tumors. CpGs induce TLR9 down-regulation, followed by apoptosis of GL261 cells in vitro as well as in vivo. Furthermore, the effects of CpG stimulation appear to enhance the antigen presenting capacity of microglia, shift the immune response toward CD8(+) T cells, and decrease the number of CD4(+)CD25(+) regulatory T cells.
16905462	Hepatocellular Carcinoma	CSF2	Promote immunity	Intravenous JX-594 was well tolerated and had highly significant efficacy, including complete responses, against intrahepatic primary tumors in both models. In addition, whereas lung metastases developed in all control rabbits, none of the i.v. JX-594-treated rabbits developed detectable metastases. Tumor-specific virus replication and gene expression, systemically detectable levels of hGM-CSF, and tumor-infiltrating CTLs were also demonstrated
16899622	colon carcinoma	IFNG	Promote immunity	The effect of CA4P was studied on tumor growth and on immune reactivity in vitro. RESULTS: Rats with preexisting tumor, immunized and treated with low-dose CA4P, had a significantly retarded tumor growth compared with rats receiving CA4P or immunization alone. Splenocytes from rats treated with this combination had a significantly enhanced antitumor immune response compared with splenocytes from control rats. Exposure of nonadherent splenocytes to CA4P in vitro did not enhance their proliferation. However, 3-hour pretreatment of adherent splenocytes with 0.3 microg/mL CA4P significantly enhanced proliferation and IFNgamma production of admixed nonadherent splenocytes, partly due to nitric oxide reduction.
16899618	Contralateral	IL13	Promote immunity	Cell depletion experiments in tumor-bearing animals indicated that both CD8(+) and CD4(+) T cells contribute to the regression of contralateral tumors through CTL activation in the periphery and cellular infiltration into tumors. In addition, intratumoral treatment into s.c. tumors of mice bearing metastatic lung tumors with IL13-PE38 showed not only the reduction of treated s.c. tumor but also the reduction of lung metastasis. Thus, IL13-PE38 mediates an antitumor effect not only directly but also indirectly by inducing a host CD8(+) T cell immune response.
16899618	Contralateral	IL13RA2	Promote immunity	When animals with IL-13Ralpha2-expressing D5 tumor (right) were injected with IL13-PE38, right flank tumors expressing the IL-13Ralpha2 chain not only showed dramatic regression but contralateral tumors (left flank) also showed tumor regression.
16899613	Bladder carcinoma	CD4	Promote immunity	Immunohistochemical staining for HLA class I, CD4, CD8, CD20, CD68, TIA-1, S-100, and FOXP3 was carried out on specimens from 30 patients who underwent BCG immunotherapy from whom both pretreatment and posttreatment specimens were obtained. Our data show that expression of HLA class I molecules on tumor cells contributes significantly to the therapeutic effect of BCG immunotherapy for bladder cancer. It is suggested that CTLs may be one of main effectors in this therapy.
16899613	Bladder carcinoma	CD8A	Promote immunity	Immunohistochemical staining for HLA class I, CD4, CD8, CD20, CD68, TIA-1, S-100, and FOXP3 was carried out on specimens from 30 patients who underwent BCG immunotherapy from whom both pretreatment and posttreatment specimens were obtained. Our data show that expression of HLA class I molecules on tumor cells contributes significantly to the therapeutic effect of BCG immunotherapy for bladder cancer. It is suggested that CTLs may be one of main effectors in this therapy.
16899613	Bladder carcinoma	MS4A1	Promote immunity	Immunohistochemical staining for HLA class I, CD4, CD8, CD20, CD68, TIA-1, S-100, and FOXP3 was carried out on specimens from 30 patients who underwent BCG immunotherapy from whom both pretreatment and posttreatment specimens were obtained. Our data show that expression of HLA class I molecules on tumor cells contributes significantly to the therapeutic effect of BCG immunotherapy for bladder cancer. It is suggested that CTLs may be one of main effectors in this therapy.
16899613	Bladder carcinoma	CD68	Promote immunity	Immunohistochemical staining for HLA class I, CD4, CD8, CD20, CD68, TIA-1, S-100, and FOXP3 was carried out on specimens from 30 patients who underwent BCG immunotherapy from whom both pretreatment and posttreatment specimens were obtained. Our data show that expression of HLA class I molecules on tumor cells contributes significantly to the therapeutic effect of BCG immunotherapy for bladder cancer. It is suggested that CTLs may be one of main effectors in this therapy.
16899613	Bladder carcinoma	S100A1	Promote immunity	Immunohistochemical staining for HLA class I, CD4, CD8, CD20, CD68, TIA-1, S-100, and FOXP3 was carried out on specimens from 30 patients who underwent BCG immunotherapy from whom both pretreatment and posttreatment specimens were obtained. Our data show that expression of HLA class I molecules on tumor cells contributes significantly to the therapeutic effect of BCG immunotherapy for bladder cancer. It is suggested that CTLs may be one of main effectors in this therapy.
16899610	melanoma; renal cell carcinoma	IL2	Promote immunity	Decitabine augmented hemoglobin F levels and altered DNA methylation and gene expression in peripheral blood mononuclear cells in a dose-independent manner that overlapped with the administration of IL-2. Objective responses occurred in 31% of melanoma patients. CONCLUSIONS: Decitabine can be safely administered with high-dose IL-2 and may enhance the activity of IL-2 in melanoma.
16891318	Glioblastoma	TGFB1	Inhibit immunity	We further delineate two independent mechanisms that can explain these expression patterns: (i) transforming growth factor-beta (TGF-beta) is upregulated during malignant progression and selectively downregulates MICA, ULBP2 and ULBP4 expression, while MICB, ULBP1 and ULBP3 are unaffected. (ii) Cleavage of MICA and ULBP2 is reduced by inhibition of metalloproteinases (MP), whereas no changes in the expression levels of other NKG2DL were detected. Consequently, NKG2DL-dependent NK cell-mediated lysis is enhanced by depletion of TGF-beta or inhibition of MP.
16891318	Glioblastoma	RAET1E	Promote immunity	We further delineate two independent mechanisms that can explain these expression patterns: (i) transforming growth factor-beta (TGF-beta) is upregulated during malignant progression and selectively downregulates MICA, ULBP2 and ULBP4 expression, while MICB, ULBP1 and ULBP3 are unaffected. (ii) Cleavage of MICA and ULBP2 is reduced by inhibition of metalloproteinases (MP), whereas no changes in the expression levels of other NKG2DL were detected. Consequently, NKG2DL-dependent NK cell-mediated lysis is enhanced by depletion of TGF-beta or inhibition of MP.
16891318	Glioblastoma	ULBP2	Promote immunity	We further delineate two independent mechanisms that can explain these expression patterns: (i) transforming growth factor-beta (TGF-beta) is upregulated during malignant progression and selectively downregulates MICA, ULBP2 and ULBP4 expression, while MICB, ULBP1 and ULBP3 are unaffected. (ii) Cleavage of MICA and ULBP2 is reduced by inhibition of metalloproteinases (MP), whereas no changes in the expression levels of other NKG2DL were detected. Consequently, NKG2DL-dependent NK cell-mediated lysis is enhanced by depletion of TGF-beta or inhibition of MP.
16891318	Glioblastoma	MICA	Promote immunity	We further delineate two independent mechanisms that can explain these expression patterns: (i) transforming growth factor-beta (TGF-beta) is upregulated during malignant progression and selectively downregulates MICA, ULBP2 and ULBP4 expression, while MICB, ULBP1 and ULBP3 are unaffected. (ii) Cleavage of MICA and ULBP2 is reduced by inhibition of metalloproteinases (MP), whereas no changes in the expression levels of other NKG2DL were detected. Consequently, NKG2DL-dependent NK cell-mediated lysis is enhanced by depletion of TGF-beta or inhibition of MP.
16891318	Glioblastoma	TGFB1	Inhibit immunity	We further delineate two independent mechanisms that can explain these expression patterns: (i) transforming growth factor-beta (TGF-beta) is upregulated during malignant progression and selectively downregulates MICA, ULBP2 and ULBP4 expression, while MICB, ULBP1 and ULBP3 are unaffected. (ii) Cleavage of MICA and ULBP2 is reduced by inhibition of metalloproteinases (MP), whereas no changes in the expression levels of other NKG2DL were detected. Consequently, NKG2DL-dependent NK cell-mediated lysis is enhanced by depletion of TGF-beta or inhibition of MP.
16891318	Glioblastoma	MMP1	Inhibit immunity	Yet again, MP inhibition by the broad spectrum inhibitors GM 6001 or MMP inhibitor III selectively enhanced the expression of MICA and ULBP2 on the surface of LNT- 229 cells but not of other NKG2DL (Fig. 4A). For MICA, this effect was significantly more prominent on control than on TGF-b1/2 siRNA cells. Thus, escape from NKG2D-mediated immune surveillance of malignant gliomas in vivo may be promoted by the inhibition of MICA and ULBP2 expression via an autocrine TGF-beta loop and by MP-dependent shedding from the cell surface.
16891318	Glioblastoma	MMP2	Promote immunity	Yet again, MP inhibition by the broad spectrum inhibitors GM 6001 or MMP inhibitor III selectively enhanced the expression of MICA and ULBP2 on the surface of LNT- 229 cells but not of other NKG2DL (Fig. 4A). For MICA, this effect was significantly more prominent on control than on TGF-b1/2 siRNA cells. Thus, escape from NKG2D-mediated immune surveillance of malignant gliomas in vivo may be promoted by the inhibition of MICA and ULBP2 expression via an autocrine TGF-beta loop and by MP-dependent shedding from the cell surface.
16891318	Glioblastoma	MMP3	Promote immunity	Yet again, MP inhibition by the broad spectrum inhibitors GM 6001 or MMP inhibitor III selectively enhanced the expression of MICA and ULBP2 on the surface of LNT- 229 cells but not of other NKG2DL (Fig. 4A). For MICA, this effect was significantly more prominent on control than on TGF-b1/2 siRNA cells. Thus, escape from NKG2D-mediated immune surveillance of malignant gliomas in vivo may be promoted by the inhibition of MICA and ULBP2 expression via an autocrine TGF-beta loop and by MP-dependent shedding from the cell surface.
16891318	Glioblastoma	MMP7	Promote immunity	Yet again, MP inhibition by the broad spectrum inhibitors GM 6001 or MMP inhibitor III selectively enhanced the expression of MICA and ULBP2 on the surface of LNT- 229 cells but not of other NKG2DL (Fig. 4A). For MICA, this effect was significantly more prominent on control than on TGF-b1/2 siRNA cells. Thus, escape from NKG2D-mediated immune surveillance of malignant gliomas in vivo may be promoted by the inhibition of MICA and ULBP2 expression via an autocrine TGF-beta loop and by MP-dependent shedding from the cell surface.
16891318	Glioblastoma	MMP13	Promote immunity	Yet again, MP inhibition by the broad spectrum inhibitors GM 6001 or MMP inhibitor III selectively enhanced the expression of MICA and ULBP2 on the surface of LNT- 229 cells but not of other NKG2DL (Fig. 4A). For MICA, this effect was significantly more prominent on control than on TGF-b1/2 siRNA cells. Thus, escape from NKG2D-mediated immune surveillance of malignant gliomas in vivo may be promoted by the inhibition of MICA and ULBP2 expression via an autocrine TGF-beta loop and by MP-dependent shedding from the cell surface.
16891318	Glioblastoma	MMP8	Promote immunity	Yet again, MP inhibition by the broad spectrum inhibitors GM 6001 or MMP inhibitor III selectively enhanced the expression of MICA and ULBP2 on the surface of LNT- 229 cells but not of other NKG2DL (Fig. 4A). For MICA, this effect was significantly more prominent on control than on TGF-b1/2 siRNA cells. Thus, escape from NKG2D-mediated immune surveillance of malignant gliomas in vivo may be promoted by the inhibition of MICA and ULBP2 expression via an autocrine TGF-beta loop and by MP-dependent shedding from the cell surface.
16891318	Glioblastoma	MMP9	Promote immunity	Yet again, MP inhibition by the broad spectrum inhibitors GM 6001 or MMP inhibitor III selectively enhanced the expression of MICA and ULBP2 on the surface of LNT- 229 cells but not of other NKG2DL (Fig. 4A). For MICA, this effect was significantly more prominent on control than on TGF-b1/2 siRNA cells. Thus, escape from NKG2D-mediated immune surveillance of malignant gliomas in vivo may be promoted by the inhibition of MICA and ULBP2 expression via an autocrine TGF-beta loop and by MP-dependent shedding from the cell surface.
16891318	Glioblastoma	KLRK1	Promote immunity	NKG2D ligands (NKG2DL) are expressed by infected and transformed cells. They transmit danger signals to NKG2D-expressing immune cells, leading to lysis of NKG2DL-expressing cells.
16888001	Breast Carcinoma	PTGS2	Inhibit immunity	Enhanced CTL activity was attributed to a significant decrease in levels of tumor-associated IDO, a negative regulator of T cell activity. We present data suggesting that inhibiting COX-2 activity in vivo regulates IDO expression within the tumor microenvironment; this is further corroborated in the MDA-MB-231 human breast cancer cell line.
16888001	Breast Carcinoma	IDO1	Inhibit immunity	Enhanced CTL activity was attributed to a significant decrease in levels of tumor-associated IDO, a negative regulator of T cell activity. We present data suggesting that inhibiting COX-2 activity in vivo regulates IDO expression within the tumor microenvironment; this is further corroborated in the MDA-MB-231 human breast cancer cell line.
16885376	Breast Carcinoma	FOXP3	Inhibit immunity	Repeated administration of anti-CD25 antibodies extends tumor-free survival, reduces carcinoma multiplicity, and leads to the manifestation of a natural antibody and CTL-mediated reactivity against r-Erbb2. Loss of Foxp3(+) Treg cells during anti-CD25 treatment remarkably caused the disappearance of Gr1(+) immature myeloid cells, suggesting a cross-talk between these two inhibitory immune cell types. Treg cell expansion associated with r-Erbb2 overexpression may be seen as a physiologic response to dampen the immune reaction elicited by local anomalous overexpression of a self-antigen.
16885333	colon carcinoma	IL10	Inhibit immunity	These data suggest that infections with enteric pathogens enhance T(R)-cell potency and protect against epithelial cancers later in life, potentially explaining paradoxical increases in cancer risk in developed countries having more stringent hygiene practices. The mammary and intestinal tumor development as well as the increase in proinflammatory mediators is suppressed by adoptive transfer of interleukin 10-competent CD4+CD45RB(lo)CD25+ regulatory (T(R)) cells.
16882704	Melanoma	CD8A	Promote immunity	We found that genetic removal of CTLA-4 induced activation and acquisition of effector functions in pmel-1 CD8 T cells, resulting in the rapid development of severe autoimmune vitiligo. These effects were abrogated by the removal of the CD4 T-cell population. Therefore, we propose that the lack of CTLA-4 on self/tumor antigen–specific CD8 T cells results in autoimmunity and tumor immunity only in the presence of nonspecific, dysregulated CD4 CTLA-4 / T cells.
16882704	Melanoma	CD4	Promote immunity	We found that genetic removal of CTLA-4 induced activation and acquisition of effector functions in pmel-1 CD8 T cells, resulting in the rapid development of severe autoimmune vitiligo. These effects were abrogated by the removal of the CD4 T-cell population. Therefore, we propose that the lack of CTLA-4 on self/tumor antigen–specific CD8 T cells results in autoimmunity and tumor immunity only in the presence of nonspecific, dysregulated CD4 CTLA-4 / T cells.
16882704	Melanoma	CTLA4	Inhibit immunity	We found that genetic removal of CTLA-4 induced activation and acquisition of effector functions in pmel-1 CD8 T cells, resulting in the rapid development of severe autoimmune vitiligo. These effects were abrogated by the removal of the CD4 T-cell population. Therefore, we propose that the lack of CTLA-4 on self/tumor antigen–specific CD8 T cells results in autoimmunity and tumor immunity only in the presence of nonspecific, dysregulated CD4 CTLA-4 / T cells.
16880256	Multiple myeloma(IgA, IgD, IgE, IgM, IgG)	BCL6	Inhibit immunity	In this study, we show that the clonogenicity of several human tumor cell lines and primary tumor cells from myeloma patients is enhanced by their interactions with DCs. Myeloma cells cultured in the presence of DCs have an altered phenotype with an increased proportion of cells lacking terminal plasma cell differentiation marker CD138. DC-tumor interaction also leads to the up-regulation of B cell lymphoma 6 expression in myeloma cells. Effects of DCs on myeloma cells are inhibited by blockade of the receptor activator of NF-kB (RANK)-RANK ligand and B cell-activating factor-APRIL (a proliferation-inducing ligand)-mediated interactions.
16880256	Multiple myeloma(IgA, IgD, IgE, IgM, IgG)	SDC1	Promote immunity	In this study, we show that the clonogenicity of several human tumor cell lines and primary tumor cells from myeloma patients is enhanced by their interactions with DCs. Myeloma cells cultured in the presence of DCs have an altered phenotype with an increased proportion of cells lacking terminal plasma cell differentiation marker CD138. DC-tumor interaction also leads to the up-regulation of B cell lymphoma 6 expression in myeloma cells. Effects of DCs on myeloma cells are inhibited by blockade of the receptor activator of NF-kB (RANK)-RANK ligand and B cell-activating factor-APRIL (a proliferation-inducing ligand)-mediated interactions.
16880256	Multiple myeloma(IgA, IgD, IgE, IgM, IgG)	TNFSF11	Inhibit immunity	In this study, we show that the clonogenicity of several human tumor cell lines and primary tumor cells from myeloma patients is enhanced by their interactions with DCs. Myeloma cells cultured in the presence of DCs have an altered phenotype with an increased proportion of cells lacking terminal plasma cell differentiation marker CD138. DC-tumor interaction also leads to the up-regulation of B cell lymphoma 6 expression in myeloma cells. Effects of DCs on myeloma cells are inhibited by blockade of the receptor activator of NF-kB (RANK)-RANK ligand and B cell-activating factor-APRIL (a proliferation-inducing ligand)-mediated interactions.
16880256	Multiple myeloma(IgA, IgD, IgE, IgM, IgG)	TNFSF13	Inhibit immunity	In this study, we show that the clonogenicity of several human tumor cell lines and primary tumor cells from myeloma patients is enhanced by their interactions with DCs. Myeloma cells cultured in the presence of DCs have an altered phenotype with an increased proportion of cells lacking terminal plasma cell differentiation marker CD138. DC-tumor interaction also leads to the up-regulation of B cell lymphoma 6 expression in myeloma cells. Effects of DCs on myeloma cells are inhibited by blockade of the receptor activator of NF-kB (RANK)-RANK ligand and B cell-activating factor-APRIL (a proliferation-inducing ligand)-mediated interactions.
16868249	lymphoma	GZMB	Promote immunity	Here, we aimed to develop molecular strategies to overcome the resistance of HL cells against CTL-mediated killing via granzyme B (grzB). In HL cells, grzB-induced mitochondrial release of proapoptotic Smac is blocked, which results in complete abrogation of cytotoxicity mediated by CTLs. Cytosolic expression of recombinant mature Smac enhanced caspase activity induced by grzB and restored the apoptotic response of HL cells. Similarly, down-regulation of XIAP by RNA interference markedly enhanced the susceptibility of HL cells for CTL-mediated cytotoxicity.
16868249	lymphoma	XIAP	Inhibit immunity (T cell function)	Here, we aimed to develop molecular strategies to overcome the resistance of HL cells against CTL-mediated killing via granzyme B (grzB). In HL cells, grzB-induced mitochondrial release of proapoptotic Smac is blocked, which results in complete abrogation of cytotoxicity mediated by CTLs. Cytosolic expression of recombinant mature Smac enhanced caspase activity induced by grzB and restored the apoptotic response of HL cells. Similarly, down-regulation of XIAP by RNA interference markedly enhanced the susceptibility of HL cells for CTL-mediated cytotoxicity.
16864790	Melanoma	PDCD1LG2	Inhibit immunity	In this study, we created a PDL2-deficient mouse to characterize its function in T cell activation and tolerance. Antigen-presenting cells from PDL2-/- mice were found to be more potent in activation of T cells in vitro over the wild-type controls, which depended on PD-1. Upon immunization with chicken ovalbumin, PDL2-/- mice exhibited increased activation of CD4(+) and CD8(+) T cells in vivo when compared with WT animals. In addition, T cell tolerance to an oral antigen was abrogated by the lack of PDL2.
16860661	PAN-Cancer	KLRK1	Promote immunity	In particular, NKG2D is a type II transmembrane-anchored glycoprotein expressed as a disulfide-linked homodimer on the surface of all mouse and human natural killer cells (NK cells). Stimulation of NK cell through NKG2D triggers cell-mediated cytotoxicity and in some cases induces production of cytokines. NKG2D binds to family of ligands with structural homology to major histocompatibility complex (MHC) class I, however, NKG2D ligands often display upregulated surface expression on stressed cells and are frequently overexpressed by tumors unlike conventional MHC class I molecules. Evidence clearly implicate that NKG2D recognition plays an important role in tumor immune surveillance.
16857809	Carcinomatous Ascites	IFNG	Promote immunity	CuNG treatment could resolve drug-resistant cancers through induction of apoptogenic cytokines, such as IFN-gamma and/or tumor necrosis factor-alpha, from splenic mononuclear cells or patient peripheral blood mononuclear cells and reduce the number of T regulatory marker-bearing cells while increase infiltration of IFN-gamma-producing T cells in the ascetic tumor site.
16857805	Glioma	IL2RA	Inhibit immunity	Systemic anti-CD25 administration hinders detection of CD25+ cells but fails to completely eliminate T(regs), reducing their number only moderately, yet eliminating their suppressive function. This elimination of T(reg) function permits enhanced lymphocyte proliferative and IFN-gamma responses and up to 80% specific lysis of glioma cell targets in vitro. When combined with dendritic cell immunization, anti-CD25 elicits tumor rejection in 100% of challenged mice without precipitating experimental allergic encephalitis.
16849578	Melanoma	TLR9	Promote immunity	Analysis of the underlying mechanism revealed that in situ tumor ablation synergizes with TLR9 stimulation to induce DC maturation and efficient cross-presentation in tumor-bearing mice, leading to superior DC function in vivo. Therefore, in situ tumor destruction in combination with CpG-oligodeoxynucleotide administration creates a unique "in situ DC vaccine" that is readily applicable in the clinic.
16849577	Melanoma	CTLA4	Inhibit immunity	This notion is supported by a recent clinical trial involving an anti-CTL antigen-4 (CTLA-4) antibody that showed significant clinical responses but severe autoimmune diseases in melanoma patients
16849475	lymphoma	SYK	Promote immunity	This activity evidently derives from a 25-kDa fragment of beta-glucan released by macrophage processing of the parent polysaccharide. This fragment, but not parent beta-glucan, binds to neutrophil CR3, induces CBRM 1/5 neoepitope expression, and elicits CR3-dependent cytotoxicity. Thus, beta-glucan enhances tumor killing through a cascade of events, including in vivo macrophage cleavage of the polysaccharide, dual CR3 ligation, and CR3-Syk-PI3K signaling. These results are important inasmuch as beta-glucan, an agent without evident toxicity, may be used to amplify tumor cell killing and may open new opportunities in the immunotherapy of cancer.
16849475	lymphoma	PIK3CD	Promote immunity	This activity evidently derives from a 25-kDa fragment of beta-glucan released by macrophage processing of the parent polysaccharide. This fragment, but not parent beta-glucan, binds to neutrophil CR3, induces CBRM 1/5 neoepitope expression, and elicits CR3-dependent cytotoxicity. Thus, beta-glucan enhances tumor killing through a cascade of events, including in vivo macrophage cleavage of the polysaccharide, dual CR3 ligation, and CR3-Syk-PI3K signaling. These results are important inasmuch as beta-glucan, an agent without evident toxicity, may be used to amplify tumor cell killing and may open new opportunities in the immunotherapy of cancer.
16849468	lymphoma	CD8A	Promote immunity	E.G7-OVA growth in the skin was not inhibited in immunodeficient Rag(-/-) or CD8 T cell-deficient mice, suggesting that CD8(+) CTLs mediate tumor elimination. CD8(+) T cell numbers were significantly increased in eyes of mice primed with E.G7-OVA, but few were detected in primary ocular tumors.
16849468	lymphoma	ITGAM	Inhibit immunity	However, CD11b(+) cells accumulated in primary ocular tumors and contained potent immunosuppressive activity when assayed in vitro. Thus, CD11b(+) cells that accumulate within the eye as tumors develop in the a.c. may contribute to immune evasion by primary ocular tumors by inhibiting CTLs within the eye
16849461	Melanoma	HYOU1	Promote immunity	The continued secretion of grp170 dramatically reduced the tumorigenicity of B16 tumor cells in vivo, although the modification did not alter its transformation phenotype and cell growth rate. C57BL/6 mice that rejected grp170-secreting B16 tumor cells (B16-sgrp170) developed a strong CTL response recognizing melanocyte differentiation Ag TRP2 and were resistant to subsequent tumor challenge.
16844772	Melanoma	CD40LG	Promote immunity	When glycolipid is targeted to dendritic cells in spleen together with antigens in dying cells, such as irradiated tumor cells, alpha-C-GalCer is active as an adjuvant for T cell-mediated immunity at lower doses, just 20 ng per mouse, where it is also able to up-regulate the required CD40L costimulatory molecule on NKT cells.
16844772	Melanoma	IL12B	Promote immunity	We find that a recently described analogue, alpha-C-galactosylceramide (alpha-C-GalCer), more potently induces these innate and adaptive immune responses in mice. alpha-C-GalCer acts as a more effective trigger for IL-12 and IFN-gamma production, although it minimally elicits IL-4 and TNF-alpha release into the serum. Also, alpha-C-GalCer better mobilizes NKT and natural killer cells to resist B16 melanoma.
16844772	Melanoma	IL12A	Promote immunity	We find that a recently described analogue, alpha-C-galactosylceramide (alpha-C-GalCer), more potently induces these innate and adaptive immune responses in mice. alpha-C-GalCer acts as a more effective trigger for IL-12 and IFN-gamma production, although it minimally elicits IL-4 and TNF-alpha release into the serum. Also, alpha-C-GalCer better mobilizes NKT and natural killer cells to resist B16 melanoma.
16844772	Melanoma	IFNG	Promote immunity	We find that a recently described analogue, alpha-C-galactosylceramide (alpha-C-GalCer), more potently induces these innate and adaptive immune responses in mice. alpha-C-GalCer acts as a more effective trigger for IL-12 and IFN-gamma production, although it minimally elicits IL-4 and TNF-alpha release into the serum. Also, alpha-C-GalCer better mobilizes NKT and natural killer cells to resist B16 melanoma.
16841332	Lung Carcinoma	EGFR	Inhibit immunity	Noteworthy, vaccination of mice with mEGFR-ECD/VSSP stimulated a potent antimetastatic effect in the EGFR+ Lewis lung carcinoma model, while reproduction-associated side effects were absent. Curiously, mice immunized with the human EGFR-ECD (Her1-ECD) in VSSP though induced highly specific IgG antibodies with strong in vitro cytotoxic effect over EGFR+ human cell lines, showed low cross-reactivity with the mEGFR-ECD. These results further encouraged the development of the Her1-ECD/VSSP vaccine project for patients with EGFR+ tumors.
16837029	Endometrial adenocarcinoma	LDHA	Inhibit immunity	Endometrial adenocarcinomas displayed LDH-5 expression in 31/68 (45.5%) cases with those having a high LDH-5 expression being connected with a low lymphocytic response; this may suggest an important role of LDH-5 and, presumably, lactate release in tumor escape from host immuno-surveillance.
16826163	lymphoma	GADD45B	Inhibit immunity	These results demonstrated that this immunization may activate T cells in vivo. Furthermore, the splenocytes from immunized mice revealed resistance to activation-induced cell death (AICD) in vitro. To further study the relative genes that are responsible for the higher proliferation and resistance to AICD, the expression of Fas/Fas ligand (FasL) and GADD45b was measured by real-time PCR. The results indicated that GADD45beta transcription was higher in the splenocytes from immunized mice than that in the naive mice. In addition, the Fas expression showed a parallel higher, but FasL did not change obviously.
16818795	Melanoma	MLANA	Promote immunity	In this study, using a novel ex vivo molecular-based approach at the single-cell level, we identified a single, naturally primed T cell clone that dominated the human CD8(+) T cell response to the Melan-A/MART-1 Ag. The dominant clone expressed a high-avidity TCR to cognate tumor Ag, efficiently killed tumor cells, and prevailed in the differentiated effector-memory T lymphocyte compartment.
16818744	colon carcinoma	IL10	Inhibit immunity	These findings suggest that tumor growth facilitates the induction or recruitment of CD4+ regulatory T cells that secrete IL-10 and TGF-beta and suppress effector CD8+ T cell responses. However, CD8+ T regulatory cells expressing IL-10 and TGF-beta are also recruited or activated by the immunosuppressive environment of the lung, where they may suppress the induction of antitumor immunity.
16818744	colon carcinoma	TGFB1	Inhibit immunity	These findings suggest that tumor growth facilitates the induction or recruitment of CD4+ regulatory T cells that secrete IL-10 and TGF-beta and suppress effector CD8+ T cell responses. However, CD8+ T regulatory cells expressing IL-10 and TGF-beta are also recruited or activated by the immunosuppressive environment of the lung, where they may suppress the induction of antitumor immunity.
16818744	colon carcinoma	IFNG	Promote immunity	In contrast, T cell IFN-gamma production was weak and CD8+ CTL responses were undetectable in mice with CT26 lung metastases and weak and transient following s.c. injection of CT26 cells, but were enhanced in the presence of anti-IL-10 and anti-TGF-beta. These findings suggest that tumor growth facilitates the induction or recruitment of CD4+ regulatory T cells that secrete IL-10 and TGF-beta and suppress effector CD8+ T cell responses.
16818683	Head and Neck Squamous Carcinoma	MICA	Promote immunity	Recent revival of interest in the role of immune surveillance in the pathogenesis and control of malignant diseases has focused attention on escape mechanisms used by tumor cells to evade immune recognition. Defects in the host's tumor antigen-specific immune responses and abnormalities in tumor cell expression of HLA class I molecules and tumor antigen are known to contribute to tumor progression.
16818683	Head and Neck Squamous Carcinoma	IFNG	Promote immunity	Here, we discuss evidence pointing to functional defects in the antigen-processing machinery as one mechanism underlying resistance of SCCHN cells to recognition and lysis by HLA class I antigen-restricted, tumor antigen-specific CTL. In addition, based on the restoration by IFN-gamma of SCCHN cell sensitivity to recognition by these CTL, we suggest strategies that may improve the clinical course of the disease by enhancing susceptibility of malignant cells to immune recognition.
16818662	lymphoma	CD1D	Promote immunity	We found that the addition of the iNKT ligand alpha-galactosylceramide (alphaGalCer) to peptide-loaded B cells overcame peptide-specific T-cell unresponsiveness and allowed for the generation of peptide-specific memory CTL immunity.
16801397	Melanoma	MAPK1	Inhibit immunity	Here, we demonstrate a novel role of the activated MAPK pathway in immune evasion by melanoma cells with the mutation of BRAF, which encodes a MAPKKs, (BRAF(V600E)). MEK inhibitor U0126 or RNA interference (RNAi) for BRAF(V600E) decreased production of the immunosuppressive soluble factors interleukin (IL)-10, VEGF, or IL-6 from melanoma cells to levels comparable to those after signal transducer and activator of transcription (STAT)3 inactivation
16801397	Melanoma	MAP2K7	Inhibit immunity	Here, we demonstrate a novel role of the activated MAPK pathway in immune evasion by melanoma cells with the mutation of BRAF, which encodes a MAPKKs, (BRAF(V600E)). MEK inhibitor U0126 or RNA interference (RNAi) for BRAF(V600E) decreased production of the immunosuppressive soluble factors interleukin (IL)-10, VEGF, or IL-6 from melanoma cells to levels comparable to those after signal transducer and activator of transcription (STAT)3 inactivation
16801397	Melanoma	IL10	Inhibit immunity	Here, we demonstrate a novel role of the activated MAPK pathway in immune evasion by melanoma cells with the mutation of BRAF, which encodes a MAPKKs, (BRAF(V600E)). MEK inhibitor U0126 or RNA interference (RNAi) for BRAF(V600E) decreased production of the immunosuppressive soluble factors interleukin (IL)-10, VEGF, or IL-6 from melanoma cells to levels comparable to those after signal transducer and activator of transcription (STAT)3 inactivation
16801397	Melanoma	VEGFA	Inhibit immunity	Here, we demonstrate a novel role of the activated MAPK pathway in immune evasion by melanoma cells with the mutation of BRAF, which encodes a MAPKKs, (BRAF(V600E)). MEK inhibitor U0126 or RNA interference (RNAi) for BRAF(V600E) decreased production of the immunosuppressive soluble factors interleukin (IL)-10, VEGF, or IL-6 from melanoma cells to levels comparable to those after signal transducer and activator of transcription (STAT)3 inactivation
16801397	Melanoma	IL6	Inhibit immunity	Here, we demonstrate a novel role of the activated MAPK pathway in immune evasion by melanoma cells with the mutation of BRAF, which encodes a MAPKKs, (BRAF(V600E)). MEK inhibitor U0126 or RNA interference (RNAi) for BRAF(V600E) decreased production of the immunosuppressive soluble factors interleukin (IL)-10, VEGF, or IL-6 from melanoma cells to levels comparable to those after signal transducer and activator of transcription (STAT)3 inactivation
16801397	Melanoma	STAT3	Inhibit immunity	These results indicate that the MAPK signal, along with the STAT3 signal, is essential for immune evasion by human melanomas that have constitutively active MAPK signaling and is a potential molecular target for overcoming melanoma cell evasion of the immune system.