TISIDB

Summary
Symbol	TNFRSF4
Name	tumor necrosis factor receptor superfamily, member 4
Aliases	ACT35; OX40; CD134; TXGP1L; IMD16; ACT35 antigen; ATC35 antigen; CD134 antigen; OX40 antigen; OX40 cell surf ......
Chromosomal Location	1p36
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Basic function annotation. > Subcellular Location, Domain and Function > Gene Ontology > KEGG and Reactome Pathway

> Subcellular Location, Domain and Function [ TOP ]
Subcellular Location	Membrane; Single-pass type I membrane protein.
Domain	PF00020 TNFR/NGFR cysteine-rich region
Function	Receptor for TNFSF4/OX40L/GP34. Is a costimulatory molecule implicated in long-term T-cell immunity. ; FUNCTION: (Microbial infection) Acts as a receptor for human herpesvirus 6B/HHV-6B.

> Gene Ontology [ TOP ]
Biological Process	GO:0002237 response to molecule of bacterial origin GO:0002377 immunoglobulin production GO:0002440 production of molecular mediator of immune response GO:0002637 regulation of immunoglobulin production GO:0002639 positive regulation of immunoglobulin production GO:0002694 regulation of leukocyte activation GO:0002696 positive regulation of leukocyte activation GO:0002697 regulation of immune effector process GO:0002699 positive regulation of immune effector process GO:0002700 regulation of production of molecular mediator of immune response GO:0002702 positive regulation of production of molecular mediator of immune response GO:0007159 leukocyte cell-cell adhesion GO:0009306 protein secretion GO:0019058 viral life cycle GO:0030260 entry into host cell GO:0030888 regulation of B cell proliferation GO:0030890 positive regulation of B cell proliferation GO:0032496 response to lipopolysaccharide GO:0032943 mononuclear cell proliferation GO:0032944 regulation of mononuclear cell proliferation GO:0032946 positive regulation of mononuclear cell proliferation GO:0033209 tumor necrosis factor-mediated signaling pathway GO:0034612 response to tumor necrosis factor GO:0042098 T cell proliferation GO:0042100 B cell proliferation GO:0042110 T cell activation GO:0042113 B cell activation GO:0043410 positive regulation of MAPK cascade GO:0043433 negative regulation of sequence-specific DNA binding transcription factor activity GO:0044409 entry into host GO:0046651 lymphocyte proliferation GO:0046718 viral entry into host cell GO:0048305 immunoglobulin secretion GO:0050670 regulation of lymphocyte proliferation GO:0050671 positive regulation of lymphocyte proliferation GO:0050708 regulation of protein secretion GO:0050714 positive regulation of protein secretion GO:0050864 regulation of B cell activation GO:0050865 regulation of cell activation GO:0050867 positive regulation of cell activation GO:0050871 positive regulation of B cell activation GO:0051023 regulation of immunoglobulin secretion GO:0051024 positive regulation of immunoglobulin secretion GO:0051047 positive regulation of secretion GO:0051090 regulation of sequence-specific DNA binding transcription factor activity GO:0051222 positive regulation of protein transport GO:0051249 regulation of lymphocyte activation GO:0051251 positive regulation of lymphocyte activation GO:0051701 interaction with host GO:0051806 entry into cell of other organism involved in symbiotic interaction GO:0051828 entry into other organism involved in symbiotic interaction GO:0070486 leukocyte aggregation GO:0070489 T cell aggregation GO:0070661 leukocyte proliferation GO:0070663 regulation of leukocyte proliferation GO:0070665 positive regulation of leukocyte proliferation GO:0071356 cellular response to tumor necrosis factor GO:0071593 lymphocyte aggregation GO:1903532 positive regulation of secretion by cell GO:1904951 positive regulation of establishment of protein localization
Molecular Function	GO:0001618 virus receptor activity GO:0005031 tumor necrosis factor-activated receptor activity GO:0005035 death receptor activity
Cellular Component	-

> KEGG and Reactome Pathway [ TOP ]
KEGG	hsa04060 Cytokine-cytokine receptor interaction
Reactome	R-HSA-1280215: Cytokine Signaling in Immune system R-HSA-168256: Immune System R-HSA-5668541: TNFR2 non-canonical NF-kB pathway R-HSA-5669034: TNFs bind their physiological receptors

Summary
Symbol	TNFRSF4
Name	tumor necrosis factor receptor superfamily, member 4
Aliases	ACT35; OX40; CD134; TXGP1L; IMD16; ACT35 antigen; ATC35 antigen; CD134 antigen; OX40 antigen; OX40 cell surf ......
Chromosomal Location	1p36
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Literatures that report relations between TNFRSF4 and anti-tumor immunity. The specific mechanism were also collected if the literature reports that a gene specifically promotes or inhibits the infiltration or function of T/NK cells.

> Text Mining

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Literatures describing the relation between TNFRSF4 and anti-tumor immunity in human cancer.

PMID	Cancer type	Relation to immunity	Evidence sentences
26729864	Melanoma	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.
25744203	Glioblastoma	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.
29321210	Acute Myeloid Leukemia	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.
18362171	Colon carcinoma; Breast carcinoma	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.
28905118	Lymphoma	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.
23008334	Melanoma	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.
19414558	Melanoma	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.
28483787	Breast Neoplasm	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.
21239696	Hodgkin Lymphoma	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.
19672905	Prostate Carcinoma	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.
19455675	Embryonal Carcinoma	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.
27549124	Sarcoma; Neuroblastoma	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
23728179	Central Nervous System Lymphoma	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.
18025166	Prostate Carcinoma	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.
24732076	Colorectal Carcinoma	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.
24030703	Hepatocellular Carcinoma	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.
22936666	Mastocytoma	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.
22030616	Colon Carcinoma	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.
16148096	Thymoma	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.

Summary
Symbol	TNFRSF4
Name	tumor necrosis factor receptor superfamily, member 4
Aliases	ACT35; OX40; CD134; TXGP1L; IMD16; ACT35 antigen; ATC35 antigen; CD134 antigen; OX40 antigen; OX40 cell surf ......
Chromosomal Location	1p36
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	High-throughput screening data (e.g. CRISPR-Cas9, shRNA and RNAi) for T cell-mediated killing. Genetic screen techniques can identify mechanisms of tumor cell resistance (e.g., PTPN2) and sensitivity (e.g., APLNR) to killing by cytotoxic T cells, the central effectors of anti-tumor immunity. After comprehensively searching, eight groups of screening data sets were collected in the current database. In this tab, users can check whether their selected genes cause resistance or increase sensitivity to T cell-mediated killing in various data sets.

> High-throughput Screening

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Statistical results of TNFRSF4 in screening data sets for detecting immune reponses.

PMID	Screening System	Cancer Type	Cell Line	Data Set	Statistical Results	Relation to immunity
29301958	CRISPR-Cas9	melanoma	B16F10	Pmel-1 T cell	NA/NS	NA/NS
29301958	CRISPR-Cas9	melanoma	B16F10	OT-1 T cell	NA/NS	NA/NS
28783722	CRISPR-Cas9	melanoma	Mel624	2CT-CRISPR	NA/NS	NA/NS
28723893	CRISPR-Cas9	melanoma	B16	GVAX+Anti-PD1	NA/NS	NA/NS
28723893	CRISPR-Cas9	melanoma	B16	GVAX	NA/NS	NA/NS
25691366	RNAi	Breast cancer	MCF7	Luc-CTL assay	NA/NS	NA/NS
24476824	shRNA	melanoma	B16	Primary screen	NA/NS	NA/NS
24476824	shRNA	melanoma	B16	Secondary screen	NA/NS	NA/NS

Summary
Symbol	TNFRSF4
Name	tumor necrosis factor receptor superfamily, member 4
Aliases	ACT35; OX40; CD134; TXGP1L; IMD16; ACT35 antigen; ATC35 antigen; CD134 antigen; OX40 antigen; OX40 cell surf ......
Chromosomal Location	1p36
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Transcriptomic and genomic profiling of pre-treated tumor biopsies from responders and non-responders to immunotherapy. These data were used to identify signatures and mechanisms of response to checkpoint blockade (e.g., anti-PDL1 and anti-PD1). One example is that mutations in the gene PBRM1 benefit clinical survival of patients with clear cell renal cell carcinoma. After comprehensively searching, we collected 5 and 6 of transcriptomic and genomic data sets, respectively. In this tab, users can check whether their selected genes have significant difference of expression or mutation between responders and non-responders in various data sets. > Expression difference between responders and non-responders > Mutation difference between responders and non-responders

> Expression difference between responders and non-responders

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Points in the above scatter plot represent the expression difference of TNFRSF4 in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	Log2 (Fold Change)	P value
1	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	14	12	-1.142	0.0264
2	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	6	5	-1.183	0.414
3	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	7	-1.114	0.322
4	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	-0.064	0.906
5	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	-0.23	0.857
6	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0.151	0.928
7	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	26	23	0.506	0.311
8	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	15	11	0.505	0.501
9	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	11	12	0.503	0.525
10	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	4	8	0.905	0.41
11	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	2	0	0	1
12	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	2	8	-0.152	0.92
13	29443960	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	68	230	-0.223	0.23

> Mutation difference between responders and non-responders

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Points in the above scatter plot represent the mutation difference of TNFRSF4 in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	% Mut/NRes	% Diff (R vs NR)	Pval
1	25765070	Non-small cell lung cancer (NSCLC)	all	Anti-PD-1 (pembrolizumab)	14	17	5.9	-5.9	1
2	25765070	Non-small cell lung cancer (NSCLC)	smoking	Anti-PD-1 (pembrolizumab)	10	3	33.3	-33.3	0.231
3	25765070	Non-small cell lung cancer (NSCLC)	non-smoking	Anti-PD-1 (pembrolizumab)	4	14	0	0	1
4	26359337	Melanoma	all	Anti-CTLA-4 (ipilimumab)	27	73	0	0	1
5	26359337	Melanoma	BRAFi	Anti-CTLA-4 (ipilimumab)	0	14	0	0	1
6	26359337	Melanoma	non-BRAFi	Anti-CTLA-4 (ipilimumab)	27	59	0	0	1
7	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	21	17	0	0	1
8	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	6	0	0	1
9	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	13	11	0	0	1
10	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	0	0	1
11	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	0	0	1
12	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0	0	1
13	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	38	27	0	0	1
14	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	22	13	0	0	1
15	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	16	14	0	0	1
16	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	11	13	0	0	1
17	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	6	1	0	0	1
18	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	5	12	0	0	1

Summary
Symbol	TNFRSF4
Name	tumor necrosis factor receptor superfamily, member 4
Aliases	ACT35; OX40; CD134; TXGP1L; IMD16; ACT35 antigen; ATC35 antigen; CD134 antigen; OX40 antigen; OX40 cell surf ......
Chromosomal Location	1p36
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between abundance of tumor-infiltrating lymphocytes (TILs) and expression, copy number, methylation, or mutation of TNFRSF4. The immune-related signatures of 28 TIL types from Charoentong's study, which can be viewed in the download page. For each cancer type, the relative abundance of TILs were inferred by using gene set variation analysis (GSVA) based on gene expression profile. In this tab, users can examine which kinds of TILs might be regulated by the current gene.

> Lymphocyte [ TOP ]

Summary
Symbol	TNFRSF4
Name	tumor necrosis factor receptor superfamily, member 4
Aliases	ACT35; OX40; CD134; TXGP1L; IMD16; ACT35 antigen; ATC35 antigen; CD134 antigen; OX40 antigen; OX40 cell surf ......
Chromosomal Location	1p36
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between three kinds of immunomodulators and expression, copy number, methylation, or mutation of TNFRSF4. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by TNFRSF4. > Immunoinhibitor > Immunostimulator > MHC molecule

> Immunoinhibitor [ TOP ]

> Immunostimulator [ TOP ]

> MHC molecule [ TOP ]

Summary
Symbol	TNFRSF4
Name	tumor necrosis factor receptor superfamily, member 4
Aliases	ACT35; OX40; CD134; TXGP1L; IMD16; ACT35 antigen; ATC35 antigen; CD134 antigen; OX40 antigen; OX40 cell surf ......
Chromosomal Location	1p36
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between chemokines (or receptors) and expression, copy number, methylation, or mutation of TNFRSF4. In this tab, users can examine which chemokines (or receptors) might be regulated by the current gene. > Chemokine > Receptor

> Chemokine [ TOP ]

> Receptor [ TOP ]

Summary
Symbol	TNFRSF4
Name	tumor necrosis factor receptor superfamily, member 4
Aliases	ACT35; OX40; CD134; TXGP1L; IMD16; ACT35 antigen; ATC35 antigen; CD134 antigen; OX40 antigen; OX40 cell surf ......
Chromosomal Location	1p36
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Distribution of TNFRSF4 expression across immune and molecular subtypes. > Immune subtype > Molecular subtype

> Immune subtype [ TOP ]

> Molecular subtype [ TOP ]

Summary
Symbol	TNFRSF4
Name	tumor necrosis factor receptor superfamily, member 4
Aliases	ACT35; OX40; CD134; TXGP1L; IMD16; ACT35 antigen; ATC35 antigen; CD134 antigen; OX40 antigen; OX40 cell surf ......
Chromosomal Location	1p36
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Associations between TNFRSF4 and clinical features. > Overall survival analysis > Cancer stage > Tumor grade

> Overall survival [ TOP ]

> Stage [ TOP ]

> Grade [ TOP ]

Summary
Symbol	TNFRSF4
Name	tumor necrosis factor receptor superfamily, member 4
Aliases	ACT35; OX40; CD134; TXGP1L; IMD16; ACT35 antigen; ATC35 antigen; CD134 antigen; OX40 antigen; OX40 cell surf ......
Chromosomal Location	1p36
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Drugs targeting TNFRSF4 collected from DrugBank database.

> Drugs from DrugBank database [ TOP ]
There is no record.

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