TISIDB

Summary
Symbol	TNFSF10
Name	tumor necrosis factor (ligand) superfamily, member 10
Aliases	TRAIL; Apo-2L; TL2; CD253; APO2L; Apo-2 ligand; TNF-related apoptosis inducing ligand TRAIL; chemokine tumor ......
Chromosomal Location	3q26
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 II membrane protein
Domain	PF00229 TNF(Tumour Necrosis Factor) family
Function	Cytokine that binds to TNFRSF10A/TRAILR1, TNFRSF10B/TRAILR2, TNFRSF10C/TRAILR3, TNFRSF10D/TRAILR4 and possibly also to TNFRSF11B/OPG (PubMed:26457518, PubMed:10549288). Induces apoptosis. Its activity may be modulated by binding to the decoy receptors TNFRSF10C/TRAILR3, TNFRSF10D/TRAILR4 and TNFRSF11B/OPG that cannot induce apoptosis.

> Gene Ontology [ TOP ]
Biological Process	GO:0001836 release of cytochrome c from mitochondria GO:0006919 activation of cysteine-type endopeptidase activity involved in apoptotic process GO:0007249 I-kappaB kinase/NF-kappaB signaling GO:0007548 sex differentiation GO:0008406 gonad development GO:0008584 male gonad development GO:0008625 extrinsic apoptotic signaling pathway via death domain receptors GO:0008637 apoptotic mitochondrial changes GO:0010821 regulation of mitochondrion organization GO:0010822 positive regulation of mitochondrion organization GO:0010950 positive regulation of endopeptidase activity GO:0010952 positive regulation of peptidase activity GO:0032868 response to insulin GO:0043122 regulation of I-kappaB kinase/NF-kappaB signaling GO:0043123 positive regulation of I-kappaB kinase/NF-kappaB signaling GO:0043280 positive regulation of cysteine-type endopeptidase activity involved in apoptotic process GO:0043281 regulation of cysteine-type endopeptidase activity involved in apoptotic process GO:0043434 response to peptide hormone GO:0045137 development of primary sexual characteristics GO:0045862 positive regulation of proteolysis GO:0046546 development of primary male sexual characteristics GO:0046661 male sex differentiation GO:0048608 reproductive structure development GO:0052547 regulation of peptidase activity GO:0052548 regulation of endopeptidase activity GO:0061458 reproductive system development GO:0090199 regulation of release of cytochrome c from mitochondria GO:0090200 positive regulation of release of cytochrome c from mitochondria GO:0097191 extrinsic apoptotic signaling pathway GO:0097296 activation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway GO:1901652 response to peptide GO:1902041 regulation of extrinsic apoptotic signaling pathway via death domain receptors GO:1902042 negative regulation of extrinsic apoptotic signaling pathway via death domain receptors GO:2000116 regulation of cysteine-type endopeptidase activity GO:2001056 positive regulation of cysteine-type endopeptidase activity GO:2001233 regulation of apoptotic signaling pathway GO:2001234 negative regulation of apoptotic signaling pathway GO:2001235 positive regulation of apoptotic signaling pathway GO:2001236 regulation of extrinsic apoptotic signaling pathway GO:2001237 negative regulation of extrinsic apoptotic signaling pathway GO:2001238 positive regulation of extrinsic apoptotic signaling pathway GO:2001267 regulation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway GO:2001269 positive regulation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway
Molecular Function	GO:0005125 cytokine activity GO:0005126 cytokine receptor binding GO:0005164 tumor necrosis factor receptor binding GO:0032813 tumor necrosis factor receptor superfamily binding
Cellular Component	-

> KEGG and Reactome Pathway [ TOP ]
KEGG	hsa04060 Cytokine-cytokine receptor interaction hsa04068 FoxO signaling pathway hsa04210 Apoptosis hsa04650 Natural killer cell mediated cytotoxicity
Reactome	R-HSA-109581: Apoptosis R-HSA-5218900: CASP8 activity is inhibited R-HSA-5357769: Caspase activation via extrinsic apoptotic signalling pathway R-HSA-73887: Death Receptor Signalling R-HSA-69416: Dimerization of procaspase-8 R-HSA-140534: Ligand-dependent caspase activation R-HSA-5357801: Programmed Cell Death R-HSA-5213460: RIPK1-mediated regulated necrosis R-HSA-5218859: Regulated Necrosis R-HSA-3371378: Regulation by c-FLIP R-HSA-5675482: Regulation of necroptotic cell death R-HSA-162582: Signal Transduction R-HSA-75158: TRAIL signaling

> KEGG and Reactome Pathway

[ TOP ]

KEGG

hsa04060 Cytokine-cytokine receptor interaction
hsa04068 FoxO signaling pathway
hsa04210 Apoptosis
hsa04650 Natural killer cell mediated cytotoxicity

Reactome

R-HSA-109581: Apoptosis
R-HSA-5218900: CASP8 activity is inhibited
R-HSA-5357769: Caspase activation via extrinsic apoptotic signalling pathway
R-HSA-73887: Death Receptor Signalling
R-HSA-69416: Dimerization of procaspase-8
R-HSA-140534: Ligand-dependent caspase activation
R-HSA-5357801: Programmed Cell Death
R-HSA-5213460: RIPK1-mediated regulated necrosis
R-HSA-5218859: Regulated Necrosis
R-HSA-3371378: Regulation by c-FLIP
R-HSA-5675482: Regulation of necroptotic cell death
R-HSA-162582: Signal Transduction
R-HSA-75158: TRAIL signaling

Summary
Symbol	TNFSF10
Name	tumor necrosis factor (ligand) superfamily, member 10
Aliases	TRAIL; Apo-2L; TL2; CD253; APO2L; Apo-2 ligand; TNF-related apoptosis inducing ligand TRAIL; chemokine tumor ......
Chromosomal Location	3q26
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Literatures that report relations between TNFSF10 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 TNFSF10 and anti-tumor immunity in human cancer.

PMID	Cancer type	Relation to immunity	Evidence sentences
24639349	Melanoma	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.
18413798	Colon carcinoma; breast carcinoma; Plasma Cell Myeloma; Glioma; Prostate carcinoma	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.
19427690	Giloma	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.
19361506	Colon carcinoma	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.
23530146	Lymphoma	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.
16680149	Breast Carcinoma; Renal Cell Carcinoma; Colon Carcinoma; Lung Carcinoma	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.
19147771	Renal Cell Carcinoma	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).
22027835	Colon Carcinoma	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).
20580220	Colorectal Carcinoma	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.
20378565	Rhabdomyosarcoma	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.
18830416	Colon Carcinoma	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.
11875499	colon carcinoma	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.

Summary
Symbol	TNFSF10
Name	tumor necrosis factor (ligand) superfamily, member 10
Aliases	TRAIL; Apo-2L; TL2; CD253; APO2L; Apo-2 ligand; TNF-related apoptosis inducing ligand TRAIL; chemokine tumor ......
Chromosomal Location	3q26
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 TNFSF10 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	TNFSF10
Name	tumor necrosis factor (ligand) superfamily, member 10
Aliases	TRAIL; Apo-2L; TL2; CD253; APO2L; Apo-2 ligand; TNF-related apoptosis inducing ligand TRAIL; chemokine tumor ......
Chromosomal Location	3q26
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 TNFSF10 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	-0.183	0.745
2	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	6	5	-0.523	0.802
3	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	7	0.076	0.957
4	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	0.361	0.483
5	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	0.226	0.902
6	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0.54	0.83
7	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	26	23	0.557	0.339
8	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	15	11	1.029	0.513
9	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	11	12	-0.023	0.99
10	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	4	8	0.401	0.876
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	0.104	0.979
13	29443960	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	68	230	-0.264	0.128

> Mutation difference between responders and non-responders

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Points in the above scatter plot represent the mutation difference of TNFSF10 in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	% Mut/Res	% Mut/NRes	% Diff (R vs NR)	Pval
1	25765070	Non-small cell lung cancer (NSCLC)	all	Anti-PD-1 (pembrolizumab)	14	17	0	0	0	1
2	25765070	Non-small cell lung cancer (NSCLC)	smoking	Anti-PD-1 (pembrolizumab)	10	3	0	0	0	1
3	25765070	Non-small cell lung cancer (NSCLC)	non-smoking	Anti-PD-1 (pembrolizumab)	4	14	0	0	0	1
4	26359337	Melanoma	all	Anti-CTLA-4 (ipilimumab)	27	73	7.4	2.7	4.7	0.294
5	26359337	Melanoma	BRAFi	Anti-CTLA-4 (ipilimumab)	0	14	0	0	0	1
6	26359337	Melanoma	non-BRAFi	Anti-CTLA-4 (ipilimumab)	27	59	7.4	3.4	4	0.587
7	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	21	17	0	0	0	1
8	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	6	0	0	0	1
9	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	13	11	0	0	0	1
10	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	0	0	0	1
11	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	0	0	0	1
12	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0	0	0	1
13	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	38	27	10.5	3.7	6.8	0.393
14	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	22	13	13.6	7.7	5.9	1
15	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	16	14	6.2	0	6.2	1
16	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	11	13	0	7.7	-7.7	1
17	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	6	1	0	0	0	1
18	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	5	12	0	8.3	-8.3	1

Summary
Symbol	TNFSF10
Name	tumor necrosis factor (ligand) superfamily, member 10
Aliases	TRAIL; Apo-2L; TL2; CD253; APO2L; Apo-2 ligand; TNF-related apoptosis inducing ligand TRAIL; chemokine tumor ......
Chromosomal Location	3q26
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between abundance of tumor-infiltrating lymphocytes (TILs) and expression, copy number, methylation, or mutation of TNFSF10. 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	TNFSF10
Name	tumor necrosis factor (ligand) superfamily, member 10
Aliases	TRAIL; Apo-2L; TL2; CD253; APO2L; Apo-2 ligand; TNF-related apoptosis inducing ligand TRAIL; chemokine tumor ......
Chromosomal Location	3q26
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between three kinds of immunomodulators and expression, copy number, methylation, or mutation of TNFSF10. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by TNFSF10. > Immunoinhibitor > Immunostimulator > MHC molecule

> Immunoinhibitor [ TOP ]

> Immunostimulator [ TOP ]

> MHC molecule [ TOP ]

Summary
Symbol	TNFSF10
Name	tumor necrosis factor (ligand) superfamily, member 10
Aliases	TRAIL; Apo-2L; TL2; CD253; APO2L; Apo-2 ligand; TNF-related apoptosis inducing ligand TRAIL; chemokine tumor ......
Chromosomal Location	3q26
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between chemokines (or receptors) and expression, copy number, methylation, or mutation of TNFSF10. 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	TNFSF10
Name	tumor necrosis factor (ligand) superfamily, member 10
Aliases	TRAIL; Apo-2L; TL2; CD253; APO2L; Apo-2 ligand; TNF-related apoptosis inducing ligand TRAIL; chemokine tumor ......
Chromosomal Location	3q26
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Distribution of TNFSF10 expression across immune and molecular subtypes. > Immune subtype > Molecular subtype

> Immune subtype [ TOP ]

> Molecular subtype [ TOP ]

Summary
Symbol	TNFSF10
Name	tumor necrosis factor (ligand) superfamily, member 10
Aliases	TRAIL; Apo-2L; TL2; CD253; APO2L; Apo-2 ligand; TNF-related apoptosis inducing ligand TRAIL; chemokine tumor ......
Chromosomal Location	3q26
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Associations between TNFSF10 and clinical features. > Overall survival analysis > Cancer stage > Tumor grade

> Overall survival [ TOP ]

> Stage [ TOP ]

> Grade [ TOP ]

Summary
Symbol	TNFSF10
Name	tumor necrosis factor (ligand) superfamily, member 10
Aliases	TRAIL; Apo-2L; TL2; CD253; APO2L; Apo-2 ligand; TNF-related apoptosis inducing ligand TRAIL; chemokine tumor ......
Chromosomal Location	3q26
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Drugs targeting TNFSF10 collected from DrugBank database.

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

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