TISIDB

Summary
Symbol	TNFSF9
Name	tumor necrosis factor (ligand) superfamily, member 9
Aliases	4-1BB-L; receptor 4-1BB ligand; homolog of mouse 4-1BB-L; CD137L; 4-1BB ligand; 4-1BBL; Tumor necrosis facto ......
Chromosomal Location	19p13.3
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 TNFRSF9. Induces the proliferation of activated peripheral blood T-cells. May have a role in activation-induced cell death (AICD). May play a role in cognate interactions between T-cells and B-cells/macrophages.

> Gene Ontology [ TOP ]
Biological Process	GO:0002521 leukocyte differentiation GO:0002694 regulation of leukocyte activation GO:0002696 positive regulation of leukocyte activation GO:0007159 leukocyte cell-cell adhesion GO:0022407 regulation of cell-cell adhesion GO:0022409 positive regulation of cell-cell adhesion GO:0030098 lymphocyte differentiation GO:0030217 T cell differentiation GO:0032943 mononuclear cell proliferation GO:0032944 regulation of mononuclear cell proliferation GO:0032946 positive regulation of mononuclear cell proliferation GO:0042098 T cell proliferation GO:0042102 positive regulation of T cell proliferation GO:0042104 positive regulation of activated T cell proliferation GO:0042110 T cell activation GO:0042129 regulation of T cell proliferation GO:0045065 cytotoxic T cell differentiation GO:0045580 regulation of T cell differentiation GO:0045582 positive regulation of T cell differentiation GO:0045583 regulation of cytotoxic T cell differentiation GO:0045585 positive regulation of cytotoxic T cell differentiation GO:0045619 regulation of lymphocyte differentiation GO:0045621 positive regulation of lymphocyte differentiation GO:0045785 positive regulation of cell adhesion GO:0046006 regulation of activated T cell proliferation GO:0046651 lymphocyte proliferation GO:0050670 regulation of lymphocyte proliferation GO:0050671 positive regulation of lymphocyte proliferation GO:0050798 activated T cell proliferation GO:0050863 regulation of T cell activation GO:0050865 regulation of cell activation GO:0050867 positive regulation of cell activation GO:0050870 positive regulation of T cell activation GO:0051249 regulation of lymphocyte activation GO:0051251 positive regulation of lymphocyte activation 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:0071593 lymphocyte aggregation GO:1902105 regulation of leukocyte differentiation GO:1902107 positive regulation of leukocyte differentiation GO:1903037 regulation of leukocyte cell-cell adhesion GO:1903039 positive regulation of leukocyte cell-cell adhesion GO:1903706 regulation of hemopoiesis GO:1903708 positive regulation of hemopoiesis
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
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	TNFSF9
Name	tumor necrosis factor (ligand) superfamily, member 9
Aliases	4-1BB-L; receptor 4-1BB ligand; homolog of mouse 4-1BB-L; CD137L; 4-1BB ligand; 4-1BBL; Tumor necrosis facto ......
Chromosomal Location	19p13.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Literatures that report relations between TNFSF9 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 TNFSF9 and anti-tumor immunity in human cancer.

PMID	Cancer type	Relation to immunity	Evidence sentences
18364008	Melanoma; Renal Cell Carcinoma; Ovarian Carcinoma; Non-Small Cell Lung Carcinoma	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.
29508025	Hepatocellular Carcinoma	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.
17170077	Acute Myeloid Leukemia	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.
20008791	Acute Myeloid Leukemia	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.
23204227	lymphoma	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.

Summary
Symbol	TNFSF9
Name	tumor necrosis factor (ligand) superfamily, member 9
Aliases	4-1BB-L; receptor 4-1BB ligand; homolog of mouse 4-1BB-L; CD137L; 4-1BB ligand; 4-1BBL; Tumor necrosis facto ......
Chromosomal Location	19p13.3
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 TNFSF9 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	Second most enriched score: 0.58	Sensitive to T cell-mediated killing
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	TNFSF9
Name	tumor necrosis factor (ligand) superfamily, member 9
Aliases	4-1BB-L; receptor 4-1BB ligand; homolog of mouse 4-1BB-L; CD137L; 4-1BB ligand; 4-1BBL; Tumor necrosis facto ......
Chromosomal Location	19p13.3
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 TNFSF9 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	-0.279	0.504
2	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	6	5	-0.07	0.955
3	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	7	-0.431	0.648
4	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	-0.762	0.324
5	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	-0.528	0.641
6	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	-1.042	0.447
7	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	26	23	0.019	0.959
8	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	15	11	-0.365	0.616
9	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	11	12	0.403	0.624
10	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	4	8	0.874	0.326
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	0.507	0.685
13	29443960	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	68	230	-0.188	0.401

> Mutation difference between responders and non-responders

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Points in the above scatter plot represent the mutation difference of TNFSF9 in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	% Mut/Res	% Diff (R vs NR)	Pval
1	25765070	Non-small cell lung cancer (NSCLC)	all	Anti-PD-1 (pembrolizumab)	14	17	0	0	1
2	25765070	Non-small cell lung cancer (NSCLC)	smoking	Anti-PD-1 (pembrolizumab)	10	3	0	0	1
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	7.4	7.4	0.0709
5	26359337	Melanoma	BRAFi	Anti-CTLA-4 (ipilimumab)	0	14	0	0	1
6	26359337	Melanoma	non-BRAFi	Anti-CTLA-4 (ipilimumab)	27	59	7.4	7.4	0.096
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	11.1	11.1	0.36
11	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	20	20	0.357
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	2.6	2.6	1
14	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	22	13	4.5	4.5	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	TNFSF9
Name	tumor necrosis factor (ligand) superfamily, member 9
Aliases	4-1BB-L; receptor 4-1BB ligand; homolog of mouse 4-1BB-L; CD137L; 4-1BB ligand; 4-1BBL; Tumor necrosis facto ......
Chromosomal Location	19p13.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between abundance of tumor-infiltrating lymphocytes (TILs) and expression, copy number, methylation, or mutation of TNFSF9. 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	TNFSF9
Name	tumor necrosis factor (ligand) superfamily, member 9
Aliases	4-1BB-L; receptor 4-1BB ligand; homolog of mouse 4-1BB-L; CD137L; 4-1BB ligand; 4-1BBL; Tumor necrosis facto ......
Chromosomal Location	19p13.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between three kinds of immunomodulators and expression, copy number, methylation, or mutation of TNFSF9. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by TNFSF9. > Immunoinhibitor > Immunostimulator > MHC molecule

> Immunoinhibitor [ TOP ]

> Immunostimulator [ TOP ]

> MHC molecule [ TOP ]

Summary
Symbol	TNFSF9
Name	tumor necrosis factor (ligand) superfamily, member 9
Aliases	4-1BB-L; receptor 4-1BB ligand; homolog of mouse 4-1BB-L; CD137L; 4-1BB ligand; 4-1BBL; Tumor necrosis facto ......
Chromosomal Location	19p13.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between chemokines (or receptors) and expression, copy number, methylation, or mutation of TNFSF9. 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	TNFSF9
Name	tumor necrosis factor (ligand) superfamily, member 9
Aliases	4-1BB-L; receptor 4-1BB ligand; homolog of mouse 4-1BB-L; CD137L; 4-1BB ligand; 4-1BBL; Tumor necrosis facto ......
Chromosomal Location	19p13.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Distribution of TNFSF9 expression across immune and molecular subtypes. > Immune subtype > Molecular subtype

> Immune subtype [ TOP ]

> Molecular subtype [ TOP ]

Summary
Symbol	TNFSF9
Name	tumor necrosis factor (ligand) superfamily, member 9
Aliases	4-1BB-L; receptor 4-1BB ligand; homolog of mouse 4-1BB-L; CD137L; 4-1BB ligand; 4-1BBL; Tumor necrosis facto ......
Chromosomal Location	19p13.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Associations between TNFSF9 and clinical features. > Overall survival analysis > Cancer stage > Tumor grade

> Overall survival [ TOP ]

> Stage [ TOP ]

> Grade [ TOP ]

Summary
Symbol	TNFSF9
Name	tumor necrosis factor (ligand) superfamily, member 9
Aliases	4-1BB-L; receptor 4-1BB ligand; homolog of mouse 4-1BB-L; CD137L; 4-1BB ligand; 4-1BBL; Tumor necrosis facto ......
Chromosomal Location	19p13.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Drugs targeting TNFSF9 collected from DrugBank database.

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

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