TISIDB

Summary
Symbol	TNFRSF18
Name	tumor necrosis factor receptor superfamily, member 18
Aliases	AITR; GITR; CD357; GITR-D; TNF receptor superfamily activation-inducible protein; activation-inducible TNFR ......
Chromosomal Location	1p36.3
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	Isoform 1: Cell membrane; Single-pass type I membrane protein.; SUBCELLULAR LOCATION: Isoform 2: Secreted.
Domain	-
Function	Receptor for TNFSF18. Seems to be involved in interactions between activated T-lymphocytes and endothelial cells and in the regulation of T-cell receptor-mediated cell death. Mediated NF-kappa-B activation via the TRAF2/NIK pathway.

> Gene Ontology [ TOP ]
Biological Process	GO:0002237 response to molecule of bacterial origin GO:0002685 regulation of leukocyte migration GO:0002687 positive regulation of leukocyte migration GO:0007259 JAK-STAT cascade GO:0007260 tyrosine phosphorylation of STAT protein GO:0008625 extrinsic apoptotic signaling pathway via death domain receptors GO:0018108 peptidyl-tyrosine phosphorylation GO:0018212 peptidyl-tyrosine modification GO:0030335 positive regulation of cell migration GO:0032496 response to lipopolysaccharide GO:0033209 tumor necrosis factor-mediated signaling pathway GO:0034612 response to tumor necrosis factor GO:0040017 positive regulation of locomotion GO:0042508 tyrosine phosphorylation of Stat1 protein GO:0042509 regulation of tyrosine phosphorylation of STAT protein GO:0042510 regulation of tyrosine phosphorylation of Stat1 protein GO:0042511 positive regulation of tyrosine phosphorylation of Stat1 protein GO:0042531 positive regulation of tyrosine phosphorylation of STAT protein GO:0045785 positive regulation of cell adhesion GO:0046425 regulation of JAK-STAT cascade GO:0046427 positive regulation of JAK-STAT cascade GO:0050730 regulation of peptidyl-tyrosine phosphorylation GO:0050731 positive regulation of peptidyl-tyrosine phosphorylation GO:0050900 leukocyte migration GO:0051272 positive regulation of cellular component movement GO:0071356 cellular response to tumor necrosis factor GO:0097191 extrinsic apoptotic signaling pathway GO:0097696 STAT cascade GO:1904892 regulation of STAT cascade GO:1904894 positive regulation of STAT cascade GO:2000147 positive regulation of cell motility
Molecular Function	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	TNFRSF18
Name	tumor necrosis factor receptor superfamily, member 18
Aliases	AITR; GITR; CD357; GITR-D; TNF receptor superfamily activation-inducible protein; activation-inducible TNFR ......
Chromosomal Location	1p36.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Literatures that report relations between TNFRSF18 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 TNFRSF18 and anti-tumor immunity in human cancer.

PMID	Cancer type	Relation to immunity	Evidence sentences
26423152	Colon Adenocarcinoma	Promote immunity (T cell function)	These results suggest that GITR signaling has stimulatory effects on effector T cells and inhibitory effects through Treg cells.
26239999	Renal Cell Carcinoma	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.
21106849	Melanoma	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.
16709800	Melanoma	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.
16651447	Melanoma	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.
18025180	Colon Carcinoma	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.
28069723	Colon Carcinoma	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.
24416730	Melanoma	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.
22911397	Hepatocellular Carcinoma; Colorectal Carcinoma	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.
22028176	Melanoma	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.
20460483	Colon Carcinoma; Fibrosarcoma	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.
16186187	Rectal Carcinoma; Fibrosarcoma	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.

Summary
Symbol	TNFRSF18
Name	tumor necrosis factor receptor superfamily, member 18
Aliases	AITR; GITR; CD357; GITR-D; TNF receptor superfamily activation-inducible protein; activation-inducible TNFR ......
Chromosomal Location	1p36.3
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 TNFRSF18 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	TNFRSF18
Name	tumor necrosis factor receptor superfamily, member 18
Aliases	AITR; GITR; CD357; GITR-D; TNF receptor superfamily activation-inducible protein; activation-inducible TNFR ......
Chromosomal Location	1p36.3
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 TNFRSF18 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	-0.369	0.508
2	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	6	5	-0.287	0.801
3	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	7	-0.424	0.631
4	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	0.391	0.493
5	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	0.241	0.849
6	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0.581	0.709
7	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	26	23	0.59	0.364
8	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	15	11	0.991	0.326
9	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	11	12	0.153	0.887
10	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	4	8	1.343	0.156
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	-0.516	0.671
13	29443960	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	68	230	-0.03	0.9

> Mutation difference between responders and non-responders

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Points in the above scatter plot represent the mutation difference of TNFRSF18 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	0	0	0	1
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	0	0	0	1
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	7.9	3.7	4.2	0.636
14	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	22	13	9.1	7.7	1.4	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	0	0	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	0	0	1

Summary
Symbol	TNFRSF18
Name	tumor necrosis factor receptor superfamily, member 18
Aliases	AITR; GITR; CD357; GITR-D; TNF receptor superfamily activation-inducible protein; activation-inducible TNFR ......
Chromosomal Location	1p36.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between abundance of tumor-infiltrating lymphocytes (TILs) and expression, copy number, methylation, or mutation of TNFRSF18. 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	TNFRSF18
Name	tumor necrosis factor receptor superfamily, member 18
Aliases	AITR; GITR; CD357; GITR-D; TNF receptor superfamily activation-inducible protein; activation-inducible TNFR ......
Chromosomal Location	1p36.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between three kinds of immunomodulators and expression, copy number, methylation, or mutation of TNFRSF18. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by TNFRSF18. > Immunoinhibitor > Immunostimulator > MHC molecule

> Immunoinhibitor [ TOP ]

> Immunostimulator [ TOP ]

> MHC molecule [ TOP ]

Summary
Symbol	TNFRSF18
Name	tumor necrosis factor receptor superfamily, member 18
Aliases	AITR; GITR; CD357; GITR-D; TNF receptor superfamily activation-inducible protein; activation-inducible TNFR ......
Chromosomal Location	1p36.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between chemokines (or receptors) and expression, copy number, methylation, or mutation of TNFRSF18. 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	TNFRSF18
Name	tumor necrosis factor receptor superfamily, member 18
Aliases	AITR; GITR; CD357; GITR-D; TNF receptor superfamily activation-inducible protein; activation-inducible TNFR ......
Chromosomal Location	1p36.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Distribution of TNFRSF18 expression across immune and molecular subtypes. > Immune subtype > Molecular subtype

> Immune subtype [ TOP ]

> Molecular subtype [ TOP ]

Summary
Symbol	TNFRSF18
Name	tumor necrosis factor receptor superfamily, member 18
Aliases	AITR; GITR; CD357; GITR-D; TNF receptor superfamily activation-inducible protein; activation-inducible TNFR ......
Chromosomal Location	1p36.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Associations between TNFRSF18 and clinical features. > Overall survival analysis > Cancer stage > Tumor grade

> Overall survival [ TOP ]

> Stage [ TOP ]

> Grade [ TOP ]

Summary
Symbol	TNFRSF18
Name	tumor necrosis factor receptor superfamily, member 18
Aliases	AITR; GITR; CD357; GITR-D; TNF receptor superfamily activation-inducible protein; activation-inducible TNFR ......
Chromosomal Location	1p36.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Drugs targeting TNFRSF18 collected from DrugBank database.

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

Browse TNFRSF18