TISIDB

Summary
Symbol	TNFRSF14
Name	tumor necrosis factor receptor superfamily, member 14
Aliases	HVEM; ATAR; LIGHTR; HVEA; CD270; herpesvirus entry mediator; tumor necrosis factor receptor superfamily, mem ......
Chromosomal Location	1p36.32
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 BTLA. Receptor for TNFSF14/LIGHT and homotrimeric TNFSF1/lymphotoxin-alpha. Involved in lymphocyte activation. Plays an important role in HSV pathogenesis because it enhanced the entry of several wild-type HSV strains of both serotypes into CHO cells, and mediated HSV entry into activated human T-cells. ; FUNCTION: (Microbial infection) Acts as a receptor for Herpes simplex virus 1/HHV-1. ; FUNCTION: (Microbial infection) Acts as a receptor for Herpes simplex virus 2/HHV-2.

> Gene Ontology [ TOP ]
Biological Process	GO:0001819 positive regulation of cytokine production GO:0002237 response to molecule of bacterial origin GO:0002367 cytokine production involved in immune response GO:0002374 cytokine secretion involved in immune response GO:0002440 production of molecular mediator of immune response GO:0002683 negative regulation of immune system process GO:0002685 regulation of leukocyte migration GO:0002687 positive regulation of leukocyte migration GO:0002694 regulation of leukocyte activation GO:0002695 negative 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:0002718 regulation of cytokine production involved in immune response GO:0002720 positive regulation of cytokine production involved in immune response GO:0002739 regulation of cytokine secretion involved in immune response GO:0002741 positive regulation of cytokine secretion involved in immune response GO:0007159 leukocyte cell-cell adhesion GO:0007162 negative regulation of cell adhesion GO:0009306 protein secretion GO:0018108 peptidyl-tyrosine phosphorylation GO:0018212 peptidyl-tyrosine modification GO:0019058 viral life cycle GO:0022407 regulation of cell-cell adhesion GO:0022408 negative regulation of cell-cell adhesion GO:0022409 positive regulation of cell-cell adhesion GO:0030260 entry into host cell GO:0030335 positive regulation of cell migration GO:0031294 lymphocyte costimulation GO:0031295 T cell costimulation GO:0032496 response to lipopolysaccharide GO:0032943 mononuclear cell proliferation GO:0032944 regulation of mononuclear cell proliferation GO:0032945 negative regulation of mononuclear cell proliferation GO:0033209 tumor necrosis factor-mediated signaling pathway GO:0034612 response to tumor necrosis factor GO:0040017 positive regulation of locomotion GO:0042098 T cell proliferation GO:0042110 T cell activation GO:0042129 regulation of T cell proliferation GO:0042130 negative regulation of T cell proliferation GO:0042742 defense response to bacterium GO:0043410 positive regulation of MAPK cascade GO:0044409 entry into host GO:0045785 positive regulation of cell adhesion GO:0046631 alpha-beta T cell activation GO:0046633 alpha-beta T cell proliferation GO:0046634 regulation of alpha-beta T cell activation GO:0046636 negative regulation of alpha-beta T cell activation GO:0046640 regulation of alpha-beta T cell proliferation GO:0046642 negative regulation of alpha-beta T cell proliferation GO:0046651 lymphocyte proliferation GO:0046718 viral entry into host cell GO:0050663 cytokine secretion GO:0050670 regulation of lymphocyte proliferation GO:0050672 negative regulation of lymphocyte proliferation GO:0050707 regulation of cytokine secretion GO:0050708 regulation of protein secretion GO:0050714 positive regulation of protein secretion GO:0050715 positive regulation of cytokine secretion GO:0050730 regulation of peptidyl-tyrosine phosphorylation GO:0050731 positive regulation of peptidyl-tyrosine phosphorylation GO:0050829 defense response to Gram-negative bacterium GO:0050830 defense response to Gram-positive bacterium GO:0050863 regulation of T cell activation GO:0050865 regulation of cell activation GO:0050866 negative regulation of cell activation GO:0050867 positive regulation of cell activation GO:0050868 negative regulation of T cell activation GO:0050870 positive regulation of T cell activation GO:0050900 leukocyte migration GO:0051047 positive regulation of secretion GO:0051222 positive regulation of protein transport GO:0051249 regulation of lymphocyte activation GO:0051250 negative regulation of lymphocyte activation GO:0051251 positive regulation of lymphocyte activation GO:0051272 positive regulation of cellular component movement 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:0070664 negative regulation of leukocyte proliferation GO:0071356 cellular response to tumor necrosis factor GO:0071593 lymphocyte aggregation GO:0072676 lymphocyte migration GO:0072678 T cell migration GO:0098542 defense response to other organism GO:1903037 regulation of leukocyte cell-cell adhesion GO:1903038 negative regulation of leukocyte cell-cell adhesion GO:1903039 positive regulation of leukocyte cell-cell adhesion GO:1903532 positive regulation of secretion by cell GO:1904951 positive regulation of establishment of protein localization GO:2000147 positive regulation of cell motility GO:2000401 regulation of lymphocyte migration GO:2000403 positive regulation of lymphocyte migration GO:2000404 regulation of T cell migration GO:2000406 positive regulation of T cell migration
Molecular Function	GO:0001618 virus receptor activity GO:0005031 tumor necrosis factor-activated receptor activity GO:0005035 death receptor activity GO:0031625 ubiquitin protein ligase binding GO:0044389 ubiquitin-like protein ligase binding
Cellular Component	GO:0009897 external side of plasma membrane GO:0098552 side of membrane

> KEGG and Reactome Pathway [ TOP ]
KEGG	hsa04060 Cytokine-cytokine receptor interaction
Reactome	R-HSA-1280218: Adaptive Immune System R-HSA-388841: Costimulation by the CD28 family 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	TNFRSF14
Name	tumor necrosis factor receptor superfamily, member 14
Aliases	HVEM; ATAR; LIGHTR; HVEA; CD270; herpesvirus entry mediator; tumor necrosis factor receptor superfamily, mem ......
Chromosomal Location	1p36.32
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Literatures that report relations between TNFRSF14 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 TNFRSF14 and anti-tumor immunity in human cancer.

PMID	Cancer type	Relation to immunity	Evidence sentences
25468715	Hepatocellular Carcinoma	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.
22547582	Chronic Lymphocytic Leukemia	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.
27693350	Diffuse Large B-Cell Lymphoma Germinal Center B-Cell Type	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.
27418644	Plasma cell myeloma	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	Inhibit immunity	When targeted by an anti-CD38 mAb, suppressive T-cell function by OCs is alleviated, associated with downregulation of HVEM and IDO.
28470686	Pancreatic Carcinoma; Ampulla of Vater Carcinoma	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.
19701890	Leukemia	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.
23692853	Lymphoma	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.
24249528	Esophageal Squamous Cell Carcinoma	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.

Summary
Symbol	TNFRSF14
Name	tumor necrosis factor receptor superfamily, member 14
Aliases	HVEM; ATAR; LIGHTR; HVEA; CD270; herpesvirus entry mediator; tumor necrosis factor receptor superfamily, mem ......
Chromosomal Location	1p36.32
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

[ TOP ]

Statistical results of TNFRSF14 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	TNFRSF14
Name	tumor necrosis factor receptor superfamily, member 14
Aliases	HVEM; ATAR; LIGHTR; HVEA; CD270; herpesvirus entry mediator; tumor necrosis factor receptor superfamily, mem ......
Chromosomal Location	1p36.32
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 TNFRSF14 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	-0.133	0.811
2	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	6	5	0.155	0.96
3	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	7	-0.347	0.882
4	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	0.441	0.375
5	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	0.086	0.972
6	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0.896	0.784
7	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	26	23	-0.15	0.74
8	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	15	11	0.006	0.997
9	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	11	12	-0.386	0.862
10	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	4	8	1.056	0.627
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	1.211	0.709
13	29443960	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	68	230	-0.302	0.00231

> Mutation difference between responders and non-responders

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Points in the above scatter plot represent the mutation difference of TNFRSF14 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	3.7	4.1	-0.4	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	3.7	5.1	-1.4	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	0	0	0	1
14	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	22	13	0	0	0	1
15	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	16	14	0	0	0	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	TNFRSF14
Name	tumor necrosis factor receptor superfamily, member 14
Aliases	HVEM; ATAR; LIGHTR; HVEA; CD270; herpesvirus entry mediator; tumor necrosis factor receptor superfamily, mem ......
Chromosomal Location	1p36.32
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between abundance of tumor-infiltrating lymphocytes (TILs) and expression, copy number, methylation, or mutation of TNFRSF14. 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	TNFRSF14
Name	tumor necrosis factor receptor superfamily, member 14
Aliases	HVEM; ATAR; LIGHTR; HVEA; CD270; herpesvirus entry mediator; tumor necrosis factor receptor superfamily, mem ......
Chromosomal Location	1p36.32
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between three kinds of immunomodulators and expression, copy number, methylation, or mutation of TNFRSF14. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by TNFRSF14. > Immunoinhibitor > Immunostimulator > MHC molecule

> Immunoinhibitor [ TOP ]

> Immunostimulator [ TOP ]

> MHC molecule [ TOP ]

Summary
Symbol	TNFRSF14
Name	tumor necrosis factor receptor superfamily, member 14
Aliases	HVEM; ATAR; LIGHTR; HVEA; CD270; herpesvirus entry mediator; tumor necrosis factor receptor superfamily, mem ......
Chromosomal Location	1p36.32
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between chemokines (or receptors) and expression, copy number, methylation, or mutation of TNFRSF14. 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	TNFRSF14
Name	tumor necrosis factor receptor superfamily, member 14
Aliases	HVEM; ATAR; LIGHTR; HVEA; CD270; herpesvirus entry mediator; tumor necrosis factor receptor superfamily, mem ......
Chromosomal Location	1p36.32
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Distribution of TNFRSF14 expression across immune and molecular subtypes. > Immune subtype > Molecular subtype

> Immune subtype [ TOP ]

> Molecular subtype [ TOP ]

Summary
Symbol	TNFRSF14
Name	tumor necrosis factor receptor superfamily, member 14
Aliases	HVEM; ATAR; LIGHTR; HVEA; CD270; herpesvirus entry mediator; tumor necrosis factor receptor superfamily, mem ......
Chromosomal Location	1p36.32
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Associations between TNFRSF14 and clinical features. > Overall survival analysis > Cancer stage > Tumor grade

> Overall survival [ TOP ]

> Stage [ TOP ]

> Grade [ TOP ]

Summary
Symbol	TNFRSF14
Name	tumor necrosis factor receptor superfamily, member 14
Aliases	HVEM; ATAR; LIGHTR; HVEA; CD270; herpesvirus entry mediator; tumor necrosis factor receptor superfamily, mem ......
Chromosomal Location	1p36.32
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Drugs targeting TNFRSF14 collected from DrugBank database.

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

Browse TNFRSF14