TISIDB

Summary
Symbol	CD226
Name	CD226 molecule
Aliases	DNAM-1; DNAM1; PTA1; TLiSA1; CD226 antigen; DNAX accessory molecule 1; DNAX accessory molecule-1; T lineage- ......
Chromosomal Location	18q22.3
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	Cell membrane Single-pass type I membrane protein
Domain	PF07686 Immunoglobulin V-set domain
Function	Involved in intercellular adhesion, lymphocyte signaling, cytotoxicity and lymphokine secretion mediated by cytotoxic T-lymphocyte (CTL) and NK cell (PubMed:8673704). Cell surface receptor for NECTIN2. Upon ligand binding, stimulates T-cell proliferation and cytokine production, including that of IL2, IL5, IL10, IL13, and IFNG. Competes with PVRIG for NECTIN2-binding (PubMed:26755705).

> Gene Ontology [ TOP ]
Biological Process	GO:0001819 positive regulation of cytokine production GO:0001906 cell killing GO:0001909 leukocyte mediated cytotoxicity GO:0001910 regulation of leukocyte mediated cytotoxicity GO:0001912 positive regulation of leukocyte mediated cytotoxicity GO:0002228 natural killer cell mediated immunity GO:0002250 adaptive immune response GO:0002274 myeloid leukocyte activation GO:0002347 response to tumor cell GO:0002367 cytokine production involved in immune response GO:0002370 natural killer cell cytokine production GO:0002418 immune response to tumor cell GO:0002420 natural killer cell mediated cytotoxicity directed against tumor cell target GO:0002423 natural killer cell mediated immune response to tumor cell GO:0002429 immune response-activating cell surface receptor signaling pathway GO:0002431 Fc receptor mediated stimulatory signaling pathway GO:0002440 production of molecular mediator of immune response GO:0002443 leukocyte mediated immunity GO:0002449 lymphocyte mediated immunity GO:0002460 adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains 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:0002703 regulation of leukocyte mediated immunity GO:0002705 positive regulation of leukocyte mediated immunity GO:0002706 regulation of lymphocyte mediated immunity GO:0002708 positive regulation of lymphocyte mediated immunity GO:0002712 regulation of B cell mediated immunity GO:0002714 positive regulation of B cell mediated immunity GO:0002715 regulation of natural killer cell mediated immunity GO:0002717 positive regulation of natural killer cell mediated immunity GO:0002718 regulation of cytokine production involved in immune response GO:0002720 positive regulation of cytokine production involved in immune response GO:0002727 regulation of natural killer cell cytokine production GO:0002729 positive regulation of natural killer cell cytokine production GO:0002757 immune response-activating signal transduction GO:0002764 immune response-regulating signaling pathway GO:0002768 immune response-regulating cell surface receptor signaling pathway GO:0002819 regulation of adaptive immune response GO:0002821 positive regulation of adaptive immune response GO:0002822 regulation of adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains GO:0002824 positive regulation of adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains GO:0002831 regulation of response to biotic stimulus GO:0002833 positive regulation of response to biotic stimulus GO:0002834 regulation of response to tumor cell GO:0002836 positive regulation of response to tumor cell GO:0002837 regulation of immune response to tumor cell GO:0002839 positive regulation of immune response to tumor cell GO:0002855 regulation of natural killer cell mediated immune response to tumor cell GO:0002857 positive regulation of natural killer cell mediated immune response to tumor cell GO:0002858 regulation of natural killer cell mediated cytotoxicity directed against tumor cell target GO:0002860 positive regulation of natural killer cell mediated cytotoxicity directed against tumor cell target GO:0002889 regulation of immunoglobulin mediated immune response GO:0002891 positive regulation of immunoglobulin mediated immune response GO:0007156 homophilic cell adhesion via plasma membrane adhesion molecules GO:0007157 heterophilic cell-cell adhesion via plasma membrane cell adhesion molecules GO:0008037 cell recognition GO:0016064 immunoglobulin mediated immune response GO:0019724 B cell mediated immunity GO:0031341 regulation of cell killing GO:0031343 positive regulation of cell killing GO:0031349 positive regulation of defense response GO:0032609 interferon-gamma production GO:0032649 regulation of interferon-gamma production GO:0032729 positive regulation of interferon-gamma production GO:0033003 regulation of mast cell activation GO:0033005 positive regulation of mast cell activation GO:0042267 natural killer cell mediated cytotoxicity GO:0042269 regulation of natural killer cell mediated cytotoxicity GO:0045088 regulation of innate immune response GO:0045089 positive regulation of innate immune response GO:0045576 mast cell activation GO:0045954 positive regulation of natural killer cell mediated cytotoxicity GO:0050865 regulation of cell activation GO:0050867 positive regulation of cell activation GO:0060368 regulation of Fc receptor mediated stimulatory signaling pathway GO:0060369 positive regulation of Fc receptor mediated stimulatory signaling pathway GO:0098742 cell-cell adhesion via plasma-membrane adhesion molecules
Molecular Function	GO:0005178 integrin binding GO:0050839 cell adhesion molecule binding
Cellular Component	GO:0005913 cell-cell adherens junction GO:0009897 external side of plasma membrane GO:0045121 membrane raft GO:0098552 side of membrane GO:0098589 membrane region GO:0098857 membrane microdomain

> KEGG and Reactome Pathway [ TOP ]
KEGG	hsa04514 Cell adhesion molecules (CAMs)
Reactome	R-HSA-1280218: Adaptive Immune System R-HSA-168256: Immune System R-HSA-198933: Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell

Summary
Symbol	CD226
Name	CD226 molecule
Aliases	DNAM-1; DNAM1; PTA1; TLiSA1; CD226 antigen; DNAX accessory molecule 1; DNAX accessory molecule-1; T lineage- ......
Chromosomal Location	18q22.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Literatures that report relations between CD226 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 CD226 and anti-tumor immunity in human cancer.

PMID	Cancer type	Relation to immunity	Evidence sentences
25893601	Plasma Cell Myeloma	Promote immunity (T cell function)	In this study using this unique mouse model of multiple myeloma (MM), we demonstrate the importance of NK and CD8+ T cells in MM immunosurveillance and response to treatment in vivo through CD226 and CD155 interactions.
27777574	Colorectal carcinoma	Promote immunity	CRC-NK cells displayed underexpression of CD16, NKG2D, DNAM-1, CD161, NKp46, and NKp30 activating receptors, while inhibitory receptors CD85j and NKG2A were overexpressed. This inhibited phenotype affected cytotoxic functionality against CRC cells and interferon-γ production.
24510590	Ovarian Carcinoma	Promote immunity (T and NK cell function)	Most tumor-associated NK cells displayed a CD56(bright) , CD16(neg) or CD56(bright) , CD16(dim) phenotype, and very poor cytolytic activities, despite an increased expression of the activation marker CD69. They also showed downregulation of DNAM-1, 2B4, and NTB-A activating receptors, and an altered chemokine receptor repertoire.
23192659	Mesothelioma and lung carcinoma; breast carcinoma; colon carcinoma; gastric carcinoma; bladder carcinoma; uterus carcinoma	Promote immunity	Tumor cell lysis was primarily mediated by NKG2D and NKp30 and partially by NKp46 and DNAM-1, in agreement with the expression of the corresponding ligands on tumor cells.
19404979	Hepatocellular carcinoma	Promote immunity	Finally, we showed by combined mAb-mediated blockade that DNAM-1 and NKG2D could cooperate in the cell lysis of HCC.
19349689	Melanoma	Promote immunity (NK cell function)	Here we show that human melanoma cell lines derived from LN metastases express ligands for natural cytotoxicity receptors (NCRs) and DNAX accessory molecule-1 (DNAM-1), two emerging NK cell receptors key for cancer cell recognition, but not NK group 2 member D (NKG2D).
23440424	Neuroblastoma	Promote immunity	The final products contained more than 90% CD56(+) cells and could kill neuroblastoma cells effectively that were originally highly resistant to nonprocessed NK cells. Mechanistically, cytolysis of neuroblastoma was mediated through natural cytotoxicity receptor (NCR), DNAX accessory molecule-1 (DNAM-1; CD226), perforin, and granzyme B.
21224372	Melanoma	Promote immunity (T cell function)	A dynamic label free assay was used to determine the pathways involved in the lysis of melanoma cells by IL-2-activated NK cells. NKG2D, NCR (natural cytotoxicity receptor), and DNAM-1 are involved in the NK-mediated lysis of melanoma cells.
22419581	Myeloma	Promote immunity (NK cell function)	Expanded natural killer cells killed both allogeneic and autologous primary myeloma cells avidly via a perforin-mediated mechanism in which the activating receptor NKG2D, natural cytotoxicity receptors, and DNAX-accessory molecule-1 played a central role. The transferred, expanded natural killer cells proliferated in vivo in an interleukin-2 dose-dependent fashion, persisted up to 4 weeks, were readily detectable in the human bone, inhibited myeloma growth and protected bone from myeloma-induced osteolysis.
19029379	Fibrosarcoma	Promote immunity (T cell function)	DNAM-1-deficient cytotoxic T lymphocyte (CTL) and NK cells showed significantly less cytotoxic activity against DNAM-1 ligand-expressing tumors in vitro than wild-type (WT) cells. The methylcholanthrene (MCA)-induced fibrosarcoma cell line Meth A expressed the DNAM-1 ligand CD155, and DNAM-1-deficient mice showed increased tumor development and mortality after transplantation of Meth A cells. Moreover, the DNAM-1-deficient mice developed significantly more DNAM-1 ligand-expressing fibrosarcoma and papilloma cells in response to the chemical carcinogens MCA and 7,12-dimethylbenz[a]anthracene (DMBA), respectively, than did WT mice.
19934056	Melanoma	Promote immunity (NK cell function)	Thus, both the IL-2-induced up-regulation of the surface expression of NKp44, NKp30, and DNAM-1 triggering receptors and the acquisition of cytolytic granules were inhibited in NK cells. This resulted in an impairment of the NK cell-mediated killing of melanoma target cells.
29308322	Melanoma	Promote immunity (NK cell function)	We demonstrate that BRAFV600E mutant melanoma cells cultured in the presence of vemurafenib, strongly decreased surface expression of ligands for NK activating receptors including the NKG2D-ligand, MICA, and the DNAM-1 ligand, CD155, and became significantly less susceptible to NK cell attack.
25209846	Hepatocellular Carcinoma	Promote immunity（NK cell function)	Here, we demonstrated that activated unfolded protein response (UPR) attenuated the sensitivity of human hepatocellular carcinoma cell (HCC) to NK-cell cytotoxicity by decreasing the expression level of CD226 ligand CD155 in HCC
21937679	Breast Carcinoma	Promote immunity	Functional experiments in breast cancer subtypes expressing various levels of NK cell ligands showed that NK-mediated cytotoxicity is mainly HLA, NKG2D, and DNAM dependent
21900395	colon carcinoma	Promote immunity	Mechanistic investigations revealed that IRF-1-induced NK cell cytotoxicity was independent of perforin and granzyme B but dependent on the NK cell activating receptor DNAM-1. Taken together, our findings establish IRF-1 as an essential mediator of the cross-talk between tumor cells and NK cells that mediate immune surveillance in the metastatic niche
21841316	Breast Carcinoma	Promote immunity	With disease progression, we found that expression of activating NK cell receptors (such as NKp30, NKG2D, DNAM-1, and CD16) decreased while expression of inhibitory receptors (such as NKG2A) increased and that this correlated with decreased NK cell function, most notably cytotoxicity

Summary
Symbol	CD226
Name	CD226 molecule
Aliases	DNAM-1; DNAM1; PTA1; TLiSA1; CD226 antigen; DNAX accessory molecule 1; DNAX accessory molecule-1; T lineage- ......
Chromosomal Location	18q22.3
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

[ TOP ]

Statistical results of CD226 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	CD226
Name	CD226 molecule
Aliases	DNAM-1; DNAM1; PTA1; TLiSA1; CD226 antigen; DNAX accessory molecule 1; DNAX accessory molecule-1; T lineage- ......
Chromosomal Location	18q22.3
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 CD226 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	-0.132	0.647
2	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	6	5	-0.195	0.694
3	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	7	-0.09	0.833
4	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	-0.639	0.164
5	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	-0.863	0.353
6	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	-0.351	0.763
7	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	26	23	0.327	0.433
8	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	15	11	0.681	0.352
9	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	11	12	-0.184	0.837
10	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	4	8	0.102	0.893
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	0.435	0.666
13	29443960	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	68	230	0.176	0.352

> Mutation difference between responders and non-responders

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Points in the above scatter plot represent the mutation difference of CD226 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	1.4	2.3	0.469
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	1.7	2	0.532
7	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	21	17	4.8	0	4.8	1
8	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	6	12.5	0	12.5	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	CD226
Name	CD226 molecule
Aliases	DNAM-1; DNAM1; PTA1; TLiSA1; CD226 antigen; DNAX accessory molecule 1; DNAX accessory molecule-1; T lineage- ......
Chromosomal Location	18q22.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between abundance of tumor-infiltrating lymphocytes (TILs) and expression, copy number, methylation, or mutation of CD226. 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	CD226
Name	CD226 molecule
Aliases	DNAM-1; DNAM1; PTA1; TLiSA1; CD226 antigen; DNAX accessory molecule 1; DNAX accessory molecule-1; T lineage- ......
Chromosomal Location	18q22.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between three kinds of immunomodulators and expression, copy number, methylation, or mutation of CD226. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by CD226. > Immunoinhibitor > Immunostimulator > MHC molecule

> Immunoinhibitor [ TOP ]

> Immunostimulator [ TOP ]

> MHC molecule [ TOP ]

Summary
Symbol	CD226
Name	CD226 molecule
Aliases	DNAM-1; DNAM1; PTA1; TLiSA1; CD226 antigen; DNAX accessory molecule 1; DNAX accessory molecule-1; T lineage- ......
Chromosomal Location	18q22.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between chemokines (or receptors) and expression, copy number, methylation, or mutation of CD226. 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	CD226
Name	CD226 molecule
Aliases	DNAM-1; DNAM1; PTA1; TLiSA1; CD226 antigen; DNAX accessory molecule 1; DNAX accessory molecule-1; T lineage- ......
Chromosomal Location	18q22.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Distribution of CD226 expression across immune and molecular subtypes. > Immune subtype > Molecular subtype

> Immune subtype [ TOP ]

> Molecular subtype [ TOP ]

Summary
Symbol	CD226
Name	CD226 molecule
Aliases	DNAM-1; DNAM1; PTA1; TLiSA1; CD226 antigen; DNAX accessory molecule 1; DNAX accessory molecule-1; T lineage- ......
Chromosomal Location	18q22.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Associations between CD226 and clinical features. > Overall survival analysis > Cancer stage > Tumor grade

> Overall survival [ TOP ]

> Stage [ TOP ]

> Grade [ TOP ]

Summary
Symbol	CD226
Name	CD226 molecule
Aliases	DNAM-1; DNAM1; PTA1; TLiSA1; CD226 antigen; DNAX accessory molecule 1; DNAX accessory molecule-1; T lineage- ......
Chromosomal Location	18q22.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Drugs targeting CD226 collected from DrugBank database.

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

Browse CD226