TISIDB

Summary
Symbol	ADORA2A
Name	adenosine A2a receptor
Aliases	RDC8; A2aR; adenosine receptor subtype A2a; Adenosine receptor A2a
Chromosomal Location	22q11.23
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; Multi-pass membrane protein.
Domain	PF00001 7 transmembrane receptor (rhodopsin family)
Function	Receptor for adenosine. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase.

> Gene Ontology [ TOP ]
Biological Process	GO:0001973 adenosine receptor signaling pathway GO:0003013 circulatory system process GO:0006140 regulation of nucleotide metabolic process GO:0006164 purine nucleotide biosynthetic process GO:0006171 cAMP biosynthetic process GO:0006909 phagocytosis GO:0006968 cellular defense response GO:0007187 G-protein coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger GO:0007188 adenylate cyclase-modulating G-protein coupled receptor signaling pathway GO:0007189 adenylate cyclase-activating G-protein coupled receptor signaling pathway GO:0007596 blood coagulation GO:0007599 hemostasis GO:0008015 blood circulation GO:0009150 purine ribonucleotide metabolic process GO:0009152 purine ribonucleotide biosynthetic process GO:0009165 nucleotide biosynthetic process GO:0009187 cyclic nucleotide metabolic process GO:0009190 cyclic nucleotide biosynthetic process GO:0009260 ribonucleotide biosynthetic process GO:0010578 regulation of adenylate cyclase activity involved in G-protein coupled receptor signaling pathway GO:0010579 positive regulation of adenylate cyclase activity involved in G-protein coupled receptor signaling pathway GO:0030799 regulation of cyclic nucleotide metabolic process GO:0030801 positive regulation of cyclic nucleotide metabolic process GO:0030802 regulation of cyclic nucleotide biosynthetic process GO:0030804 positive regulation of cyclic nucleotide biosynthetic process GO:0030808 regulation of nucleotide biosynthetic process GO:0030810 positive regulation of nucleotide biosynthetic process GO:0030814 regulation of cAMP metabolic process GO:0030816 positive regulation of cAMP metabolic process GO:0030817 regulation of cAMP biosynthetic process GO:0030819 positive regulation of cAMP biosynthetic process GO:0031279 regulation of cyclase activity GO:0031281 positive regulation of cyclase activity GO:0035587 purinergic receptor signaling pathway GO:0035588 G-protein coupled purinergic receptor signaling pathway GO:0045761 regulation of adenylate cyclase activity GO:0045762 positive regulation of adenylate cyclase activity GO:0045981 positive regulation of nucleotide metabolic process GO:0046058 cAMP metabolic process GO:0046390 ribose phosphate biosynthetic process GO:0050817 coagulation GO:0050878 regulation of body fluid levels GO:0051339 regulation of lyase activity GO:0051349 positive regulation of lyase activity GO:0052652 cyclic purine nucleotide metabolic process GO:0072522 purine-containing compound biosynthetic process GO:1900371 regulation of purine nucleotide biosynthetic process GO:1900373 positive regulation of purine nucleotide biosynthetic process GO:1900542 regulation of purine nucleotide metabolic process GO:1900544 positive regulation of purine nucleotide metabolic process GO:1901293 nucleoside phosphate biosynthetic process
Molecular Function	GO:0001609 G-protein coupled adenosine receptor activity GO:0035586 purinergic receptor activity
Cellular Component	-

> KEGG and Reactome Pathway [ TOP ]
KEGG	hsa04015 Rap1 signaling pathway hsa04020 Calcium signaling pathway hsa04024 cAMP signaling pathway hsa04080 Neuroactive ligand-receptor interaction hsa04270 Vascular smooth muscle contraction
Reactome	R-HSA-187015: Activation of TRKA receptors R-HSA-417973: Adenosine P1 receptors R-HSA-373076: Class A/1 (Rhodopsin-like receptors) R-HSA-418555: G alpha (s) signalling events R-HSA-388396: GPCR downstream signaling R-HSA-500792: GPCR ligand binding R-HSA-392499: Metabolism of proteins R-HSA-187037: NGF signalling via TRKA from the plasma membrane R-HSA-187024: NGF-independant TRKA activation R-HSA-418038: Nucleotide-like (purinergic) receptors R-HSA-162582: Signal Transduction R-HSA-372790: Signaling by GPCR R-HSA-166520: Signalling by NGF R-HSA-5683826: Surfactant metabolism

> KEGG and Reactome Pathway

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KEGG

hsa04015 Rap1 signaling pathway
hsa04020 Calcium signaling pathway
hsa04024 cAMP signaling pathway
hsa04080 Neuroactive ligand-receptor interaction
hsa04270 Vascular smooth muscle contraction

Reactome

R-HSA-187015: Activation of TRKA receptors
R-HSA-417973: Adenosine P1 receptors
R-HSA-373076: Class A/1 (Rhodopsin-like receptors)
R-HSA-418555: G alpha (s) signalling events
R-HSA-388396: GPCR downstream signaling
R-HSA-500792: GPCR ligand binding
R-HSA-392499: Metabolism of proteins
R-HSA-187037: NGF signalling via TRKA from the plasma membrane
R-HSA-187024: NGF-independant TRKA activation
R-HSA-418038: Nucleotide-like (purinergic) receptors
R-HSA-162582: Signal Transduction
R-HSA-372790: Signaling by GPCR
R-HSA-166520: Signalling by NGF
R-HSA-5683826: Surfactant metabolism

Summary
Symbol	ADORA2A
Name	adenosine A2a receptor
Aliases	RDC8; A2aR; adenosine receptor subtype A2a; Adenosine receptor A2a
Chromosomal Location	22q11.23
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Literatures that report relations between ADORA2A 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 ADORA2A and anti-tumor immunity in human cancer.

PMID	Cancer type	Relation to immunity	Evidence sentences
25377469	Melanoma	Inhibit immunity (T and NK cell function)	Myeloid expression of adenosine A2A receptor suppresses T and NK cell responses in the solid tumor microenvironment.
28592285	Head and Neck Squamous Cell Carcinoma	Inhibit immunity (T cell function)	The adenosine A2A receptor (A2AR) could protect cancerous tissues from immune clearance via inhibiting T cells response. Immunostaining of HNSCC tissue samples revealed that increased expression of A2AR on tumor infiltrating immune cells correlated with advanced pathological grade, larger tumor size and positive lymph node status.
23776241	Triple-Negative Breast Carcinoma	Inhibit immunity	Using mouse models of breast cancer, we demonstrated that CD73 overexpression in tumor cells conferred chemoresistance to doxorubicin, a commonly used anthracycline, by suppressing adaptive antitumor immune responses via activation of A2A adenosine receptors. Targeted blockade of CD73 enhanced doxorubicin-mediated antitumor immune responses and significantly prolonged the survival of mice with established metastatic breast cancer. Taken together, our data suggest that CD73 constitutes a therapeutic target in TNBC.
24986517	melanoma & breast carcinoma	Inhibit immunity immunotherapy target	Adenosine targeting is an attractive new approach to cancer treatment, but no clinical study has yet examined adenosine inhibition in oncology despite the safe clinical profile of adenosine A2A receptor inhibitors (A2ARi) in Parkinson disease.
23964122	B16 Malignant Melanoma	Inhibit immunity (NK cell function)	In this study, we revealed that A2A/A2B receptor antagonists were effective in reducing the metastasis of tumors expressing CD73 endogenously (4T1.2 breast tumors) and when CD73 was ectopically expressed (B16F10 melanoma). A2A(-/-) mice were strongly protected against tumor metastasis, indicating that host A2A receptors enhanced tumor metastasis. A2A blockade enhanced natural killer (NK) cell maturation and cytotoxic function in vitro, reduced metastasis in a perforin-dependent manner, and enhanced NK cell expression of granzyme B in vivo, strongly suggesting that the antimetastatic effect of A2A blockade was due to enhanced NK cell function.
29802128	Sarcoma	Inhibit immunity (T cell function); Resistant to immunotherapy	In studies of A2AR and/or A2BR gene-deficient mice, we found that A2AR deletion-but not A2BR deletion-liberates endogenous CD8+ T cell antitumor immunity against weakly immunogenic MCA205 sarcomas. Studies of adoptively transferred A2AR-/-, A2BR-/-, or A2AR-/-/A2BR-/- tumor-reactive T cells confirmed that immunosuppression in the tumor microenvironment was mediated by A2AR on CD8+ T cells. The blockade of the A2AR on adoptively transferred T cells by synthetic A2AR antagonist led to higher levels of IFN-γ secretion by tumor-infiltrating CD8+ T cells.
16916931	Melanoma	Inhibit immunity	We hypothesized that A2AR also protects cancerous tissues by inhibiting incoming antitumor T lymphocytes. Here we confirm this hypothesis by showing that genetic deletion of A2AR in the host resulted in rejection of established immunogenic tumors in approximately 60% of A2AR-deficient mice with no rejection observed in control WT mice.

Summary
Symbol	ADORA2A
Name	adenosine A2a receptor
Aliases	RDC8; A2aR; adenosine receptor subtype A2a; Adenosine receptor A2a
Chromosomal Location	22q11.23
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 ADORA2A 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	ADORA2A
Name	adenosine A2a receptor
Aliases	RDC8; A2aR; adenosine receptor subtype A2a; Adenosine receptor A2a
Chromosomal Location	22q11.23
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 ADORA2A 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	-0.321	0.412
2	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	6	5	-0.295	0.737
3	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	7	-0.343	0.639
4	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	-1.061	0.19
5	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	-1.509	0.207
6	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	-0.492	0.723
7	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	26	23	0	1
8	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	15	11	0	1
9	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	11	12	0	1
10	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	4	8	0.08	0.946
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	-0.093	0.956
13	29443960	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	68	230	-0.054	0.507

> Mutation difference between responders and non-responders

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Points in the above scatter plot represent the mutation difference of ADORA2A 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	0	5.9	-5.9	0.447
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	9.1	-9.1	0.458
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	ADORA2A
Name	adenosine A2a receptor
Aliases	RDC8; A2aR; adenosine receptor subtype A2a; Adenosine receptor A2a
Chromosomal Location	22q11.23
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between abundance of tumor-infiltrating lymphocytes (TILs) and expression, copy number, methylation, or mutation of ADORA2A. 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	ADORA2A
Name	adenosine A2a receptor
Aliases	RDC8; A2aR; adenosine receptor subtype A2a; Adenosine receptor A2a
Chromosomal Location	22q11.23
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between three kinds of immunomodulators and expression, copy number, methylation, or mutation of ADORA2A. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by ADORA2A. > Immunoinhibitor > Immunostimulator > MHC molecule

> Immunoinhibitor [ TOP ]

> Immunostimulator [ TOP ]

> MHC molecule [ TOP ]

Summary
Symbol	ADORA2A
Name	adenosine A2a receptor
Aliases	RDC8; A2aR; adenosine receptor subtype A2a; Adenosine receptor A2a
Chromosomal Location	22q11.23
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between chemokines (or receptors) and expression, copy number, methylation, or mutation of ADORA2A. 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	ADORA2A
Name	adenosine A2a receptor
Aliases	RDC8; A2aR; adenosine receptor subtype A2a; Adenosine receptor A2a
Chromosomal Location	22q11.23
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Distribution of ADORA2A expression across immune and molecular subtypes. > Immune subtype > Molecular subtype

> Immune subtype [ TOP ]

> Molecular subtype [ TOP ]

Summary
Symbol	ADORA2A
Name	adenosine A2a receptor
Aliases	RDC8; A2aR; adenosine receptor subtype A2a; Adenosine receptor A2a
Chromosomal Location	22q11.23
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Associations between ADORA2A and clinical features. > Overall survival analysis > Cancer stage > Tumor grade

> Overall survival [ TOP ]

> Stage [ TOP ]

> Grade [ TOP ]

Summary
Symbol	ADORA2A
Name	adenosine A2a receptor
Aliases	RDC8; A2aR; adenosine receptor subtype A2a; Adenosine receptor A2a
Chromosomal Location	22q11.23
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Drugs targeting ADORA2A collected from DrugBank database.

> Drugs from DrugBank database

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Details on drugs targeting ADORA2A.

ID	Name	Drug Type	Targets	#Targets
DB00201	Caffeine	Small Molecule	ADORA1, ADORA2A, ATM, ITPR1, ITPR2, ITPR3, PDE10A, PDE11A, PDE1A, ......	33
DB00277	Theophylline	Small Molecule	ADORA1, ADORA2A, ADORA2B, CPNE1, HDAC2, HM13, NOMO1, PARP1, PDE3A, ......	14
DB00358	Mefloquine	Small Molecule	ADORA2A, HBA1	2
DB00555	Lamotrigine	Small Molecule	ADORA1, ADORA2A, ADRA1A, ADRA2A, ADRB1, CACNA1E, CHRM1, CHRM2, CHR ......	44
DB00640	Adenosine	Small Molecule	ADORA1, ADORA2A, ADORA2B, ADORA3	4
DB00651	Dyphylline	Small Molecule	ADORA1, ADORA2A, PDE4A, PDE4B, PDE4C, PDE4D, PDE7A, PDE7B	8
DB00806	Pentoxifylline	Small Molecule	ADORA1, ADORA2A, NT5E, PDE4A, PDE4B, PDE5A	6
DB00824	Enprofylline	Small Molecule	ADORA1, ADORA2A, ADORA2B, ADORA3, PDE4A, PDE4B	6
DB01303	Oxtriphylline	Small Molecule	ADORA1, ADORA2A, HDAC2, PDE3A, PDE4A	5
DB01412	Theobromine	Small Molecule	ADORA1, ADORA2A, PDE4B	3
DB04853	Binodenoson	Small Molecule	ADORA2A	1
DB04932	Defibrotide	Biotech	ADORA1, ADORA2A, ADORA2B	3
DB05009	Apadenoson	Small Molecule	ADORA2A	1
DB05191	Atl146e	Small Molecule	ADORA2A	1
DB06213	Regadenoson	Small Molecule	ADORA2A	1
DB08770	4-{2-[(7-amino-2-furan-2-yl[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)amino]ethyl}phenol	Small Molecule	ADORA2A	1
DB09273	Doxofylline	Small Molecule	ADORA2A, ADRB2	2

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