{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T02:16:35Z","timestamp":1791339395605,"version":"4.3.1"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,5,18]],"date-time":"2022-05-18T00:00:00Z","timestamp":1652832000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Adenosine deaminase (ADA) plays an important role in immune response, which includes two isoenzymes: ADA1 and ADA2. This study aims to explore the roles of ADA1 and ADA2 in cancers.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Human Protein Atlas (HPA) and Gene Expression Profiling Interactive Analysis (GEPIA2) databases were used to analyze the mRNA expression of ADA1 and ADA2 in human normal cells and tumor tissues. The enzyme assay was used to detect the ADA1 and ADA2 activities in serum from cancer patients. The Kaplan\u2013Meier (KM) plotter was used to analyze the prognostic value of ADA1 and ADA2. TIMER2.0 was used to explore how ADA1 and ADA2 correlate with immune infiltration and immune checkpoints. cBioPortal database was used to investigate the mutations of ADA1 and ADA2. LinkedOmics was used to screen the ADA1 and ADA2 expression-related genes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>ADA1 was significantly increased in several tumor tissues, including cholangiocarcinoma (CHOL), lymphoid neoplasm diffuse large B-cell lymphoma (DLBC), head and neck squamous cell carcinoma (HNSC), kidney renal clear cell carcinoma (KIRC), ovarian serous cystadenocarcinoma (OV), pancreatic adenocarcinoma (PAAD), thymoma (THYM), and uterine carcinosarcoma (UCS). ADA2 expression was significantly increased in esophageal carcinoma (ESCA), glioblastoma multiforme (GBM), acute myeloid leukemia (LAML), OV, PAAD, skin cutaneous melanoma (SKCM), and stomach adenocarcinoma (STAD). There were no significant changes in serum ADA1 activities in most cancers, while serum ADA2 activities were increased in most cancers. For prognosis, high ADA1 expression was associated with the poor survival in several cancers, including esophageal squamous cell carcinoma (ESCC), HNSC, KIRC, kidney renal papillary cell carcinoma (KIRP), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), and uterine corpus endometrial carcinoma (UCEC). However, high ADA2 expression showed a favorable prognosis in breast invasive carcinoma (BRCA), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), HNSC, KIRC, KIRP, LUAD, OV, PAAD, sarcoma, and THYM. ADA1 showed a moderate positive correlation with multiple infiltrating immune cells in most cancers. ADA2 was positively correlated with B cells, CD8 T cells, monocytes\/macrophages, and dendritic cells (DCs) and was strongly negatively correlated with myeloid-derived suppressor cells. Function analysis showed that ADA1 expression-related genes were mainly enriched in cell division biological progression. However, ADA2-related genes were mainly associated with immune response.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>As isoenzymes, ADA1 and ADA2 showed opposite prognostic values and different correlative patterns with immune infiltrating. These data demonstrated the distinct roles of ADA1 and ADA2 in cancer. ADA2 might act as a protective factor in cancer.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2022.903461","type":"journal-article","created":{"date-parts":[[2022,5,18]],"date-time":"2022-05-18T05:05:42Z","timestamp":1652850342000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":24,"title":["Distinct Roles of Adenosine Deaminase Isoenzymes ADA1 and ADA2: A Pan-Cancer Analysis"],"prefix":"10.3389","volume":"13","author":[{"given":"Zhao-wei","family":"Gao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lan","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-tao","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui-zhong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,5,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20050683","article-title":"Human ADA2 Belongs to a New Family of Growth Factors With Adenosine Deaminase Activity","volume":"391","author":"Zavialov","year":"2005","journal-title":"Biochem J"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2021012300","article-title":"Built to Last: Gene Therapy for ADA SCID","volume":"138","author":"Pai","year":"2021","journal-title":"Blood"},{"key":"B3","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1182\/blood-2016-01-688226","article-title":"Update on the Safety and Efficacy of Retroviral Gene Therapy for Immunodeficiency Due to Adenosine Deaminase Deficiency","volume":"128","author":"Cicalese","year":"2016","journal-title":"Blood"},{"key":"B4","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1620\/tjem.255.49","article-title":"Enzymatic Changes in Red Blood Cells of Diamond-Blackfan Anemia","volume":"255","author":"Utsugisawa","year":"2021","journal-title":"Tohoku J Exp Med"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1002\/JLB.5A0621-314R","article-title":"Single-Cell Profiling of T Lymphocytes in Deficiency of Adenosine Deaminase 2","volume":"111","author":"Wu","year":"2022","journal-title":"J Leukoc Biol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.75.1.446","article-title":"Characterization of the Residual Adenosine Deaminating Activity in the Spleen of A Patient With Combined Immunodeficiency Disease and Adenosine Deaminase Deficiency","volume":"75","author":"Schrader","year":"1978","journal-title":"Proc Natl Acad Sci USA"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-021-01141-0","article-title":"Intrinsic Defects in B Cell Development and Differentiation, T Cell Exhaustion and Altered Unconventional T Cell Generation Characterize Human Adenosine Deaminase Type 2 Deficiency","volume":"41","author":"Yap","year":"2021","journal-title":"J Clin Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.754029","article-title":"Case Report: Deficiency of Adenosine Deaminase 2 Presenting With Overlapping Features of Autoimmune Lymphoproliferative Syndrome and Bone Marrow Failure","volume":"12","author":"Dell'Orso","year":"2021","journal-title":"Front Immunol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1007\/s10067-021-05711-w","article-title":"Expanding Spectrum of DADA2: A Review of Phenotypes, Genetics, Pathogenesis and Treatment","volume":"40","author":"Pinto","year":"2021","journal-title":"Clin Rheumatol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.725447","article-title":"Serum Biomarker Profile Including CCL1, CXCL10, VEGF, and Adenosine Deaminase Activity Distinguishes Active From Remotely Acquired Latent Tuberculosis","volume":"12","author":"Delemarre","year":"2021","journal-title":"Front Immunol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1007\/s00296-011-1836-8","article-title":"Serum Adenosine Deaminase Activity in Patients With Systemic Lupus Erythematosus: A Study Based on ADA1 and ADA2 Isoenzymes Pattern","volume":"32","author":"Saghiri","year":"2012","journal-title":"Rheumatol Int"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.5812\/hepatmon.98811","article-title":"Diagnostic Value of Serum Adenosine Deaminase and its Isoenzymes for Autoimmune Liver Disease","volume":"20","author":"Gao","year":"2020","journal-title":"Hepat Mon"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2019-216030","article-title":"Adenosine Deaminase 2 as a Biomarker of Macrophage Activation Syndrome in Systemic Juvenile Idiopathic Arthritis","volume":"79","author":"Lee","year":"2020","journal-title":"Ann Rheum Dis"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/nrc.2017.86","article-title":"Targeting Immunosuppressive Adenosine in Cancer","volume":"17","author":"Vijayan","year":"2017","journal-title":"Nat Rev Cancer"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.arcmed.2009.10.012","article-title":"Diagnostic Value of Adenosine Deaminase Activity in Benign and Malignant Breast Tumors","volume":"41","author":"Aghaei","year":"2010","journal-title":"Arch Med Res"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinbiochem.2005.05.015","article-title":"Adenosine Deaminase Activity in the Serum and Malignant Tumors of Breast Cancer: The Assessment of Isoenzyme ADA1 and ADA2 Activities","volume":"38","author":"Aghaei","year":"2005","journal-title":"Clin Biochem"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-21-0340","article-title":"Targeting Adenosine With Adenosine Deaminase 2 to Inhibit Growth of Solid Tumors","volume":"81","author":"Wang","year":"2021","journal-title":"Cancer Res"},{"key":"B18","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1038\/nprot.2008.211","article-title":"Systematic and Integrative Analysis of Large Gene Lists Using DAVID Bioinformatics Resources","volume":"4","author":"Huang","year":"2009","journal-title":"Nat Protoc"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.837230","article-title":"Adenosine-A2A Receptor Pathway in Cancer Immunotherapy","volume":"13","author":"Sun","year":"2022","journal-title":"Front Immunol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-21-2742","article-title":"Phase I Study of Taminadenant (PBF509\/NIR178), an Adenosine 2A Receptor Antagonist, With or Without Spartalizumab, in Patients With Advanced Non-Small Cell Lung Cancer","author":"Chiappori","year":"2022","journal-title":"Clin Cancer Res"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2021-004089","article-title":"Next Steps for Clinical Translation of Adenosine Pathway Inhibition in Cancer Immunotherapy","volume":"10","author":"Augustin","year":"2022","journal-title":"J Immunother Cancer"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2020-217007","article-title":"Total Adenosine Deaminase Highly Correlated With Adenosine Deaminase 2 Activity in Serum","volume":"81","author":"Gao","year":"2022","journal-title":"Ann Rheum Dis"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2020-217055","article-title":"Response to: 'Total Adenosine Deaminase Highly Correlated With Adenosine Deaminase 2 Activity in Serum' by Gao Et al","volume":"81","author":"Lee","year":"2022","journal-title":"Ann Rheum Dis"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-016-2357-0","article-title":"Human Adenosine Deaminases ADA1 and ADA2 Bind to Different Subsets of Immune Cells","volume":"74","author":"Kaljas","year":"2017","journal-title":"Cell Mol Life Sci"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.1109764","article-title":"Human Adenosine Deaminase 2 Induces Differentiation of Monocytes Into Macrophages and Stimulates Proliferation of T Helper Cells and Macrophages","volume":"88","author":"Zavialov","year":"2010","journal-title":"J Leukoc Biol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2027675","article-title":"Autologous Ex Vivo Lentiviral Gene Therapy for Adenosine Deaminase Deficiency","volume":"384","author":"Kohn","year":"2021","journal-title":"N Engl J Med"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1307361","article-title":"Early-Onset Stroke and Vasculopathy Associated With Mutations in ADA2","volume":"370","author":"Zhou","year":"2014","journal-title":"N Engl J Med"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1002\/art.40913","article-title":"Identification of Novel Adenosine Deaminase 2 Gene Variants and Varied Clinical Phenotype in Pediatric Vasculitis","volume":"71","author":"Gibson","year":"2019","journal-title":"Arthritis Rheumatol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2422-6","article-title":"IL-18BP is a Secreted Immune Checkpoint and Barrier to IL-18 Immunotherapy","volume":"583","author":"Zhou","year":"2020","journal-title":"Nature"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abi6899","article-title":"A Tumor-Specific Pro-IL-12 Activates Preexisting Cytotoxic T Cells to Control Established Tumors","volume":"7","author":"Xue","year":"2022","journal-title":"Sci Immunol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1118296109","article-title":"Tumor-Targeted TNFalpha Stabilizes Tumor Vessels and Enhances Active Immunotherapy","volume":"109","author":"Johansson","year":"2012","journal-title":"Proc Natl Acad Sci USA"},{"key":"B32","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1159\/000369674","article-title":"Adenosine Deaminase Inhibitor EHNA Exhibits a Potent Anticancer Effect Against Malignant Pleural Mesothelioma","volume":"35","author":"Nakajima","year":"2015","journal-title":"Cell Physiol Biochem"},{"key":"B33","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1016\/j.canlet.2021.12.027","article-title":"Complement C5a Induces the Formation of Neutrophil Extracellular Traps by Myeloid-Derived Suppressor Cells to Promote Metastasis","volume":"529","author":"Ortiz-Espinosa","year":"2022","journal-title":"Cancer Lett"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14051236","article-title":"Coordinated Regulation of Myeloid-Derived Suppressor Cells by Cytokines and Chemokines","volume":"14","author":"Li","year":"2022","journal-title":"Cancers (Basel)"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1172\/JCI10360","article-title":"Adenosine Deaminase Deficiency Increases Thymic Apoptosis and Causes Defective T Cell Receptor Signaling","volume":"108","author":"Apasov","year":"2001","journal-title":"J Clin Invest"},{"key":"B36","doi-asserted-by":"publisher","first-page":"23221","DOI":"10.1038\/s41598-021-02572-w","article-title":"Metabolite and Thymocyte Development Defects in ADA-SCID Mice Receiving Enzyme Replacement Therapy","volume":"11","author":"Moretti","year":"2021","journal-title":"Sci Rep"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.1984.tb01276.x","article-title":"Mechanisms of Deoxyadenosine Toxicity in Human Lymphoid Cells In Vitro: Relevance to the Therapeutic Use of Inhibitors of Adenosine Deaminase","volume":"56","author":"Lee","year":"1984","journal-title":"Br J Haematol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.903461\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,18]],"date-time":"2022-05-18T05:05:51Z","timestamp":1652850351000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.903461\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,18]]},"references-count":37,"alternative-id":["10.3389\/fimmu.2022.903461"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.903461","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,18]]},"article-number":"903461"}}