Regulatory Role of CD39 and CD73 in Tumor Immunity

Overview

Journal Future Oncol

Specialty Oncology

Date 2024 Apr 23

PMID 38652041

Authors

Nicole Kaplinsky

Kada Williams

Dean Watkins

Molly Adams

Laura Stanbery

John Nemunaitis

Affiliations

Soon will be listed here.

Abstract

CD39 is the rate-limiting enzyme for the molecular signal cascade leading to the generation of ADP and adenosine monophosphate (AMP). In conjunction with CD73, CD39 converts adenosine triphosphate (ATP) to ADP and AMP, which leads to the accumulation of immunosuppressive adenosine in the tumor microenvironment. This review focuses on the role of CD39 and CD73 in immune response and malignant progression, including the expression of CD39 within the tumor microenvironment and its relationship to immune effector cells, and its role in antigen presentation. The role of CD39- and CD73-targeting therapeutics and cancer-directed clinical trials investigating CD39 modulation are also explored.

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References

Dwyer K, Deaglio S, Gao W, Friedman D, Strom T, Robson S . CD39 and control of cellular immune responses. Purinergic Signal. 2008; 3(1-2):171-80. PMC: 2096766. DOI: 10.1007/s11302-006-9050-y. View

Levesque S, Lavoie E, Lecka J, Bigonnesse F, Sevigny J . Specificity of the ecto-ATPase inhibitor ARL 67156 on human and mouse ectonucleotidases. Br J Pharmacol. 2007; 152(1):141-50. PMC: 1978278. DOI: 10.1038/sj.bjp.0707361. View

Serra S, Horenstein A, Vaisitti T, Brusa D, Rossi D, Laurenti L . CD73-generated extracellular adenosine in chronic lymphocytic leukemia creates local conditions counteracting drug-induced cell death. Blood. 2011; 118(23):6141-52. PMC: 3342854. DOI: 10.1182/blood-2011-08-374728. View

Follo C, Cheng Y, Richards W, Bueno R, Broaddus V . Autophagy facilitates the release of immunogenic signals following chemotherapy in 3D models of mesothelioma. Mol Carcinog. 2019; 58(10):1754-1769. DOI: 10.1002/mc.23050. View

Stagg J, Divisekera U, McLaughlin N, Sharkey J, Pommey S, Denoyer D . Anti-CD73 antibody therapy inhibits breast tumor growth and metastasis. Proc Natl Acad Sci U S A. 2010; 107(4):1547-52. PMC: 2824381. DOI: 10.1073/pnas.0908801107. View

Wang L, Londono L, Cowell J, Saatci O, Aras M, Ersan P . Targeting Adenosine with Adenosine Deaminase 2 to Inhibit Growth of Solid Tumors. Cancer Res. 2021; 81(12):3319-3332. DOI: 10.1158/0008-5472.CAN-21-0340. View

Zhang M, Dai X, Xiang Y, Xie L, Sun M, Shi J . Advances in CD73 inhibitors for immunotherapy: Antibodies, synthetic small molecule compounds, and natural compounds. Eur J Med Chem. 2023; 258:115546. DOI: 10.1016/j.ejmech.2023.115546. View

Vultaggio-Poma V, Sarti A, Di Virgilio F . Extracellular ATP: A Feasible Target for Cancer Therapy. Cells. 2020; 9(11). PMC: 7698494. DOI: 10.3390/cells9112496. View

Koh J, Kim Y, Lee K, Hur J, Kim M, Kim B . MDSC subtypes and CD39 expression on CD8 T cells predict the efficacy of anti-PD-1 immunotherapy in patients with advanced NSCLC. Eur J Immunol. 2020; 50(11):1810-1819. PMC: 7689686. DOI: 10.1002/eji.202048534. View

10.

Goepfert C, Sundberg C, Sevigny J, Enjyoji K, Hoshi T, Csizmadia E . Disordered cellular migration and angiogenesis in cd39-null mice. Circulation. 2001; 104(25):3109-15. DOI: 10.1161/hc5001.100663. View

11.

Sun X, Han L, Seth P, Bian S, Li L, Csizmadia E . Disordered purinergic signaling and abnormal cellular metabolism are associated with development of liver cancer in Cd39/ENTPD1 null mice. Hepatology. 2012; 57(1):205-16. PMC: 3505255. DOI: 10.1002/hep.25989. View

12.

Bach N, Winzer R, Tolosa E, Fiedler W, Brauneck F . The Clinical Significance of CD73 in Cancer. Int J Mol Sci. 2023; 24(14). PMC: 10380759. DOI: 10.3390/ijms241411759. View

13.

Enjyoji K, Sevigny J, Lin Y, Frenette P, Christie P, Esch 2nd J . Targeted disruption of cd39/ATP diphosphohydrolase results in disordered hemostasis and thromboregulation. Nat Med. 1999; 5(9):1010-7. DOI: 10.1038/12447. View

14.

Takahashi T, KUNIYASU Y, Toda M, Sakaguchi N, Itoh M, Iwata M . Immunologic self-tolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state. Int Immunol. 1999; 10(12):1969-80. DOI: 10.1093/intimm/10.12.1969. View

15.

Hilchey S, Kobie J, Cochran M, Secor-Socha S, Wang J, Hyrien O . Human follicular lymphoma CD39+-infiltrating T cells contribute to adenosine-mediated T cell hyporesponsiveness. J Immunol. 2009; 183(10):6157-66. PMC: 2917799. DOI: 10.4049/jimmunol.0900475. View

16.

Schuler P, Schilling B, Harasymczuk M, Hoffmann T, Johnson J, Lang S . Phenotypic and functional characteristics of CD4+ CD39+ FOXP3+ and CD4+ CD39+ FOXP3neg T-cell subsets in cancer patients. Eur J Immunol. 2012; 42(7):1876-85. PMC: 3689271. DOI: 10.1002/eji.201142347. View

17.

Garcia R, Yan M, Search D, Zhang R, Carson N, Ryan C . P2Y6 receptor potentiates pro-inflammatory responses in macrophages and exhibits differential roles in atherosclerotic lesion development. PLoS One. 2014; 9(10):e111385. PMC: 4216081. DOI: 10.1371/journal.pone.0111385. View

18.

Baghbani E, Noorolyai S, Shanehbandi D, Mokhtarzadeh A, Aghebati-Maleki L, Shahgoli V . Regulation of immune responses through CD39 and CD73 in cancer: Novel checkpoints. Life Sci. 2021; 282:119826. DOI: 10.1016/j.lfs.2021.119826. View

19.

Bastid J, Regairaz A, Bonnefoy N, Dejou C, Giustiniani J, Laheurte C . Inhibition of CD39 enzymatic function at the surface of tumor cells alleviates their immunosuppressive activity. Cancer Immunol Res. 2014; 3(3):254-65. DOI: 10.1158/2326-6066.CIR-14-0018. View

20.

Cai X, Ni X, Yi Y, He H, Wang J, Fu Y . Overexpression of CD39 in hepatocellular carcinoma is an independent indicator of poor outcome after radical resection. Medicine (Baltimore). 2016; 95(40):e4989. PMC: 5059057. DOI: 10.1097/MD.0000000000004989. View