The Ectonucleotidases CD39 and CD73: Novel Checkpoint Inhibitor Targets

Overview

Journal Immunol Rev

Specialties Allergy & Immunology
General Surgery

Date 2017 Mar 5

PMID 28258700

Citations 472

Authors

Bertrand Allard

Maria Serena Longhi

Simon C Robson

John Stagg

Affiliations

Soon will be listed here.

Abstract

Cancers are able to grow by subverting immune suppressive pathways, to prevent the malignant cells as being recognized as dangerous or foreign. This mechanism prevents the cancer from being eliminated by the immune system and allows disease to progress from a very early stage to a lethal state. Immunotherapies are newly developing interventions that modify the patient's immune system to fight cancer, by either directly stimulating rejection-type processes or blocking suppressive pathways. Extracellular adenosine generated by the ectonucleotidases CD39 and CD73 is a newly recognized "immune checkpoint mediator" that interferes with anti-tumor immune responses. In this review, we focus on CD39 and CD73 ectoenzymes and encompass aspects of the biochemistry of these molecules as well as detailing the distribution and function on immune cells. Effects of CD39 and CD73 inhibition in preclinical and clinical studies are discussed. Finally, we provide insights into potential clinical application of adenosinergic and other purinergic-targeting therapies and forecast how these might develop in combination with other anti-cancer modalities.

Citing Articles

Targeting Immune Checkpoint Inhibitors for Non-Small-Cell Lung Cancer: Beyond PD-1/PD-L1 Monoclonal Antibodies.

Roussot N, Kaderbhai C, Ghiringhelli F Cancers (Basel). 2025; 17(5).

PMID: 40075753 PMC: 11898530. DOI: 10.3390/cancers17050906.

Low expression of CD39 on monocytes predicts poor survival in sepsis patients.

Li H, Ding P, Nan Y, Wu Z, Hua N, Luo L J Intensive Care. 2025; 13(1):12.

PMID: 40065471 PMC: 11892179. DOI: 10.1186/s40560-025-00784-0.

Mesenchymal stromal/stem cells from perinatal sources: biological facts, molecular biomarkers, and therapeutic promises.

Allouh M, Rizvi S, Alamri A, Jimoh Y, Aouda S, Ouda Z Stem Cell Res Ther. 2025; 16(1):127.

PMID: 40055783 PMC: 11889844. DOI: 10.1186/s13287-025-04254-0.

Expanding the horizon of CAR T cell therapy: from cancer treatment to autoimmune diseases and beyond.

Yang Z, Ha B, Wu Q, Ren F, Yin Z, Zhang H Front Immunol. 2025; 16:1544532.

PMID: 40046061 PMC: 11880241. DOI: 10.3389/fimmu.2025.1544532.

Toxoplasma gondii ROP18 induces maternal-fetal dysfunction by downregulating CD73 expression on decidual macrophages.

Guo J, Wang X, Wei L, Li S, Wang J, Zhang Y Parasit Vectors. 2025; 18(1):72.

PMID: 39994736 PMC: 11853993. DOI: 10.1186/s13071-025-06713-2.

References

MacKenzie W, Hoskin D, Blay J . Adenosine inhibits the adhesion of anti-CD3-activated killer lymphocytes to adenocarcinoma cells through an A3 receptor. Cancer Res. 1994; 54(13):3521-6. View

Di Virgilio F . Purines, purinergic receptors, and cancer. Cancer Res. 2012; 72(21):5441-7. DOI: 10.1158/0008-5472.CAN-12-1600. View

Burnstock G, Di Virgilio F . Purinergic signalling and cancer. Purinergic Signal. 2013; 9(4):491-540. PMC: 3889385. DOI: 10.1007/s11302-013-9372-5. View

Noble A, Mehta H, Lovell A, Papaioannou E, Fairbanks L . IL-12 and IL-4 activate a CD39-dependent intrinsic peripheral tolerance mechanism in CD8(+) T cells. Eur J Immunol. 2016; 46(6):1438-48. PMC: 5071739. DOI: 10.1002/eji.201545939. View

Allard D, Allard B, Gaudreau P, Chrobak P, Stagg J . CD73-adenosine: a next-generation target in immuno-oncology. Immunotherapy. 2016; 8(2):145-63. DOI: 10.2217/imt.15.106. View

Adinolfi E, Capece M, Franceschini A, Falzoni S, Giuliani A, Rotondo A . Accelerated tumor progression in mice lacking the ATP receptor P2X7. Cancer Res. 2014; 75(4):635-44. DOI: 10.1158/0008-5472.CAN-14-1259. View

Porcellini S, Traggiai E, Schenk U, Ferrera D, Matteoli M, Lanzavecchia A . Regulation of peripheral T cell activation by calreticulin. J Exp Med. 2006; 203(2):461-71. PMC: 2118200. DOI: 10.1084/jem.20051519. View

Milne G, Palmer T . Anti-inflammatory and immunosuppressive effects of the A2A adenosine receptor. ScientificWorldJournal. 2011; 11:320-39. PMC: 5720067. DOI: 10.1100/tsw.2011.22. View

Kim D, Bynoe M . A2A adenosine receptor modulates drug efflux transporter P-glycoprotein at the blood-brain barrier. J Clin Invest. 2016; 126(5):1717-33. PMC: 4855938. DOI: 10.1172/JCI76207. View

10.

Resta R, Yamashita Y, Thompson L . Ecto-enzyme and signaling functions of lymphocyte CD73. Immunol Rev. 1998; 161:95-109. DOI: 10.1111/j.1600-065x.1998.tb01574.x. View

11.

Vergani A, Tezza S, DAddio F, Fotino C, Liu K, Niewczas M . Long-term heart transplant survival by targeting the ionotropic purinergic receptor P2X7. Circulation. 2012; 127(4):463-75. PMC: 3569513. DOI: 10.1161/CIRCULATIONAHA.112.123653. View

12.

Elson G, Eisenberg M, Garg C, Outram S, Ferrante C, Hasko G . Induction of murine adenosine A(2A) receptor expression by LPS: analysis of the 5' upstream promoter. Genes Immun. 2013; 14(3):147-53. DOI: 10.1038/gene.2012.60. View

13.

Bergmann C, Strauss L, Zeidler R, Lang S, Whiteside T . Expansion and characteristics of human T regulatory type 1 cells in co-cultures simulating tumor microenvironment. Cancer Immunol Immunother. 2007; 56(9):1429-42. PMC: 11031003. DOI: 10.1007/s00262-007-0280-9. View

14.

Robertson J, Lang S, Lambert P, Martin P . Peptidoglycan derived from Staphylococcus epidermidis induces Connexin43 hemichannel activity with consequences on the innate immune response in endothelial cells. Biochem J. 2010; 432(1):133-43. DOI: 10.1042/BJ20091753. View

15.

Di Virgilio F, Adinolfi E . Extracellular purines, purinergic receptors and tumor growth. Oncogene. 2016; 36(3):293-303. PMC: 5269532. DOI: 10.1038/onc.2016.206. View

16.

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

17.

Qiu Y, Li W, Zhang H, Liu Y, Tian X, Fang W . P2X7 mediates ATP-driven invasiveness in prostate cancer cells. PLoS One. 2014; 9(12):e114371. PMC: 4259308. DOI: 10.1371/journal.pone.0114371. View

18.

Zhi X, Wang Y, Zhou X, Yu J, Jian R, Tang S . RNAi-mediated CD73 suppression induces apoptosis and cell-cycle arrest in human breast cancer cells. Cancer Sci. 2010; 101(12):2561-9. PMC: 11159901. DOI: 10.1111/j.1349-7006.2010.01733.x. View

19.

Burnstock G . Purinergic Signalling and Endothelium. Curr Vasc Pharmacol. 2015; 14(2):130-45. DOI: 10.2174/1570161114666151202204948. View

20.

Paustian C, Taylor P, Johnson T, Xu M, Ramirez N, Rosenthal K . Extracellular ATP and Toll-like receptor 2 agonists trigger in human monocytes an activation program that favors T helper 17. PLoS One. 2013; 8(1):e54804. PMC: 3561418. DOI: 10.1371/journal.pone.0054804. View