In this review, we aim at providing a broader view of how CD73 is involved in the immune evasion and tumor progression, thereby highlighting the importance of combination treatment arising from CD73 targeting currently under investigation in early phase clinical trials. The roles of CD73 on tumor and host cells as well as its prognosis and therapeutic value in human cancers have been recently discussed. These findings provide a distinct perspective on the role of CD73-generated adenosine in tumor development. This phenomenon is completely contrary to that observed in other tumor types, and results likely from context-dependent functions of the receptor in different tumor types. As the epithelial barrier function is essential for the inhibition of endometrial carcinomas with fewer intervening stromal or inflammatory cells in interconnected malignant glands, the loss of CD73 promotes adenosine deaminase endometrial tumor progression. CD73-generated adenosine seems to be required to sustain a physiological balance that maintains epithelial integrity in endometrial carcinomas with stable cell–cell adhesions mediated by A 1R. Strikingly, CD73-generated adenosine inhibits disease progression in these tumors. Unexpectedly, one recent report indicated a decrease of CD73 expression in poorly differentiated advanced-stage endometrial carcinoma and ovarian high-grade serous carcinoma. Consistent with the results from A2AR −/− and A2BR −/− mice, we and others have shown that CD73 −/− mice more readily reject tumors as compared with wild-type (WT) mice due to enhanced antitumor immunity and decreased carcinogenesis. In contrast, adenosine activation of A 2BR decreases the barrier function of vascular endothelium and promotes myeloid cells to acquire an anti-inflammatory (M2) phenotype that suppresses immune-mediated tumor cell eradication. Adenosine activation of A 2AR triggers cyclic AMP and protein kinase A signaling, which inhibits T cell receptor signaling and promotes the induction of Foxp3 + regulatory T cells (Tregs). Previous studies have underscored a negative role for extracellular adenosine within the tumor microenvironment by activating four distinct adenosine receptors (G protein-coupled receptors): A 1R, A 2AR, A 2BR and A 3R. CD73 knockout (CD73 −/−) mice also recapitulated some of the characteristics associated with arterial calcification cue to deficiency of CD73 (ACDC). However, recent work found that, CD73 insufficiency contributes to arterial calcification in humans with an autosomal recessive disease caused by loss-of-function mutations of Cd73. Strikingly, CD73 −/− mice are viable, indicating that CD73 is not vital under normal physiologic conditions. Despite the lack of extracellular adenosine signaling in CD73 −/− mice, extracellular ATP and ADP levels remain almost completely unchanged. During pathophysiological conditions, CD73-generated adenosine protects from tissue destruction through inflammation, ischemia and hypoxia. Adenosine induces immunosuppression, angiogenesis, mucosal hydration and ischemic preconditioning. CD73 is found on the surface of a variety of cell types, including endothelial cells, subtypes of lymphocytes, stromal cells and select types of tumor cells. Additionally, extracellular adenosine could be generated from the noncanonical pathway of CD38 (NAD + nucleosidase)-CD203a (ecto-nucleotide pyrophosphatase/phosphodiesterase 1)-CD73 that is independent of CD39. CD73 is essential for the generation of extracellular adenosine from 5′-adenosine monophosphate (5′-AMP) through the coordinated action of CD39 (ecto-nucleoside triphosphate diphosphohydrolase-1 ecto-NTPDase1) that catalyzes the phosphohydrolysis of ATP and ADP to AMP). CD73, known as ecto-5′-nucleotidase, is a cell surface glycosylphosphatidlinositol-anchored glycoprotein.
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