PMC:6562565 / 56350-58406 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/6562565","sourcedb":"PMC","sourceid":"6562565","source_url":"https://www.ncbi.nlm.nih.gov/pmc/6562565","text":"Along with blocking adenosine production with small molecules or mAbs, another approach to inhibit adenosine-induced signaling is to directly block binding to its receptors A2AR and A2BR. Underscoring the potent protumoral effect of A2AR-trigerring, mice devoid of this receptor present reduced rates of tumor growth and metastasis, and in some instances tumors undergo complete rejection (38, 292, 400, 402). In addition, administration of pharmacologic A2AR antagonists recapitulates the anti-tumor effects of A2AR-deletion since it results to reduced primary tumor expansion (38, 54, 389, 392, 393, 396) and metastasis formation (292, 384, 393, 394, 397) ultimately leading to prolonged survival (384, 396). Mechanistically, tumors derived from A2AR-antagonist-treated mice are more heavily infiltrated by CD8+ T cells (389, 392, 393) as well as NK cells (389, 392, 393) and encompass fewer Tregs (389, 392, 393). In addition, in vivo A2AR antagonism leads to increased expression of CD69 (393), T-bet (396), and 4-1BB (396) as well as production of IFNγ and TNFα (392, 396) by intra-tumoral CD8+ T cells. Furthermore, this intervention increases the fraction of intra-tumoral NK cells producing GzB (292) and reduces the expression of PD-1, LAG3, FoxP3 and A2AR by tumor-infiltrating Tregs (392, 396). Interestingly, the A2AR antagonists ZM241385 and SCH58261 exhibit the capacity to curb primary tumor growth even in a T cell-independent manner (54). Notably, A2A antagonism in vivo increases activation induced cell death (AICD) of intra-tumoral T cells (395), a finding corroborating observations that cAMP-accumulation in the T cell cytosol averts terminal effector differentiation and AICD (421, 422). Three A2AR antagonists are currently being evaluated as single agents in Phase I/II trials to treat cancer patients bearing solid tumors. In particular, Corvus Pharmaceuticals, AstraZeneca, and Novartis have undertaken the clinical development of CPI-444 (NCT02655822), AZD4635 (NCT02740985), and NIR178 (NCT02403193, NCT03207867), 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