A2A Adenosine Receptor antagonists to weaken the hypoxia-HIF-1α driven immunosuppression and improve immunotherapies of cancer

Abstract

Hypoxic and adenosine rich tumor microenvironments represent an important barrier that must be overcome to enable T and NK cells to reject tumors. The A2A adenosine receptor (A2AR) on activated immune cells was identified as a critical and non-redundant mediator of physiological immunosuppression. Observations showing that tumor-protecting A2AR also suppress and redirect the anti-tumor immune response pointed to the importance of inhibiting this pathway to improve cancer immunotherapy. We advocated i) blocking immunosuppressive Adenosine-A2AR-cAMP–mediated intracellular signaling by A2AR antagonists and ii) weakening Hypoxia-HIF-1α-mediated accumulation of extracellular adenosine by oxygenation agents that also inhibit CD39/CD73 adenosine-generating enzymes. In view of commencing clinical trials of synthetic A2AR antagonists in combination with cancer immunotherapies, we discuss their promise and exclusion criteria.