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 inhibits 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.
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