A2A adenosine receptor antagonists to weaken the hypoxia-HIF-1α driven immunosuppression and improve immunotherapies of cancer. (August 2016)

• Record Type: Journal Article
• Authors: Hatfield, Stephen M; Sitkovsky, Michail
• Is Part Of: Current opinion in pharmacology. Volume 29(2016)
• Page Start: 90
• Page End: 96
• Publication Date: 2016-08
• Subjects: Pharmacology -- Periodicals; Pharmaceutical Preparations -- Periodicals; Drug Therapy -- Periodicals; Biopharmaceutics -- Periodicals; Pharmacologie -- Périodiques; Pharmacology; Periodicals; 615.105
• DOI: 10.1016/j.coph.2016.06.009
• Languages: English
• ISSNs: 1471-4892

Abstract

Highlights: A2AR and hypoxia in TME are important barriers that must be overcome in cancer immunotherapy. A2AR on immune cells are critical and non-redundant mediators of physiological immunosuppression. Blocking immunosuppressive A2AR-mediated signaling may improve current cancer immunotherapy. 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 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.