title: 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 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.
authors.affiliation: New England Inflammation and Tissue Protection Institute, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Hatfield
authors.affiliation: New England Inflammation and Tissue Protection Institute, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA. Electronic address: m.sitkovsky@neu.edu.
authors.forename: Michail
authors.initials: M
authors.lastname: Sitkovsky
mesh_terms: D000241:Adenosine / Q000378:metabolism; D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology; D007167:Immunotherapy / Q000379:methods*; D007694:Killer Cells, Natural / Q000276:immunology; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D059016:Tumor Microenvironment / Q000276:immunology
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000241:Adenosine