Targeting the adenosine 2A receptor enhances chimeric antigen receptor T cell efficacy

Paul A. Beavis, Melissa A. Henderson, Lauren Giuffrida, Jane K. Mills, Kevin Sek, Ryan S. Cross, Alexander J Davenport, Liza B John, Sherly Mardiana, Clare Y. Slaney, Ricky W Johnstone, Joseph A. Trapani, John Stagg, Sherene Loi, Lev Kats, David E Gyorki, Michael H. Kershaw, Phillip K. Darcy

Research output: Contribution to journalArticleResearchpeer-review

155 Citations (Scopus)

Abstract

Chimeric antigen receptor (CAR) T cells have been highly successful in treating hematological malignancies, including acute and chronic lymphoblastic leukemia. However, treatment of solid tumors using CAR T cells has been largely unsuccessful to date, partly because of tumor-induced immunosuppressive mechanisms, including adenosine production. Previous studies have shown that adenosine generated by tumor cells potently inhibits endogenous antitumor T cell responses through activation of adenosine 2A receptors (A2ARs). Herein, we have observed that CAR activation resulted in increased A2AR expression and suppression of both murine and human CAR T cells. This was reversible using either A2AR antagonists or genetic targeting of A2AR using shRNA. In 2 syngeneic HER2+ self-antigen tumor models, we found that either genetic or pharmacological targeting of the A2AR profoundly increased CAR T cell efficacy, particularly when combined with PD-1 blockade. Mechanistically, this was associated with increased cytokine production of CD8+ CAR T cells and increased activation of both CD8+ and CD4+ CAR T cells. Given the known clinical relevance of the CD73/adenosine pathway in several solid tumor types, and the initiation of phase I trials for A2AR antagonists in oncology, this approach has high translational potential to enhance CAR T cell efficacy in several cancer types.

Original languageEnglish
Pages (from-to)929-941
Number of pages13
JournalJournal of Clinical Investigation
Volume127
Issue number3
DOIs
Publication statusPublished - 1 Mar 2017

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