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

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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 (A_2ARs). Herein, we have observed that CAR activation resulted in increased A_2AR expression and suppression of both murine and human CAR T cells. This was reversible using either A_2AR antagonists or genetic targeting of A_2AR using shRNA. In 2 syngeneic HER2⁺ self-antigen tumor models, we found that either genetic or pharmacological targeting of the A_2AR 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 A_2AR antagonists in oncology, this approach has high translational potential to enhance CAR T cell efficacy in several cancer types.

Authors

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 Gyorki, Michael H. Kershaw, Phillip K. Darcy