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

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