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

J Clin Invest. 2017 Mar 1;127(3):929-941. doi: 10.1172/JCI89455. Epub 2017 Feb 6.


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.

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / immunology*
  • Female
  • Humans
  • Mammary Neoplasms, Experimental / genetics
  • Mammary Neoplasms, Experimental / immunology*
  • Mammary Neoplasms, Experimental / therapy*
  • Mice
  • Receptor, Adenosine A2A / genetics
  • Receptor, Adenosine A2A / immunology*
  • Receptor, ErbB-2 / genetics
  • Receptor, ErbB-2 / immunology
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / immunology*


  • Receptor, Adenosine A2A
  • Receptors, Antigen, T-Cell
  • Recombinant Fusion Proteins
  • ERBB2 protein, human
  • Erbb2 protein, mouse
  • Receptor, ErbB-2