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

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.

• 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
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 127 Issue 3 Pg. 929-941 (Mar 01 2017) ISSN: 1558-8238 [Electronic] United States
• PMID: 28165340 (Publication Type: Journal Article)

Chemical References

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

Topics

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