Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 127, Issue 3, Pages 929-941Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI89455
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Funding
- National Health and Medical Research Council (NHMRC) [APP1062580, APP1122444]
- Cancer Council Victoria Project Grant [APP1084420]
- Peter MacCallum Cancer Centre Foundation
- National Breast Cancer Foundation Fellowships [PF-14-008, ECF-16-005]
- NHMRC Senior Research Fellowships [APP1041828, APP1058388]
- Senior Principal Research Fellowship from the NHMRC
- National Breast Cancer Foundation [IN-16-005, ECF-17-005, ECF-16-005] Funding Source: researchfish
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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.
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