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.
Highlights
The success of immunotherapy in cancer in recent years has highlighted the potential to utilize a patient’s immune system to eradicate cancer
To determine whether activation of the chimeric antigen receptor (CAR) induced upregulation of the adenosine 2A receptors (A2ARs), T cells were activated with either an anti-myc tag antibody that directly stimulates the CAR via a c-myc epitope incorporated within the scFv, or anti-CD3/CD28 monoclonal antibodies as a positive control
Coculture with 24JK-HER2 tumor cells significantly increased A2AR expression on anti-HER2 CAR T cells, confirming that CAR activation resulted in upregulation of the A2AR (Figure 1B)
Summary
The success of immunotherapy in cancer in recent years has highlighted the potential to utilize a patient’s immune system to eradicate cancer. This conventionally involves ex vivo expansion of a patient’s tumor-infiltrating lymphocytes (TILs) to reinfuse a population of T lymphocytes that contains clones responsive to tumor antigens While this approach has been successful in melanoma [1], and to a lesser extent in other cancers such as renal cell carcinoma [2] and glioma [3], it is not broadly applicable to multiple cancer types because of the low frequency of TILs within the microenvironment of less immunogenic tumors. The incorporation of CD28/4-1BB signaling domains leads to more robust T cell activation and
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