Immunotherapy is rapidly emerging as a cancer treatment with high potential. Recent clinical trials with anti-CTLA-4 and anti-PD-1/PDL-1 antibodies (mAbs) suggest that targeting multiple immunosuppressive pathways may significantly improve patient survival. The generation of adenosine by CD73 also suppresses anti-tumor immune responses through the activation of A2A receptors on T cells and NK cells. We sought to determine whether blockade of A2A receptors could enhance the efficacy of anti-PD-1 mAb. The expression of CD73 by tumor cells limited the efficacy of anti-PD-1 mAb in two tumor models and this was alleviated with concomitant treatment with an A2A adenosine receptor antagonist. The blockade of PD-1 enhanced A2A receptor expression on tumor-infiltrating CD8+ T cells, making them more susceptible to A2A mediated suppression. Thus, dual blockade of PD-1 and A2A significantly enhanced the expression of IFNγ and Granzyme B by tumor-infiltrating CD8+ T cells and accordingly, increased growth inhibition of CD73+ tumors and survival of mice. Our study indicates that CD73 expression may constitute a potential biomarker for the efficacy of anti-PD-1 mAb in cancer patients and that the efficacy of anti-PD-1 mAb can be significantly enhanced by A2A antagonists. We have therefore revealed a potentially novel biomarker for the efficacy of anti-PD-1 that warrants further investigation in patients. Our studies utilized SYN-115, a drug that has already undergone phase IIb testing in Parkinson's Disease and so our findings therefore have immediate translational relevance for cancer patients.
- Received November 11, 2014.
- Revision received January 29, 2015.
- Accepted February 2, 2015.
- Copyright © 2015, American Association for Cancer Research.