Adenosine Receptor 2A Blockade Increases the Efficacy of Anti-PD-1 through Enhanced Antitumor T-cell Responses

作者：Beavis, Paul A.; Milenkovski, Nicole; Henderson, Melissa A.; John, Liza B.; Allard, Bertrand; Loi, Sherene; Kershaw, Michael H.; Stagg, John; Darcy, Phillip K.^*

来源：Cancer Immunology Research, 2015, 3(5): 506-517.

DOI：10.1158/2326-6066.CIR-14-0211

• PD-1 BLOCKADE
• CANCER CELLS
• TUMOR-GROWTH
• CTLA-4
• ACTIVATION
• REJECTION
• ANTIBODY
• PATHWAY
• CD73
• ERADICATION

Immunotherapy is rapidly emerging as a cancer treatment with high potential. Recent clinical trials with anti-CTLA-4 and anti-PD-1/PD-L1 antibodies (mAbs) suggest that targeting multiple immunosuppressive pathways may significantly improve patient survival. The generation of adenosine by CD73 also suppresses antitumor immune responses through the activation of A(2A) receptors on T cells and natural killer (NK) cells. We sought to determine whether blockade of A(2A) 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 A(2A) adenosine receptor antagonist. The blockade of PD-1 enhanced A(2A) receptor expression on tumor-infiltrating CD8(+) T cells, making them more susceptible to A(2A)-mediated suppression. Thus, dual blockade of PD-1 and A(2A) significantly enhanced the expression of IFN gamma and Granzyme B by tumor-infiltrating CD8(+) T cells and, accordingly, increased growth inhibition of CD73(+) tumors and survival of mice. The results of our study indicate that CD73 expression may constitute a potential biomarker for the efficacy of anti-PD-1 mAb in patients with cancer and that the efficacy of anti-PD-1 mAb can be significantly enhanced by A(2A) antagonists. We have therefore revealed a potentially novel biomarker for the efficacy of anti-PD-1 that warrants further investigation in patients. Because our studies used SYN-115, a drug that has already undergone phase IIb testing in Parkinson disease, our findings have immediate translational relevance for patients with cancer.

• 出版日期2015-5