Adenosine Receptor 2A Blockade Increases the Efficacy of Anti-PD-1 through Enhanced Antitumor T-cell Responses
Adenosine Receptor 2A Blockade Increases the Efficacy of Anti-PD-1 through Enhanced Antitumor T-cell Responses
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DOI：
10.1158/2326-6066.cir-14-0211
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发表时间：
2015-05-01
影响因子：
10.1
通讯作者：
Darcy, Phillip K.
中科院分区：
文献类型：
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作者：
Beavis, Paul A.;Milenkovski, Nicole;Darcy, Phillip K.
免疫疗法正迅速成为一种极具潜力的癌症治疗方法。最近针对抗ctla -4和抗pd -1/PD-L1抗体（mab）的临床试验表明，靶向多种免疫抑制途径可能显著提高患者的生存率。CD73生成腺苷还通过激活T细胞和自然杀伤细胞（NK）上的A（2A）受体来抑制抗肿瘤免疫反应。我们试图确定阻断A（2A）受体是否可以增强抗pd -1单抗的疗效。在两种肿瘤模型中，肿瘤细胞对CD73的表达限制了抗pd -1单抗的疗效，与A（2A）腺苷受体拮抗剂联合治疗可以缓解这种情况。PD-1的阻断增强了肿瘤浸润性CD8(+) T细胞上A（2A）受体的表达，使它们更容易受到A（2A）介导的抑制。因此，双重阻断PD-1和A（2A）可显著增强肿瘤浸润性CD8(+) T细胞中IFN γ和颗粒酶B的表达，从而增加对CD73（+）肿瘤的生长抑制和小鼠的存活率。我们的研究结果表明，CD73表达可能构成癌症患者抗pd -1单抗疗效的潜在生物标志物，并且a （2A）拮抗剂可以显著增强抗pd -1单抗的疗效。因此，我们发现了一种潜在的抗pd -1疗效的新型生物标志物，值得在患者中进一步研究。因为我们的研究使用了SYN-115，一种已经在帕金森病中进行了IIb期测试的药物，我们的发现对癌症患者具有直接的转化相关性。(c) 2015 AACR。
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. (c) 2015 AACR.