Cancer Discovery ( IF 28.2 ) Pub Date : 2018-02-01 , DOI: 10.1158/2159-8290.cd-17-0915 Jiehui Deng 1, 2 , Eric S Wang 3 , Russell W Jenkins 1, 4 , Shuai Li 1 , Ruben Dries 1, 5 , Kathleen Yates 6 , Sandeep Chhabra 3 , Wei Huang 1, 6 , Hongye Liu 1, 7 , Amir R Aref 1, 7 , Elena Ivanova 1, 7 , Cloud P Paweletz 1, 7 , Michaela Bowden 1, 8 , Chensheng W Zhou 1, 8 , Grit S Herter-Sprie 1 , Jessica A Sorrentino 9 , John E Bisi 9 , Patrick H Lizotte 1, 7 , Ashley A Merlino 1 , Max M Quinn 1 , Lauren E Bufe 1 , Annan Yang 1 , Yanxi Zhang 1 , Hua Zhang 1 , Peng Gao 1 , Ting Chen 1 , Megan E Cavanaugh 1, 7 , Amanda J Rode 1, 7 , Eric Haines 1 , Patrick J Roberts 9 , Jay C Strum 9 , William G Richards 10 , Jochen H Lorch 1 , Sareh Parangi 11 , Viswanath Gunda 11 , Genevieve M Boland 11 , Raphael Bueno 10 , Sangeetha Palakurthi 1, 7 , Gordon J Freeman 1, 12 , Jerome Ritz 13 , W Nicholas Haining 6 , Norman E Sharpless 14 , Haribabu Arthanari 3 , Geoffrey I Shapiro 1, 12 , David A Barbie 1, 12 , Nathanael S Gray 3 , Kwok-Kin Wong 1, 2, 7, 12
Immune checkpoint blockade, exemplified by antibodies targeting the PD-1 receptor, can induce durable tumor regressions in some patients. To enhance the efficacy of existing immunotherapies, we screened for small molecules capable of increasing the activity of T cells suppressed by PD-1. Here, we show that short-term exposure to small-molecule inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) significantly enhances T-cell activation, contributing to antitumor effects in vivo, due in part to the derepression of NFAT family proteins and their target genes, critical regulators of T-cell function. Although CDK4/6 inhibitors decrease T-cell proliferation, they increase tumor infiltration and activation of effector T cells. Moreover, CDK4/6 inhibition augments the response to PD-1 blockade in a novel ex vivo organotypic tumor spheroid culture system and in multiple in vivo murine syngeneic models, thereby providing a rationale for combining CDK4/6 inhibitors and immunotherapies.
Significance: Our results define previously unrecognized immunomodulatory functions of CDK4/6 and suggest that combining CDK4/6 inhibitors with immune checkpoint blockade may increase treatment efficacy in patients. Furthermore, our study highlights the critical importance of identifying complementary strategies to improve the efficacy of immunotherapy for patients with cancer. Cancer Discov; 8(2); 216–33. ©2017 AACR.
See related commentary by Balko and Sosman, p. 143.
See related article by Jenkins et al., p. 196.
This article is highlighted in the In This Issue feature, p. 127
中文翻译：
CDK4/6 抑制通过增强 T 细胞活化增强抗肿瘤免疫
免疫检查点阻断，例如针对 PD-1 受体的抗体，可以在一些患者中诱导持久的肿瘤消退。为了提高现有免疫疗法的功效，我们筛选了能够增加被 PD-1 抑制的 T 细胞活性的小分子。在这里，我们表明短期暴露于细胞周期蛋白依赖性激酶 4 和 6 (CDK4/6) 的小分子抑制剂可显着增强 T 细胞活化，有助于体内抗肿瘤作用，部分原因是 NFAT 家族的去抑制作用蛋白质及其靶基因，是 T 细胞功能的关键调节剂。尽管 CDK4/6 抑制剂会降低 T 细胞增殖，但它们会增加肿瘤浸润和效应 T 细胞的活化。此外，CDK4/6 抑制增强了对 PD-1 阻断的反应离体器官型肿瘤球体培养系统和多个体内鼠同源模型，从而为结合 CDK4/6 抑制剂和免疫疗法提供了理论基础。
意义：我们的结果定义了以前未被认识的 CDK4/6 免疫调节功能，并表明将 CDK4/6 抑制剂与免疫检查点阻断联合使用可能会提高患者的治疗效果。此外，我们的研究强调了确定补充策略以提高癌症患者免疫疗法疗效的关键重要性。癌症发现；8（2）；216-33。©2017 AACR。
见 Balko 和 Sosman 的相关评论，p. 143 .
参见 Jenkins 等人的相关文章，p. 196 .
本文在 In This Issue 功能中突出显示，p。127
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