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CDK4/6 Inhibition Augments Antitumor Immunity by Enhancing T-cell Activation.


ABSTRACT: 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. 143See related article by Jenkins et al., p. 196This article is highlighted in the In This Issue feature, p. 127.

SUBMITTER: Deng J 

PROVIDER: S-EPMC5809273 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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CDK4/6 Inhibition Augments Antitumor Immunity by Enhancing T-cell Activation.

Deng Jiehui J   Wang Eric S ES   Jenkins Russell W RW   Li Shuai S   Dries Ruben R   Yates Kathleen K   Chhabra Sandeep S   Huang Wei W   Liu Hongye H   Aref Amir R AR   Ivanova Elena E   Paweletz Cloud P CP   Bowden Michaela M   Zhou Chensheng W CW   Herter-Sprie Grit S GS   Sorrentino Jessica A JA   Bisi John E JE   Lizotte Patrick H PH   Merlino Ashley A AA   Quinn Max M MM   Bufe Lauren E LE   Yang Annan A   Zhang Yanxi Y   Zhang Hua H   Gao Peng P   Chen Ting T   Chen Ting T   Cavanaugh Megan E ME   Rode Amanda J AJ   Haines Eric E   Roberts Patrick J PJ   Strum Jay C JC   Richards William G WG   Lorch Jochen H JH   Parangi Sareh S   Gunda Viswanath V   Boland Genevieve M GM   Bueno Raphael R   Palakurthi Sangeetha S   Freeman Gordon J GJ   Ritz Jerome J   Haining W Nicholas WN   Sharpless Norman E NE   Arthanari Haribabu H   Shapiro Geoffrey I GI   Barbie David A DA   Gray Nathanael S NS   Wong Kwok-Kin KK  

Cancer discovery 20171103 2


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 <i>in vivo</i>, due in  ...[more]

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