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.

• Authors: Jiehui Deng, Eric S Wang, Russell W Jenkins, Shuai Li, Ruben Dries, Kathleen Yates, Sandeep Chhabra, Wei Huang, Hongye Liu, Amir R Aref, Elena Ivanova, Cloud P Paweletz, Michaela Bowden, Chensheng W Zhou, Grit S Herter-Sprie, Jessica A Sorrentino, John E Bisi, Patrick H Lizotte, Ashley A Merlino, Max M Quinn, Lauren E Bufe, Annan Yang, Yanxi Zhang, Hua Zhang, Peng Gao, Ting Chen, Megan E Cavanaugh, Amanda J Rode, Eric Haines, Patrick J Roberts, Jay C Strum, William G Richards, Jochen H Lorch, Sareh Parangi, Viswanath Gunda, Genevieve M Boland, Raphael Bueno, Sangeetha Palakurthi, Gordon J Freeman, Jerome Ritz, W Nicholas Haining, Norman E Sharpless, Haribabu Arthanari, Geoffrey I Shapiro, David A Barbie, Nathanael S Gray, Kwok-Kin Wong
• Journal: Cancer discovery (Cancer Discov) Vol. 8 Issue 2 Pg. 216-233 (02 2018) ISSN: 2159-8290 [Electronic] United States
• PMID: 29101163 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2017 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Antineoplastic Agents, Immunological
• Protein Kinase Inhibitors
• CDK4 protein, human
• CDK6 protein, human
• Cyclin-Dependent Kinase 4
• Cyclin-Dependent Kinase 6

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Antineoplastic Agents, Immunological (pharmacology)
• Cell Line, Tumor
• Cyclin-Dependent Kinase 4 (antagonists & inhibitors)
• Cyclin-Dependent Kinase 6 (antagonists & inhibitors)
• Humans
• Lymphocyte Activation (drug effects, immunology)
• Lymphocytes, Tumor-Infiltrating (drug effects, immunology, metabolism)
• Mice
• Neoplasms (diagnosis, genetics, immunology, metabolism)
• Protein Kinase Inhibitors (pharmacology)
• T-Lymphocytes (drug effects, immunology, metabolism)
• Xenograft Model Antitumor Assays