CDK4/6 inhibition augments antitumor immunity by enhancing T-cell activation

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. QuinnLauren 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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

300 Scopus citations

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 cyclindependent 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.

Original languageEnglish (US)
Pages (from-to)216-233
Number of pages18
JournalCancer discovery
Volume8
Issue number2
DOIs
StatePublished - Feb 2018
Externally publishedYes

ASJC Scopus subject areas

  • Oncology

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