@article{07c77f6dc21e4ddabfbfeb1a5fd85f8f,
title = "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 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.",
author = "Jiehui Deng and Wang, {Eric S.} and Jenkins, {Russell W.} and Shuai Li and Ruben Dries and Kathleen Yates and Sandeep Chhabra and Wei Huang and Hongye Liu and Aref, {Amir R.} and Elena Ivanova and Paweletz, {Cloud P.} and Michaela Bowden and Zhou, {Chensheng W.} and Herter-Sprie, {Grit S.} and Sorrentino, {Jessica A.} and Bisi, {John E.} and Lizotte, {Patrick H.} and Merlino, {Ashley A.} and Quinn, {Max M.} and Bufe, {Lauren E.} and Annan Yang and Yanxi Zhang and Hua Zhang and Peng Gao and Ting Chen and Cavanaugh, {Megan E.} and Rode, {Amanda J.} and Eric Haines and Roberts, {Patrick J.} and Strum, {Jay C.} and Richards, {William G.} and Lorch, {Jochen H.} and Sareh Parangi and Viswanath Gunda and Boland, {Genevieve M.} and Raphael Bueno and Sangeetha Palakurthi and Freeman, {Gordon J.} and Jerome Ritz and {Nicholas Haining}, W. and Sharpless, {Norman E.} and Haribabu Arthanari and Shapiro, {Geoffrey I.} and Barbie, {David A.} and Gray, {Nathanael S.} and Wong, {Kwok Kin}",
note = "Funding Information: We thank the Dana-Farber Cancer Institute Animal Resources Facility staff for their support of the animal studies. We would also like to acknowledge the Brigham and Women{\textquoteright}s Hospital, Dana-Farber Cancer Institute, and Massachusetts General Hospital for providing the patient specimens used in this study. We thank the Broad Institute for facilitating the single-cell sequencing experiment. And finally, we appreciate the generous gift of anti-PD-1 antibody from G.J. Freeman used for the mouse studies. This work was supported by a Damon Runyon Cancer Research Fellowship DRG-2270-16 (to E.S. Wang), CA154303-05 (to N.S. Gray), and CA179483-03 (to N.S. Gray), NIH/ NCI P01CA120964 (to K.-K. Wong), 5R01CA163896-04 (to K.-K. Wong), 5R01CA140594-07 (to K.-K. Wong), 5R01CA122794-10 (to K.-K. Wong), and 5R01CA166480-04 (to K.-K. Wong), and funding from a Medical Oncology Discovery grant, Dana-Farber Cancer Institute. Significance: Our results defi ne previously unrecognized immunomodulatory functions of CDK4/6 and suggest that combining CDK4/6 inhibitors with immune checkpoint blockade may increase treatment effi cacy in patients. Furthermore, our study highlights the critical importance of identifying complementary strategies to improve the effi cacy of immunotherapy for patients with cancer. Publisher Copyright: {\textcopyright} 2017 American Association for Cancer Research.",
year = "2018",
month = feb,
doi = "10.1158/2159-8290.CD-17-0915",
language = "English (US)",
volume = "8",
pages = "216--233",
journal = "Cancer discovery",
issn = "2159-8274",
publisher = "American Association for Cancer Research Inc.",
number = "2",
}