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

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 sh...

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Veröffentlicht in:	Cancer discovery Jg. 8; H. 2; S. 216
Hauptverfasser:	Deng, Jiehui, Wang, Eric S, Jenkins, Russell W, Li, Shuai, Dries, Ruben, Yates, Kathleen, Chhabra, Sandeep, Huang, Wei, Liu, Hongye, Aref, Amir R, Ivanova, Elena, Paweletz, Cloud P, Bowden, Michaela, Zhou, Chensheng W, Herter-Sprie, Grit S, Sorrentino, Jessica A, Bisi, John E, Lizotte, Patrick H, Merlino, Ashley A, Quinn, Max M, Bufe, Lauren E, Yang, Annan, Zhang, Yanxi, Zhang, Hua, Gao, Peng, Chen, Ting, Cavanaugh, Megan E, Rode, Amanda J, Haines, Eric, Roberts, Patrick J, Strum, Jay C, Richards, William G, Lorch, Jochen H, Parangi, Sareh, Gunda, Viswanath, Boland, Genevieve M, Bueno, Raphael, Palakurthi, Sangeetha, Freeman, Gordon J, Ritz, Jerome, Haining, W Nicholas, Sharpless, Norman E, Arthanari, Haribabu, Shapiro, Geoffrey I, Barbie, David A, Gray, Nathanael S, Wong, Kwok-Kin
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	United States 01.02.2018
Schlagworte:	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 Lymphocyte Activation - immunology Lymphocytes, Tumor-Infiltrating - drug effects Lymphocytes, Tumor-Infiltrating - immunology Lymphocytes, Tumor-Infiltrating - metabolism Mice Neoplasms - diagnosis Neoplasms - genetics Neoplasms - immunology Neoplasms - metabolism Protein Kinase Inhibitors - pharmacology T-Lymphocytes - drug effects T-Lymphocytes - immunology T-Lymphocytes - metabolism Xenograft Model Antitumor Assays
ISSN:	2159-8290, 2159-8290
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Zusammenfassung:	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 , 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 organotypic tumor spheroid culture system and in multiple murine syngeneic models, thereby providing a rationale for combining CDK4/6 inhibitors and immunotherapies. 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. .
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2159-8290 2159-8290
DOI:	10.1158/2159-8290.CD-17-0915