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Cancer Discov. 2018 Feb;8(2):216-233. doi: 10.1158/2159-8290.CD-17-0915. Epub 2017 Nov 3.

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

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
2
Division of Hematology & Medical Oncology, Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, New York.
3
Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts.
4
Division of Medical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
5
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
6
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
7
Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
8
Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.
9
G1 Therapeutics, Research Triangle Park, North Carolina.
10
Division of Thoracic Surgery, Brigham and Women's Hospital, Boston, Massachusetts.
11
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
12
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
13
Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts.
14
The Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
15
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. kwok-kin.wong@nyumc.org Nathanael_Gray@dfci.harvard.edu dbarbie@partners.org.
16
Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts. kwok-kin.wong@nyumc.org Nathanael_Gray@dfci.harvard.edu dbarbie@partners.org.
#
Contributed equally

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.

PMID:
29101163
PMCID:
PMC5809273
[Available on 2019-02-01]
DOI:
10.1158/2159-8290.CD-17-0915

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