In a screen for small molecules that could increase T cell activity (measured by IL-2 production), Deng et al. found that CDK4/6 inhibitors increase IL-2 even in the presence of suppressive PD-1 signaling. Dosing for short-term exposure to CDK4/6 inhibitors decreased T cell proliferation, but increased effector T cell activation (in part due to de-repression of NFAT family proteins) and tumor infiltration and decreased expression of coinhibitory signals and myeloid subpopulations, ultimately yielding antitumor effects that enhanced the efficacy of PD-1 blockade.
Immune checkpoint blockade, exemplified by antibodies targeting the programmed death-1 (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 anti-tumor effects in vivo, due in part to de-repression of Nuclear Factor of Activated T cell (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 Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute. (2) Department of Cancer Biology, Dana-Farber Cancer Institute. (3) Department of Medical Oncology, Dana-Farber Ca
Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute. (2) Department of Cancer Biology, Dana-Farber Cancer Institute. (3) Department of Medical Oncology, Dana-Farber Cancer Institute. (4) Department of Medical Oncology, Dana-Farber Cancer Institute. (5) Department of Medical Oncology, Dana-Farber Cancer Institute. (6) Department of Pediatric Oncology, Dana-Farber Cancer Institute. (7) Department of Cancer Biology, Dana-Farber Cancer Institute. (8) Department of Medical Oncology, Dana-Farber Cancer Institute. (9) Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute. (10) Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute. (11) Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute. (12) Department of Medical Oncology, Dana-Farber Cancer Institute. (13) Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute. (14) Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute. (15) Department of Medical Oncology, Dana-Farber Cancer Institute. (16) G1 Therapeutics. (17) G1 Therapeutics. (18) Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute. (19) Department of Medical Oncology, Dana-Farber Cancer Institute. (20) Department of Medical Oncology, Dana-Farber Cancer Institute. (21) Department of Medical Oncology, Dana-Farber Cancer Institute. (22) Department of Medical Oncology, Dana-Farber Cancer Institute. (23) Department of Medical Oncology, Dana-Farber Cancer Institute. (24) Department of Medical Oncology, Dana-Farber Cancer Institute. (25) Department of Medical Oncology, Dana-Farber Cancer Institute. (26) Department of Medical Oncology, Dana-Farber Cancer Institute. (27) Department of Medical Oncology, Dana-Farber Cancer Institute. (28) Department of Medical Oncology, Dana-Farber Cancer Institute. (29) Department of Medical Oncology, Dana-Farber Cancer Institute. (30) G1 Therapeutics. (31) G1 Therapeutics. (32) Division of Thoracic Surgery, Brigham and Women's Hospital, Harvard Medical School. (33) Department of Medical Oncology, Dana-Farber Cancer Institute. (34) Department of Surgery, Massachusetts General Hospital, Harvard Medical School. (35) Department of Surgery, Massachusetts General Hospital, Harvard Medical School. (36) Department of Surgery, Massachusetts General Hospital, Harvard Medical School. (37) Division of Thoracic Surgery, Brigham and Women's Hospital, Harvard Medical School. (38) Department of Medical Oncology, Dana-Farber Cancer Institute. (39) Department of Medical Oncology, Dana-Farber Cancer Institute. (40) Division of Hematologic Malignancies, Dana-Farber Cancer Institute. (41) Department of Pediatric Oncology, Dana-Farber Cancer Institute. (42) The Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine. (43) Department of Cancer Biology, Dana-Farber Cancer Institute. (44) Department of Medicine, Brigham and Women's Hospital, Harvard Medical School. (45) Department of Medical Oncology, Dana-Farber Cancer Institute. (46) Department of Cancer Biology, Dana-Farber Cancer Institute. (47) Department of Medical Oncology, Dana-Farber Cancer Institute kwok-kin.wong@nyumc.org.
