CDK4/6 Inhibition Augments Anti-Tumor Immunity by Enhancing T Cell Activation
By Jiehui Deng, Eric S. Wang, Russell W. Jenkins, Shuai Li, Ruben Dries, Kathleen B. Yates, Sandeep Chhabra, Wei Huang, Hongye Liu, A. Aref and 37 more. Cancer Discovery, 2017
614 citations recorded by the source corpus.
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.
Subfields: Oncology, Pulmonary and Respiratory Medicine
View Paper: https://www.semanticscholar.org/paper/62e5dfaa3f50ff9454cbdd38182c5eeadb879a7c
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In Oncology
- William C. Hahn
- Peter K. Sorger
- P. Ott
- D. Barbie
- Russell W. Jenkins
- E. Buchbinder
- Meenhard Herlyn
- F. Hodi
In Pulmonary and Respiratory Medicine
Citations in the corpus
- Organoid modeling of the tumor immune microenvironment (2018, methodology): “Alternatively, custom microfluidic devices with human tumor suspension-derived microspheroids containing immune cells exhibit response to immunotherapeutics, but without tumor-immune specificity (Deng et al., 2018; Jenkins et al., 2018).”
- A Cancer Cell Program Promotes T Cell Exclusion and Resistance to Checkpoint Blockade (2018, positive): “CDK4/6 Inhibitors Repress the Resistance Program in Melanoma Cells We therefore tested if CDK4/6i could shift the malignant cell population to a less immune resistant state.”