2. Academic Validation
  3. CDK4/6 inhibition triggers anti-tumour immunity

CDK4/6 inhibition triggers anti-tumour immunity

  • Nature. 2017 Aug 24;548(7668):471-475. doi: 10.1038/nature23465.
Shom Goel 1 2,  Molly J DeCristo 3 4,  April C Watt 1,  Haley BrinJones 1,  Jaclyn Sceneay 3 4,  Ben B Li 1,  Naveed Khan 1,  Jessalyn M Ubellacker 3 4,  Shaozhen Xie 1,  Otto Metzger-Filho 2,  Jeremy Hoog 5,  Matthew J Ellis 6,  Cynthia X Ma 5,  Susanne Ramm 7 8,  Ian E Krop 2,  Eric P Winer 2,  Thomas M Roberts 1,  Hye-Jung Kim 9 10,  Sandra S McAllister 3 4 11 12,  Jean J Zhao 1 12 13
Affiliations

Affiliations

  • 1 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
  • 2 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
  • 3 Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
  • 4 Hematology Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
  • 5 Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
  • 6 Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas 77030, USA.
  • 7 Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, Massachusetts 02115, USA.
  • 8 Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
  • 9 Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
  • 10 Department of Microbiology and Immunobiology, Division of Immunology, Harvard Medical School, Boston, Massachusetts 02115, USA.
  • 11 Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
  • 12 Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
  • 13 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
PMID: 28813415 DOI: 10.1038/nature23465
Abstract

Cyclin-dependent kinases 4 and 6 (CDK4/6) are fundamental drivers of the cell cycle and are required for the initiation and progression of various malignancies. Pharmacological inhibitors of CDK4/6 have shown significant activity against several solid tumours. Their primary mechanism of action is thought to be the inhibition of phosphorylation of the retinoblastoma tumour suppressor, inducing G1 cell cycle arrest in tumour cells. Here we use mouse models of breast carcinoma and other solid tumours to show that selective CDK4/6 inhibitors not only induce tumour cell cycle arrest, but also promote anti-tumour immunity. We confirm this phenomenon through transcriptomic analysis of serial biopsies from a clinical trial of CDK4/6 inhibitor treatment for breast Cancer. The enhanced anti-tumour immune response has two underpinnings. First, CDK4/6 inhibitors activate tumour cell expression of endogenous retroviral elements, thus increasing intracellular levels of double-stranded RNA. This in turn stimulates production of type III interferons and hence enhances tumour antigen presentation. Second, CDK4/6 inhibitors markedly suppress the proliferation of regulatory T cells. Mechanistically, the effects of CDK4/6 inhibitors both on tumour cells and on regulatory T cells are associated with reduced activity of the E2F target, DNA Methyltransferase 1. Ultimately, these events promote cytotoxic T-cell-mediated clearance of tumour cells, which is further enhanced by the addition of immune checkpoint blockade. Our findings indicate that CDK4/6 inhibitors increase tumour immunogenicity and provide a rationale for new combination regimens comprising CDK4/6 inhibitors and immunotherapies as anti-cancer treatment.

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