Regulation of the immune CD155–CD226–TIGIT axis by cyclin D-CDK4/6
Abstract
Cyclin D-CDK4/6 is a component of mammalian cell-cycle machinery that drives cell proliferation. Small-molecule inhibitors of CDK4/6 have been approved for treatment of breast cancer patients. In addition to halting cell-cycle progression, inhibition of CDK4/6 can affect other tumor cell-intrinsic and -extrinsic functions. Here, we examined the impact of CDK4/6 inhibition on the CD155–CD226–TIGIT pathway that operates at the interface of tumor cells and the immune environment. We demonstrate that inhibition of CDK4/6 upregulates the expression of surface CD155 protein in cancer cells and downregulates an immuno-inhibitory receptor TIGIT in tumor-infiltrating lymphocytes. We observed these effects in human breast cancer cell lines, in mouse mammary carcinoma allograft models, in freshly resected human breast tumors and in paired pre-/on-treatment biopsies of breast cancers from patients undergoing monotherapy with a CDK4/6 inhibitor. We propose that inhibition of CDK4/6, through its tumor cell-intrinsic and -extrinsic effects, may shift the balance from the immunoinhibitory CD155–TIGIT to the immunostimulatory CD155–CD226 interaction, and through this mechanism may augment the antitumor immunity. Our results suggest that coadministration of CDK4/6 inhibitors and anti-TIGIT antibodies may further promote CD155–CD226-signaling and may have a strong synergistic antitumor effect.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (22)
Anne Fassl
Department of Cancer Biology, Dana-Farber Cancer Institute
Miriam Palacios Espinoza
Department of Cancer Biology, Dana-Farber Cancer Institute
Deborah Butter
Department of Cancer Biology, Dana-Farber Cancer Institute
Aleksandra Kolodziejczyk
Department of Cancer Biology, Dana-Farber Cancer Institute
Marco Seehawer
Department of Medical Oncology, Dana-Farber Cancer Institute
Charlotte Hill
Boston Children’s Hospital, Department of Pediatrics, Harvard Medical School
Xiaohan Ning
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.
Timothy B. Branigan
Department of Medical Oncology, Dana-Farber Cancer Institute
Johany Peñailillo
Department of Pathology, Dana-Farber Cancer Institute, Harvard Medical School
Charupong Saengboonmee
Heta Jadhav
Department of Medical Oncology, Dana-Farber Cancer Institute
Krzysztof W. Kotowski
Department of Cancer Biology, Dana-Farber Cancer Institute
Louis-Marie Charbonnier
Boston Children’s Hospital, Department of Pediatrics, Harvard Medical School
Adrienne G. Waks
Department of Medical Oncology, Dana-Farber Cancer Institute
Corinne Strawser
Department of Pharmacology and Cancer Biology, Duke University School of Medicine
Donald P. McDonnell
Department of Pharmacology and Cancer Biology, Duke University School of Medicine
Geoffrey I. Shapiro
Sara M. Tolaney
Department of Medical Oncology, Dana-Farber Cancer Institute
Kornelia Polyak
Department of Medical Oncology, Dana-Farber Cancer Institute
Sarah Sammons
Department of Medical Oncology, Dana-Farber Cancer Institute
Kai W. Wucherpfennig
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.
Piotr Sicinski
Department of Cancer Biology, Dana-Farber Cancer Institute