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.