CDK4/6 inhibition triggers anti-tumor immunity

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 ^{1, 2} . Pharmacologic inhibitors of CDK4/6 have shown significant activity against several solid tumors ^{3, 4} . Their primary mechanism of action is thought to be the inhibition of phosphorylation of the retinoblastoma (RB) tumor suppressor, inducing G1 cell cycle arrest in tumor cells ⁵ . Here, we use murine models of breast carcinoma and other solid tumors to show that selective CDK4/6 inhibitors not only induce tumor cell cycle arrest, but also promote anti-tumor 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-tumor immune response has two underpinnings. First, CDK4/6 inhibitors activate tumor 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 tumor antigen presentation. Second, CDK4/6 inhibitors markedly suppress the proliferation of regulatory T cells (Tregs). Mechanistically, the effects of CDK4/6 inhibitors on both tumor cells and Tregs are associated with reduced activity of the E2F target, DNA methyltransferase 1. Ultimately, these events promote cytotoxic T cell-mediated clearance of tumor cells, which is further enhanced by the addition of immune checkpoint blockade. Our findings indicate that CDK4/6 inhibitors increase tumor immunogenicity and provide rationale for new combination regimens comprising CDK4/6 inhibitors and immunotherapies as anti-cancer treatment.