Figure 3.

Immunomodulatory effects of CDK4/6 inhibition. (A) CDK4/6 inhibition modulates anti-tumor immunity through multiple mechanisms. In tumors cells, CDK4/6 inhibition leads to hypophosphorylated RB, which binds to and inhibits the activity of E2F transcription factors. Reduced E2F activity leads to an induction of Type III interferons (IFN), resulting in paracrine IFN signaling and upregulation of MHC I. This induction of IFN is due to the suppression DNMT1, (an E2F target gene), which reduces methylation of endogenous retroviral (ERV) genes, thereby promoting their expression and inducing viral mimicry. Hypophosphorylated RB also promotes activation of NFκB and subsequent upregulation of T cell chemoattractants and PD-L1. (B) CDK4/6 inhibition also prevents PD-L1 degradation, further enhancing PD-L1 protein expression on the cells surface. In T cells, NFAT activity is restrained by CDK4/6-mediated phosphorylation. Following CDK4/6 inhibition, hypophosphorylated NFAT translocates to the nucleus and upregulates expression of effector genes. Compared to other lymphocyte populations, T regulatory cells appear particularly susceptible to the anti-proliferative effects of CDK4/6 inhibition.