CDK4/6 Inhibition Augments Anti-Tumor Immunity by Enhancing T Cell Activation

Immune checkpoint blockade, exemplified by antibodies targeting the programmed death-1 (PD-1) receptor, can induce durable tumor regressions in some patients. To enhance the efficacy of existing immunotherapies, we screened for small molecules capable of increasing the activity of T cells suppressed by PD-1. Here, we show that short-term exposure to small molecule inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) significantly enhances T cell activation, contributing to anti-tumor effects in vivo , due in part to de-repression of Nuclear Factor of Activated T cell (NFAT) family proteins and their target genes, critical regulators of T cell function. Although CDK4/6 inhibitors decrease T cell proliferation, they increase tumor infiltration and activation of effector T cells. Moreover, CDK4/6 inhibition augments the response to PD-1 blockade in a novel ex vivo organotypic tumor spheroid culture system and in multiple in vivo murine syngeneic models, thereby providing a rationale for combining CDK4/6 inhibitors and immunotherapies.