In a screen for small molecules that could increase T cell activity (measured by IL-2 production), Deng et al. found that CDK4/6 inhibitors increase IL-2 even in the presence of suppressive PD-1 signaling. Dosing for short-term exposure to CDK4/6 inhibitors decreased T cell proliferation, but increased effector T cell activation (in part due to de-repression of NFAT family proteins) and tumor infiltration and decreased expression of coinhibitory signals and myeloid subpopulations, ultimately yielding antitumor effects that enhanced the efficacy of PD-1 blockade.
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.