RT Journal Article SR Electronic T1 Activation of CD8+ T Cells Contributes to Antitumor Effects of CDK4/6 Inhibitors plus MEK Inhibitors JF Cancer Immunology Research JO Cancer Immunol Res FD American Association for Cancer Research SP 1114 OP 1121 DO 10.1158/2326-6066.CIR-19-0743 VO 8 IS 9 A1 Teh, Jessica L.F. A1 Erkes, Dan A. A1 Cheng, Phil F. A1 Tiago, Manoela A1 Wilski, Nicole A. A1 Field, Conroy O. A1 Chervoneva, Inna A1 Levesque, Mitch P. A1 Xu, Xiaowei A1 Dummer, Reinhard A1 Aplin, Andrew E. YR 2020 UL http://cancerimmunolres.aacrjournals.org/content/8/9/1114.abstract AB Concurrent MEK and CDK4/6 inhibition shows promise in clinical trials for patients with advanced-stage mutant BRAF/NRAS solid tumors. The effects of CDK4/6 inhibitor (CDK4/6i) in combination with BRAF/MEK-targeting agents on the tumor immune microenvironment are unclear, especially in melanoma, for which immune checkpoint inhibitors are effective in approximately 50% of patients. Here, we show that patients progressing on CDK4/6i/MEK pathway inhibitor combinations exhibit T-cell exclusion. We found that MEK and CDK4/6 targeting was more effective at delaying regrowth of mutant BRAF melanoma in immunocompetent versus immune-deficient mice. Although MEK inhibitor (MEKi) treatment increased tumor immunogenicity and intratumoral recruitment of CD8+ T cells, the main effect of CDK4/6i alone and in combination with MEKi was increased expression of CD137L, a T-cell costimulatory molecule on immune cells. Depletion of CD8+ T cells or blockade of the CD137 ligand–receptor interaction reduced time to regrowth of melanomas in the context of treatment with CDK4/6i plus MEKi treatment in vivo. Together, our data outline an antitumor immune-based mechanism and show the efficacy of targeting both the MEK pathway and CDK4/6.