Activation of CD8+ T Cells Contributes to Antitumor Effects of CDK4/6 Inhibitors plus MEK Inhibitors
Abstract
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Sep 01, 2020
- Source ID
- 10.1158/2326-6066.cir-19-0743
Entities
People
- Andrew E Aplin
- Conroy O. Field
- Dan A. Erkes
- Inna Chervoneva
- Jessica Lf Teh
- Manoela Tiago
- Mitch P. Levesque
- Nicole A Wilski
- Phil F Cheng
- Reinhard Dummer
- Xiaowei Xu
Organizations
- National Cancer Institute
- National Institutes of Health
- Thomas Jefferson University
- United States Department of Defense
- University of Pennsylvania
- University of Zurich