Funding
Pediatrics/Winship Flow Cytometry Core of Winship Cancer Institute of Emory University, Children's Healthcare of Atlanta
NIH
NCI
Johns Hopkins Bloomberg‐Kimmel Institute for Cancer Immunotherapy
Winship Cancer Institute
Pediatric/Winship Flow Cytometry Core
National Cancer Institute Specialized Program of Research Excellence (SPORE) in Gastrointestinal Cancers
NIH Center Core Grant
Experimental Therapeutics Clinical Trials Network
Passano Foundation
F. Hoffmann-La Roche, Ltd
ARTICLE ABSTRACT
MEK inhibition (MEKi) is proposed to enhance antitumor immunity but has demonstrated mixed results as an immunomodulatory strategy in human clinical trials. MEKi exerts direct immunomodulatory effects on tumor cells and tumor-infiltrating lymphocytes (TIL), but these effects have not been independently investigated. Here we modeled tumor-specific MEKi through CRISPR/Cas-mediated genome editing of tumor cells [MEK1 knockout (KO)] and pharmacologic MEKi with cobimetinib in a RAS-driven model of colorectal cancer. This approach allowed us to distinguish tumor-mediated and tumor-independent mechanisms of MEKi immunomodulation. MEK1 KO tumors demonstrated upregulation of JAK/STAT signaling, enhanced MHCI expression, CD8+ T-cell infiltration and T-cell activation, and impaired tumor growth that is immune dependent. Pharmacologic MEKi recapitulated tumor-intrinsic effects but simultaneously impaired T-cell activation in the tumor microenvironment. We confirmed a reduction in human peripheral-lymphocyte activation from a clinical trial of anti–PD-L1 (atezolizumab) with or without cobimetinib in biliary tract cancers. Impaired activation of TILs treated with pharmacologic MEKi was reversible and was rescued with the addition of a 4-1BB agonist. Collectively, these data underscore the ability of MEKi to induce context-dependent immunomodulatory effects and suggest that T cell–agonist therapy maximizes the beneficial effects of MEKi on the antitumor immune response.
