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Context-Dependent Immunomodulatory Effects of MEK Inhibition Are Enhanced with T-cell Agonist Therapy

Authors :
Mark Yarchoan
Skylar Woolman
Lauren Dennison
Gregory B. Lesinski
Kayla Cruz
James M. Leatherman
Nilofer S. Azad
Elizabeth M. Jaffee
Aditya Mohan
Amanda Ruggieri
Source :
Cancer Immunol Res
Publication Year :
2021
Publisher :
American Association for Cancer Research (AACR), 2021.

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.

Details

ISSN :
23266074 and 23266066
Volume :
9
Database :
OpenAIRE
Journal :
Cancer Immunology Research
Accession number :
edsair.doi.dedup.....73ab73c6f60172498a82dab02cf687b3
Full Text :
https://doi.org/10.1158/2326-6066.cir-21-0147