TY - JOUR
T1 - Context-dependent immunomodulatory effects of MEK inhibition are enhanced with T-cell agonist therapy
AU - Dennison, Lauren
AU - Ruggieri, Amanda
AU - Mohan, Aditya
AU - Leatherman, James
AU - Cruz, Kayla
AU - Woolman, Skylar
AU - Azad, Nilofer
AU - Lesinski, Gregory B.
AU - Jaffee, Elizabeth M.
AU - Yarchoan, Mark
N1 - Funding Information:
by the Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy, the Winship Cancer Institute, the Pediatric/Winship Flow Cytometry Core, the National Cancer Institute Specialized Program of Research Excellence (SPORE) in Gastrointestinal Cancers (P50 CA062924), the NIH Center Core Grant (P30 CA006973), NCI Experimental Therapeutics Clinical Trials Network (ETCTN), RO1 CA228414–01, UM1CA186691, the Passano Foundation, and F. Hoffmann-La Roche, Ltd.
Funding Information:
The authors thank the patients who participated in CTEP10139, the clinical investigators, clinical study sites, and the CTEP of the NCI. Research reported in this publication was supported in part by the Pediatrics/Winship Flow Cytometry Core of Winship Cancer Institute of Emory University, Children’s Healthcare of Atlanta, and NIH/NCI under award number P30CA138292. Funding for this work was provided
Publisher Copyright:
© 2021 American Association for Cancer Research
PY - 2021/10
Y1 - 2021/10
N2 - 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, CD8þ 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.
AB - 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, CD8þ 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.
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U2 - 10.1158/2326-6066.CIR-21-0147
DO - 10.1158/2326-6066.CIR-21-0147
M3 - Article
C2 - 34389557
AN - SCOPUS:85116821623
SN - 2326-6066
VL - 9
SP - 1187
EP - 1201
JO - Cancer immunology research
JF - Cancer immunology research
IS - 10
ER -