Back to Search
Start Over
Context-Dependent Immunomodulatory Effects of MEK Inhibition Are Enhanced with T-cell Agonist Therapy
- 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.
- Subjects :
- Male
Agonist
Cancer Research
medicine.drug_class
T cell
Immunology
Context (language use)
CD8-Positive T-Lymphocytes
B7-H1 Antigen
Article
Immunomodulation
Mice
chemistry.chemical_compound
Lymphocytes, Tumor-Infiltrating
Immune system
Downregulation and upregulation
Atezolizumab
Cell Line, Tumor
Tumor Microenvironment
Animals
Humans
Medicine
Protein Kinase Inhibitors
Mitogen-Activated Protein Kinase Kinases
Cobimetinib
Mice, Inbred BALB C
Tumor microenvironment
business.industry
Xenograft Model Antitumor Assays
Mice, Inbred C57BL
medicine.anatomical_structure
chemistry
Cancer research
Female
Colorectal Neoplasms
business
Signal Transduction
Subjects
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