Immune Activation in Mismatch Repair-Deficient Carcinogenesis: More Than Just Mutational Rate

Mismatch repair (MMR)-deficient colorectal cancers (dMMR colorectal cancer) are characterized by the expression of highly immunogenic neoantigen peptides, which stimulate lymphocytic infiltration as well as upregulation of inflammatory cytokines. These features are key to understanding why immunothe...

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Bibliographic Details
Published in:Clinical cancer research 2020-01, Vol.26 (1), p.11-17
Main Authors: Willis, Jason A, Reyes-Uribe, Laura, Chang, Kyle, Lipkin, Steven M, Vilar, Eduardo
Format: Article
Language:English
Subjects:
Biomarkers, Tumor - genetics
DNA Mismatch Repair
Humans
Microsatellite Instability
Mutation
Neoplasms - genetics
Neoplasms - immunology
Neoplasms - pathology
Tumor Microenvironment - immunology
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Summary:Mismatch repair (MMR)-deficient colorectal cancers (dMMR colorectal cancer) are characterized by the expression of highly immunogenic neoantigen peptides, which stimulate lymphocytic infiltration as well as upregulation of inflammatory cytokines. These features are key to understanding why immunotherapy (specifically PD-1 and/or CTLA-4 checkpoint blockade) has proved to be highly effective for the treatment of patients with advanced dMMR colorectal cancer. Importantly, preclinical studies also suggest that this correlation between potent tumor neoantigens and the immune microenvironment is present in early (premalignant) stages of dMMR colorectal tumorigenesis as well, even in the absence of a high somatic mutation burden. Here, we discuss recent efforts to characterize how neoantigens and the tumor immune microenvironment coevolve throughout the dMMR adenoma-to-carcinoma pathway. We further highlight how this preclinical evidence forms the rational basis for developing novel immunotherapy-based colorectal cancer prevention strategies for patients with Lynch syndrome.
ISSN:1078-0432
1557-3265
1557-3265
DOI:10.1158/1078-0432.ccr-18-0856