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

Abstract

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.

• Authors: Jason A Willis, Laura Reyes-Uribe, Kyle Chang, Steven M Lipkin, Eduardo Vilar
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 26 Issue 1 Pg. 11-17 (01 01 2020) ISSN: 1557-3265 [Electronic] United States
• PMID: 31383734 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Biomarkers, Tumor

Topics

• Biomarkers, Tumor (genetics)
• DNA Mismatch Repair
• Humans
• Microsatellite Instability
• Mutation
• Neoplasms (genetics, immunology, pathology)
• Tumor Microenvironment (immunology)