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.

Fig. 1.

Correlation between immune activation (lower track) and neoantigen burden (middle track) along the adenoma-to-carcinoma pathway (top track) in Lynch syndrome-related CRC. The colonic epithelium is shown as confluent cells with an admixture of different colors to represent intralesional mutation and/or neoantigen diversity. Early colorectal adenomas (left column) display markers of immunoreactivity even in the absence of high somatic mutation or neoantigen burden. As the lesions progress to advanced adenomas (middle column) and carcinomas (right column), there is a corresponding rise in mutation/neoantigen burden and markers of immune tolerance. LS, Lynch syndrome. Redrawn with permission; copyright The University of Texas MD Anderson Cancer Center.