Willis et al. review genetic and immune factors associated with early development of mismatch repair-deficient (dMMR) colorectal cancers (CRC). These cancers have recognizable neoantigens which interact with CD8+ T cells as early as the non-neoplastic stage, yet evade immunity and progress independent of total mutational burden or neoantigen level. In Lynch syndrome patients predisposed to dMMR CRC, preventative strategies include checkpoint blockade therapy and/or cancer vaccines, both of which are being tested clinically.
Contributed by Alex Najibi
MMR-deficient colorectal cancers (dMMR CRC) are characterized by the expression of highly-immunogenic neoantigen peptides, which stimulate lymphocytic infiltration as well as up-regulation 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 CRC. Importantly, pre-clinical studies also suggest that this correlation between potent tumor neoantigens and the immune microenvironment is present in early (pre-malignant) 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 co-evolve throughout the dMMR adenoma-to-carcinoma pathway. We further highlight how this pre-clinical evidence forms the rational basis for developing novel immunotherapy-based CRC prevention strategies for patients with Lynch syndrome.