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.
Author Info: (1) Cancer Medicine, The University of Texas MD Anderson Cancer CenterD Anderson Cancer Center. (2) Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center. (3) e
Author Info: (1) Cancer Medicine, The University of Texas MD Anderson Cancer CenterD Anderson Cancer Center. (2) Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center. (3) epidemiology, University of Texas MD Anderson Cancer Center. (4) Medicine, Weill Cornell Medicine. (5) Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center evilar@mdanderson.org.
