Genetic and pharmacological modulation of DNA mismatch repair heterogeneous tumors promotes immune surveillance.

Patients affected by colorectal cancer (CRC) with DNA mismatch repair deficiency (MMRd), often respond to immune checkpoint blockade therapies, while those with mismatch repair-proficient (MMRp) tumors generally do not. Interestingly, a subset of MMRp CRCs contains variable fractions of MMRd cells, but it is unknown how their presence impacts immune surveillance. We asked whether modulation of the MMRd fraction in MMR heterogeneous tumors acts as an endogenous cancer vaccine by promoting immune surveillance. To test this hypothesis, we use isogenic MMRp (Mlh1 +/+ ) and MMRd (Mlh1 −/− ) mouse CRC cells. MMRp/MMRd cells mixed at different ratios are injected in immunocompetent mice and tumor rejection is observed when at least 50% of cells are MMRd. To enrich the MMRd fraction, MMRp/MMRd tumors are treated with 6-thioguanine, which leads to tumor rejection. These results suggest that genetic and pharmacological modulation of the DNA mismatch repair machinery potentiate the immunogenicity of MMR heterogeneous tumors. [Display omitted] • MMR heterogeneity affects immune surveillance in mouse CRC • In vivo 6TG treatment increases the MMRd fraction of MMR heterogeneous tumors • Pharmacological selection of MMRd cells improves immune surveillance in MMR tumors The impact of MMR heterogeneity on immune surveillance of colon cancers is largely unexplored. This proof-of-concept study by Amodio et al. suggests that MMR heterogeneity can be exploited through an endogenous vaccination approach based on pharmacological modulation of the DNA MMR, which potentiates cancer immunogenicity. [ABSTRACT FROM AUTHOR]