Genetic and pharmacological modulation of DNA mismatch repair heterogeneous tumors promotes immune surveillance
Menée à l'aide d'une lignée cellulaire de cancer colorectal et d'un modèle murin, cette étude démontre que l'inhibition génétique ou pharmacologique du système de réparation des mésappariements de l'ADN (MMR)améliore l'immunogénicité des tumeurs dont une partie des cellules présentent un système MMR non altéré
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.
Cancer Cell 2023