6533b7d1fe1ef96bd125d8b2

RESEARCH PRODUCT

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

Vito AmodioSimona LambaRosaria ChilàChiara M. CattaneoBenedetta MussolinGiorgio CortiGiuseppe RospoEnrico BerrinoClaudio TripodoFederica PisatiAlice BartoliniMaria Costanza AquilanoSilvia MarsoniGianluca MauriCaterina MarchiòSergio AbrignaniFederica Di NicolantonioGiovanni GermanoAlberto Bardelli

subject

Cancer Research6-thioguaninemismatch repairOncology6-thioguanine; heterogeneity; immune checkpoint blockade; immune evasion; immune surveillance; microsatellite unstable tumors (MSI); mismatch repair; temozolomide6-thioguanine heterogeneity immune checkpoint blockade immune evasion immune surveillance microsatellite unstable tumors (MSI) mismatch repair temozolomideimmune surveillancemicrosatellite unstable tumors (MSI)temozolomideheterogeneityimmune checkpoint blockadeSettore MED/08 - Anatomia Patologicaimmune evasion

description

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.

yearjournalcountryeditionlanguage
2023-01-01Cancer cell
10.1016/j.ccell.2022.12.003https://pubmed.ncbi.nlm.nih.gov/36584674