Séminaire CIRI (10.06.2025): Dr. Guillaume MESTRALLET

 Guillaume MESTRALLET, Mont Sinai Hospital (NY); “ Preventing and overcoming resistance in MMRd tumors ”

Abstract: Mismatch repair deficiency (MMRd) in colorectal cancer (CRC) and other malignancies drives heightened immunogenicity but also immune escape, limiting responses to anti-PD-1 therapy. Using human and murine models, we identified key macrophage and T cell interactions that mediate immune control of MMRd tumors, while resistance is linked to upregulation of inhibitory receptors and infiltration by immunosuppressive myeloid cells. Combination immunotherapy targeting LAG3, CTLA4, and TREM2 dramatically enhanced tumor clearance in both MMRd and MMRp CRC. Additionally, we uncovered conserved CD8+ T cell-driven immune responses and shared neoantigens across MMRd tumors in different organs and species. Leveraging these findings, we demonstrated that mRNA/LNP-based vaccination encoding these neoantigens effectively limits tumor growth, even in ICB-resistant settings, by promoting antigen spreading and stem-like T cell expansion. These insights provide a rationale for next-generation immunotherapies combining checkpoint blockade and neoantigen-targeting strategies to overcome immune escape in MMRd and MMRp cancers.