CD4+ T cell-licensed CD8+ T cells drive immunotherapy response in MHC-I negative DNA mismatch repair deficient cancer

ABSTRACT: DNA mismatch repair deficiency (MMRd) occurs in multiple malignancies including 10–15% of colorectal cancers (CRC), where it causes increased tumor mutational burden (TMB) and T cell response. MMRd CRC display multiple mechanisms of immune evasion, yet are highly sensitive to immune checkpoint blockade (ICB), with underlying mechanisms only partially understood. We generated genetically engineered mouse models (GEMM) of hereditary (Lynch syndrome) and sporadic MMRd CRC, and found that accelerated tumorigenesis was accompanied by universal tumor loss of major histocompatibility class I (MHC-I) expression and exclusion of cytotoxic CD8+ T cells, but not helper CD4+ T cells. MHC-I deletion (MHC-IKO) in a syngeneic MMRd CRC model reduced tumor CD8+ but not CD4+ cell infiltrate, and accelerated tumor growth. MMRd MHC-IKO tumors were resistant to anti-PDL1 ICB, but sensitive to anti-PD1 and anti-CTLA4 combination ICB (cICB) with response dependent on both CD4+ and CD8+ T cells, but not γδ-T cells. cICB resistance caused by CD4+ cell depletion was reversed by CD40 agonism, suggesting a mechanism where CD4+ cells license CD8+ cells to kill cancer cells by MHC-I-independent activity. Multimodal analysis revealed that CD4+ T cell help increases the cytotoxic state of CD8+ T cells, potentially lowering their MHC-I-independent activation threshold against cancer cells. Our results underscore the central role of MHC-I loss in tumor immune evasion, and the cooperative role of CD4+ and CD8+ cells in cICB response of MHC-I negative tumors. Our data suggest that MHC-I status may be useful as a biomarker to stratify for ICB monotherapy versus combination therapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE333300 | GEO | 2026/08/10

REPOSITORIES: GEO