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

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.