CD4⁺ T cell-licensed CD8⁺ T cells are required for immunotherapy response in MHC-I negative MMRd cancer

DNA mismatch repair deficiency (MMRd) causes hypermutation and increased T cell response in multiple tumor types. MMRd colorectal cancers (CRC) display frequent immune evasion, but respond to immune checkpoint blockade (ICB), through uncertain mechanisms. We generated mouse models of MMRd CRC, and found that accelerated tumorigenesis was accompanied by 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-I^KO) in a syngeneic MMRd CRC model reduced tumor CD8⁺ but not CD4⁺ cell infiltrate, and accelerated tumor growth. MMRd MHC-I^KO tumors were resistant to anti-PD1 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. CD4⁺ cell depletion-induced cICB resistance was reversed by CD40 agonism, suggesting that CD4⁺ cells directly or indirectly license CD8⁺ cell for MHC-I-independent cytotoxicity. Investigation of MHC-I status as predictor of cICB vs ICB monotherapy appears worthwhile.