Time targeting of IL-17A+ CD4+ T cells reduces colorectal cancer without colitogenic effects

In colorectal cancer (CRC), targeting immune components has limited efficacy, potentially due to CRC intertwining with inflammation. IL-17A-producing CD4+T cells are enriched in CRC, but their role remains unclear. We use multi-omics and functional approaches in human and mouse CRC to decipher their heterogeneity, origin, and function. CRC-infiltrating IL-17A-producing CD4+T cells are functionally heterogenous and differentially correlate with patient survival depending on the expression level of IL-17A and co-expression of FOXP3. Trajectory models in humans, fate-mapping mouse models and cell-transfer experiments suggest that suppressive IL-17AlowFOXP3+ CD4+T cells can originate from TH17 cells and progress on a conversion path to FOXP3 TREG cells. Early deletion of IL-17AlowFOXP3+ CD4+T cells reduces tumor burden but exacerbates colon inflammation. Instead, conditional deletion of all IL-17A-producing CD4+T cells in mice with established tumors leads to tumor shrinkage without promoting colonic inflammation. Our data suggest the therapeutic potential of modulating the whole spectrum of IL-17A-producing CD4+T cells to control tumor progression and prevent off-target inflammation in established CRC.