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

DOI

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.

Identifier
DOI https://doi.org/10.25592/uhhfdm.15921
Related Identifier IsPartOf https://doi.org/10.25592/uhhfdm.15920
Metadata Access https://www.fdr.uni-hamburg.de/oai2d?verb=GetRecord&metadataPrefix=oai_datacite&identifier=oai:fdr.uni-hamburg.de:15921
Provenance
Creator Cortesi, Filippo; Konzcalla, Leonie; Kumar, Yogesh; Wahib, Ramez; Sturmheit, Tabea; Steglich, Babett; Huber, Samuel; Gagliani, Nicola
Publisher Universität Hamburg
Publication Year 2025
Rights Creative Commons Attribution 4.0 International; Open Access; https://creativecommons.org/licenses/by/4.0/legalcode; info:eu-repo/semantics/openAccess
OpenAccess true
Representation
Language English
Resource Type Dataset
Discipline Medicine