Microbiome-derived RORyT+ tregs are recruited to mucosal tumors by the CCL20-CCR6 chemokine axis 2538

Abstract Description Regulatory T cells (Tregs) are an immunosuppressive T cell population implicated in promoting tumor tolerance. Recent work has identified Helios + (IKZF2) Tregs as largely thymically-derived (nTregs or tTregs), while RORyT+ Tregs are largely peripherally induced (pTregs or iTregs). Through mining publicly available data, single cell RNA sequencing analyses show that RORyT+ Tregs are the predominant Treg population present in gastrointestinal (GI) tumors and they express the chemokine receptor CCR6. Further, the data show that CCL20, the only ligand for CCR6, is upregulated in GI cancers with deeper analysis indicating specific subsets of tumor cells and macrophages as the primary producers. The upregulation of CCL20 in GI cancers is largely influenced by epigenetic gene demethylation, rather than mutations, and is driven by NF-kB. Mouse models of pancreatic ductal adenocarcinoma (PDAC) confirmed these findings and showed that CCR6KO results in more anti-tumorigenic immune infiltration. RORyT+ Tregs require the gut microbiome for their induction, thus the gut microbiome’s role in influencing Treg populations within PDAC tumors was investigated. Depletion of the gut microbiome resulted in a shifting of intratumor Treg populations from RORyT+, CCR6+, CTLA4-high Tregs to Helios+, CCR6-, CTLA4-low Tregs. Cumulatively, these data support the notion that GI tumor-produced CCL20 shapes the immunosuppressive tumor microenvironment through recruitment of RORyT+ CCR6+ Tregs. Funding Sources Supported by NIH 1F30CA291095-01 and 5R01DK133247-02 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)