Adamczyk, AlexandraAlexandraAdamczykPastille, EvaEvaPastilleKehrmann, JanJanKehrmannVu, Vivian PhamVivian PhamVuGeffers, RobertRobertGeffersWasmer, Marie-Hélène ChristinMarie-Hélène ChristinWasmerKasper, StefanStefanKasperSchuler, MartinMartinSchulerLange, Christian MChristian MLangeMuggli, BeatBeatMuggliRau, TilmanTilmanRau0000-0002-1251-950XKlein, DianaDianaKleinHansen, WiebkeWiebkeHansenKrebs, PhilippePhilippeKrebs0000-0003-4918-6654Buer, JanJanBuerWestendorf, Astrid MAstrid MWestendorf2024-10-052024-10-052021-06-01https://boris-portal.unibe.ch/handle/20.500.12422/56521Colorectal cancer (CRC) is one of the most frequent malignancies worldwide. Despite considerable progress in early detection and treatment, there is still an unmet need for novel anti-tumor therapies, particularly in advanced CRC. Regulatory T cells (Tregs) are increased in the peripheral blood and tumor tissue of CRC patients. Recently, transient ablation of tumor-associated Tregs was shown to foster CD8+ T cell-mediated anti-tumoral immunity in murine CRC models. However, before considering therapies, targeting Tregs in cancer patients and detailed knowledge of the phenotype and features of tumor-associated Tregs is indispensable. Here we demonstrate in a murine model of inflammation-induced CRC that tumor-associated Tregs are mainly of thymic origin and equipped with a specific set of molecules strongly associated with enhanced migratory properties. Particularly, a dense infiltration of Tregs in mouse and human CRC lesions correlated with increased expression of the orphan chemoattractant receptor GPR15 on these cells. Comprehensive gene expression analysis revealed that tumor-associated GPR15+ Tregs have a Th17-like phenotype, thereby producing IL-17 and TNF-α. Gpr15 deficiency repressed Treg infiltration in CRC, which paved the way for enhanced anti-tumoral CD8+ T cell immunity and reduced tumorigenesis. In conclusion, GPR15 represents a promising novel target for modifying T cell-mediated anti-tumoral immunity in CRC.en500 - Science::570 - Life sciences; biology600 - Technology::610 - Medicine & healtharticle10.48350/1544873372722910.1158/0008-5472.CAN-20-2133