GPR15 facilitates recruitment of regulatory T cells to promote colorectal cancer.

Adamczyk, Alexandra; Pastille, Eva; Kehrmann, Jan; Vu, Vivian P.; Geffers, Robert; Wasmer, Marie-Hélène; Kasper, Stefan; Schuler, Martin; Lange, Christian M; Muggli, Beat; Rau, Tilman T.; Klein, Diana; Hansen, Wiebke; Krebs, Philippe; Buer, Jan; Westendorf, Astrid M (2021). GPR15 facilitates recruitment of regulatory T cells to promote colorectal cancer. Cancer research, 81(11), pp. 2970-2982. American Association for Cancer Research AACR 10.1158/0008-5472.CAN-20-2133

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Colorectal 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.

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