Search

Supplementary Data

Colorectal cancer is one of the most frequent malignancies worldwide. Despite considerable progress in early detection and treatment, there is still an unmet need for novel antitumor therapies, particularly in advanced colorectal cancer. Regulatory T cells (Treg) are increased in the peripheral blood and tumor tissue of patients with colorectal cancer. Recently, transient ablation of tumor-associated Tregs was shown to foster CD8+ T-cell–mediated antitumoral immunity in murine colorectal cancer models. However, before considering therapies on targeting Tregs in patients with cancer, detailed knowledge of the phenotype and features of tumor-associated Tregs is indispensable. Here, we demonstrate in a murine model of inflammation-induced colorectal cancer 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 colorectal cancer 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 IL17 and TNFα. Gpr15 deficiency repressed Treg infiltration in colorectal cancer, which paved the way for enhanced antitumoral CD8+ T-cell immunity and reduced tumorigenesis. In conclusion, GPR15 represents a promising novel target for modifying T-cell–mediated antitumoral immunity in colorectal cancer.Significance:The G protein–coupled receptor 15, an unconventional chemokine receptor, directs Tregs into the colon, thereby modifying the tumor microenvironment and promoting intestinal tumorigenesis.See related commentary by Chakraborty and Zappasodi, p. 2817

In the past decade, single-cell transcriptomics has helped uncover new cell types and states and led to the construction of a cellular compendium of health and disease. Still, some difficult-to-sequence cells remain absent from tissue atlases. Eosinophils, elusive granulocytes implicated in a plethora of human pathologies, are among these uncharted cell types. To date, the heterogeneity of eosinophils and the gene programs underpinning their pleiotropic functions remain poorly understood. In the present study, we provide the first comprehensive single-cell transcriptomic profiling of murine eosinophils. We identify an active and a basal population of intestinal eosinophils, differing in their transcriptome, surface proteome and spatial localization. By means of a genome wide CRISPR inhibition screen and functional assays, we dissect a mechanism by which IL-33 and IFN-ɣ induce active eosinophil accumulation in the inflamed colon. Active eosinophils are endowed with bactericidal and T cell regulatory activity, and express the co-stimulatory molecules CD80 and PD-L1. Notably, active eosinophils are enriched in the lamina propria of a small cohort of inflammatory bowel disease patients and tightly associate with CD4+ T cells. Our findings provide novel insights into the biology of this elusive cell type and highlight its crucial contribution to intestinal homeostasis, immune regulation and host defence. Furthermore, we lay a framework for the characterization of eosinophils in human gastrointestinal diseases., Nature, 615 (7950), ISSN:0028-0836, ISSN:1476-4687

Interleukin-33 (IL-33) is a member of the IL-1 family of cytokines that is constitutively expressed in the nucleus of epithelial, endothelial and fibroblast-like cells. Upon cell stress, damage or necrosis, IL-33 is released into the cytoplasm to exert its prime role as an alarmin by binding to its specific receptor moiety, ST2. IL-33 exhibits pleiotropic function in inflammatory diseases and particularly in cancer. IL-33 may play a dual role as both a pro-tumorigenic and anti-tumorigenic cytokine, dependent on tumor and cellular context, expression levels, bioactivity and the nature of the inflammatory environment. In this review, we discuss the differential contribution of IL-33 to malignant or inflammatory conditions, its multifaceted effects on the tumor microenvironment, while providing possible explanations for the discrepant findings described in the literature. Additionally, we examine the emerging and divergent functions of IL-33 in the nucleus, and aspects of IL-33 biology that are currently under-addressed.