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The IL-33/ST2 pathway shapes the regulatory T cell phenotype to promote intestinal cancer

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Pastille Eva, Wasmer Marie-Hélène, Adamczyk Alexandra, Vu Vivian P., Mager Lukas F., Phuong Nhi Ngo Thi, Palmieri Vittoria, Simillion Cedric, Hansen Wiebke, Kasper Stefan, Schuler Martin, Muggli Beat, McCoy Kathy D., Buer Jan, Zlobec Inti, Westendorf Astrid M., Krebs Philippe,
Project mRNA splicing and epithelial integrity
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Original article (peer-reviewed)

Journal Mucosal Immunology
Page(s) 1 - 14
Title of proceedings Mucosal Immunology
DOI 10.1038/s41385-019-0176-y

Open Access

Type of Open Access Publisher (Gold Open Access)


The composition of immune infiltrates strongly affects the prognosis of patients with colorectal cancer (CRC). Interleukin (IL)-33 and regulatory T cells (Tregs) in the tumor microenvironment have been separately implicated in CRC; however their contribution to intestinal carcinogenesis is still controversial. Here, we reveal that IL-33 signaling promotes CRC by changing the phenotype of Tregs. In mice with CRC, tumor-infiltrating Tregs preferentially upregulate IL-33 receptor (ST2), and IL-33/ST2 signaling positively correlates with tumor number and size. Transcriptomic and flow cytometry analyses demonstrate that ST2 expression induces a more activated and migratory phenotype in FOXP3+ Tregs, which favors their accumulation in the tumor environment. Consequently, genetic ablation of St2 reduces Treg infiltration and concomitantly enhances the frequencies of effector CD8+ T cells, thereby restraining CRC. Mechanistically, IL-33 curtails IL-17 production by FOXP3+ Tregs and inhibits Th17 differentiation. In humans, numbers of activated ST2-expressing Tregs are increased in blood and tumor lesions of CRC patients, suggesting a similar mode of regulation. Together, these data indicate a central role of IL-33/ST2 signaling in shaping an immunosuppressive environment during intestinal tumorigenesis. Blockade of this pathway may provide a strategy to modulate the composition of CRC immune infiltrates.