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

Pastille, Eva; Wasmer, Marie-Hélène Christin; Adamczyk, Alexandra; Vu, Vivian Pham; Mager, Lukas F; Phuong, Nhi Ngo Thi; Palmieri, Vittoria; Simillion, Cedric André Marie; Hansen, Wiebke; Kasper, Stefan; Schuler, Martin; Muggli, Beat; McCoy, Kathy D; Buer, Jan; Zlobec, Inti; Westendorf, Astrid M; Krebs, Philippe (2019). The IL-33/ST2 pathway shapes the regulatory T cell phenotype to promote intestinal cancer. Mucosal immunology, 12(4), pp. 990-1003. Nature Publishing Group 10.1038/s41385-019-0176-y

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)
04 Faculty of Medicine > Service Sector > Institute of Pathology
04 Faculty of Medicine > Service Sector > Institute of Pathology > Immunopathology
04 Faculty of Medicine > Service Sector > Institute of Pathology > Translational Research Unit

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Wasmer, Marie-Hélène Christin; Vu, Vivian Pham; Simillion, Cedric André Marie; Zlobec, Inti and Krebs, Philippe

Subjects:

600 Technology > 610 Medicine & health
500 Science > 570 Life sciences; biology

ISSN:

1933-0219

Publisher:

Nature Publishing Group

Language:

English

Submitter:

Philippe Krebs

Date Deposited:

05 Aug 2019 17:00

Last Modified:

22 Oct 2019 18:19

Publisher DOI:

10.1038/s41385-019-0176-y

PubMed ID:

31165767

BORIS DOI:

10.7892/boris.131498

URI:

https://boris.unibe.ch/id/eprint/131498

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