Interleukin 33 Signaling Restrains Sporadic Colon Cancer in an Interferon-γ-Dependent Manner.

Moritz F Eissmann,Mercedes Davalos-Salas,Matthias Ernst,Frederick Masson,John M Mariadason,Dmitri Mouradov,Tracy L Putoczki,Christine Dijkstra,Oliver M Sieber,David Baloyan,Merridee A Wouters,Paul M Nguyen

doi:10.1158/2326-6066.cir-17-0218

Abstract

Interleukin 33 (IL33) is an inflammatory cytokine released during necrotic cell death. The epithelium and stroma of the intestine express large amounts of IL33 and its receptor St2. IL33 is therefore continuously released during homeostatic turnover of the intestinal mucosa. Although IL33 can prevent colon cancer associated with inflammatory colitis, the contribution of IL33 signaling to sporadic colon cancer remains unknown. Here, we utilized a mouse model of sporadic colon cancer to investigate the contribution of IL33 signaling to tumorigenesis in the absence of preexisting inflammation. We demonstrated that genetic ablation of St2 enhanced colon tumor development. Conversely, administration of recombinant IL33 reduced growth of colon cancer cell allografts. In reciprocal bone marrow chimeras, the concurrent loss of IL33 signaling within radioresistant nonhematopoietic, and the radiosensitive hematopoietic, compartments was associated with increased tumor burden. We detected St2 expression within the radioresistant mesenchymal cell compartment of the colon whose stimulation with IL33 induced expression of bona fide NF-κB target genes. Mechanistically, we discovered that St2 deficiency within the nonhematopoietic compartment coincided with increased abundance of regulatory T cells and suppression of an IFNγ gene expression signature, whereas IL33 administration triggered IFNγ expression by tumor allograft-infiltrating T cells. The decrease of this IFNγ gene expression signature was associated with more aggressive disease in human colon cancer patients, suggesting that lack of IL33 signaling impaired the generation of a potent IFNγ-mediated antitumor immune response. Collectively, our data reveal that IL33 functions as a tumor suppressor in sporadic colon cancer. Cancer Immunol Res; 6(4); 409-21. ©2018 AACR.

Highlights

Accumulating evidence links gastrointestinal malignancies to inflammation, a correlation highlighted by an increased incidence of colon cancer in patients with inflammatory bowel disease [1, 2]
Sporadic colon cancer was induced by weekly administration of AOM over 6 consecutive weeks (6ÂAOM) to WT and St2À/À mice and analysis occurred 9–15 weeks after the last AOM injection depending on the onset of tumor development
Interleukin 33 (IL33) triggers NF-kB signaling in colon mesenchymal cells Because our results suggest that the lack of IL33 signaling in the nonhematopoietic compartment contributes to the increased tumor burden, we aimed to identify the cell type(s) within this compartment that could respond to IL33 signals

Summary

Introduction

Accumulating evidence links gastrointestinal malignancies to inflammation, a correlation highlighted by an increased incidence of colon cancer in patients with inflammatory bowel disease [1, 2]. We and others have shown that excessive activation of the STAT3 signaling pathway through the inflammatory cytokines interleukin (IL)-6 and IL11 licenses the development and progression of colon cancers that harbor bona fide driver mutations [3, 4]. The inflammatory cytokines that elicit antitumor immune responses and prevent colon tumor development remain obscure. IL33, an unconventional cytokine, functions as a dangerassociated molecular signal that is released upon necrotic cell death [5, 6]. St2 is expressed in many immune cell types, including type II innate lymphocytes St2 is expressed in many immune cell types, including type II innate lymphocytes (ILC2; ref. 15), regulatory T cells (Treg; refs. 16–19), Th2 CD4þ T cells [20], CD8þ T cells [21], mast cells [22], as well as nonhematopoietic cells including fibroblasts, endothelial, and epithelial cells [23,24,25,26]

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Results

Conclusion