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

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

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

Cited by 31 publications

(40 citation statements)

References 44 publications

(60 reference statements)

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“…Of note, another study recently reported an anti-tumoral effect of the IL-33/ST2 pathway on the development of sporadic CRC, with an increased frequency of tumor-infiltrating FOXP3 + Tregs in BM chimeric mice lacking ST2 expression on both the hematopoietic and the radio-resistant compartments. 34 These differences with our investigation may rely on the type of CRC model applied-AOM only versus AOM and DSS treatment-or the genetic background of the St2 −/− mice used-BALB/c versus C57BL/6J. Nevertheless, our data indicate that ST2 + CD4 + FOXP3 + Tregs may also promote tumorigenesis in other murine models of CRC based on genetic ablation of tumor suppressor genes critically regulating intestinal cancer.…”

Section: Discussionmentioning

confidence: 65%

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

et al. 2019

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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.

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Section: Discussionmentioning

confidence: 65%

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

et al. 2019

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“…Mechanistically, Twist1 can form a complex with runt‐related transcription factor 3 (Runx3) to reduce the binding of Runx3 and T‐bet to Ifng locus, which resultantly suppresses IFNγ expression . In a mouse model of sporadic colon cancer, IL‐33 treatment induces IFNγ secretion by tumor allograft‐infiltrating T cells and the deficiency of its receptor ST2 within the nonhematopoietic cells resulted in a reduced IFNγ gene expression signature . However, the mechanism underlying IL‐33‐induced IFNγ expression is needed to investigate.…”

Section: Ifnγ Expression and Significance In Cancermentioning

confidence: 99%

Interferon gamma in cancer immunotherapy

2018

Cancer Medicine

274

181

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Immune system can recognize self vs transformed self. That is why cancer immunotherapy achieves notable benefits in a wide variety of cancers. Recently, several papers reported that immune checkpoint blockade therapy led to upregulation of IFNγ and in turn clearance of tumor cells. In this review, we conducted an extensive literature search of recent 5‐year studies about the roles of IFNγ signaling in both tumor immune surveillance and immune evasion. In addition to well‐known functions, IFNγ signaling also induces tumor ischemia and homeostasis program, resulting in tumor clearance and tumor escape, respectively. The yin and the yang of IFNγ signaling are summarized. Thus, this review helps us to comprehensively understand the roles of IFNγ in tumor immunity, which contributes to better design and management of clinical immunotherapy approaches.

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“…IL-33/ST2 axis seems to represent an important mediator in intestinal fibrosis. Normal epithelium and stroma of the intestine express large amounts of IL-33 and ST2 during the homeostatic turnover of the intestinal mucosa ( 39 ). It has been demonstrated that intestinal baseline IL-33 expression was present in pericryptal fibroblasts and was increased during infection ( 105 ).…”

Section: Il-33/st2 Axis In Intestinal Fibrosismentioning

confidence: 99%

IL-33/ST2 Axis in Organ Fibrosis

2018

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Interleukin 33 (IL-33) is highly expressed in barrier sites, acting via the suppression of tumorigenicity 2 receptor (ST2). IL-33/ST2 axis has long been known to play a pivotal role in immunity and cell homeostasis by promoting wound healing and tissue repair. However, it is also involved in the loss of balance between extensive inflammation and tissue regeneration lead to remodeling, the hallmark of fibrosis. The aim of the current review is to critically evaluate the available evidence regarding the role of the IL-33/ST2 axis in organ fibrosis. The role of the axis in tissue remodeling is better understood considering its crucial role reported in organ development and regeneration. Generally, the IL-33/ST2 signaling pathway has mainly anti-inflammatory/anti-proliferative effects; however, chronic tissue injury is responsible for pro-fibrogenetic responses. Regarding pulmonary fibrosis mature IL-33 enhances pro-fibrogenic type 2 cytokine production in an ST2- and macrophage-dependent manner, while full-length IL-33 is also implicated in the pulmonary fibrotic process in an ST2-independent, Th2-independent fashion. In liver fibrosis, evidence indicate that when acute and massive liver damage occurs, the release of IL-33 might act as an activator of tissue-protective mechanisms, while in cases of chronic injury IL-33 plays the role of a hepatic fibrotic factor. IL-33 signaling has also been involved in the pathogenesis of acute and chronic pancreatitis. Moreover, IL-33 could be used as an early marker for ulcer-associated activated fibroblasts and myofibroblast trans-differentiation; thus one cannot rule out its potential role in inflammatory bowel disease-associated fibrosis. Similarly, the upregulation of the IL-33/ST2 axismay contribute to tubular cell injury and fibrosis via epithelial to mesenchymal transition (EMT) of various cell types in the kidneys. Of note, IL-33 exerts a cardioprotective role via ST2 signaling, while soluble ST2 has been demonstrated as a marker of myocardial fibrosis. Finally, IL-33 is a crucial cytokine in skin pathology responsible for abnormal fibroblast proliferation, leukocyte infiltration and morphologic differentiation of human endothelial cells. Overall, emerging data support a novel contribution of the IL-33/ST2 pathway in tissue fibrosis and highlight the significant role of the Th2 pattern of immune response in the pathophysiology of organ fibrosis.

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

Cited by 31 publications

References 44 publications

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

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

Interferon gamma in cancer immunotherapy

IL-33/ST2 Axis in Organ Fibrosis

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