IL-33 signaling fuels outgrowth and metastasis of human lung cancer

Wang, Chunhong; Chen, Zengsheng; Bu, Xiangmao; Han, Yang; Shan, Shan; Ren, Tao; Song, Weiqing

doi:10.1016/j.bbrc.2016.09.081

Cited by 66 publications

(70 citation statements)

References 29 publications

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“…IL-33 has been shown to promote tumorigenesis through the recruitment of T regs and other cells in transplant and xenograft models of breast and lung cancer (Jovanovic et al, 2014;Wang et al, 2016Wang et al, , 2017 , and mice with T reg -specific ST2 deficiency have impaired growth of a transplantable tumor model (Magnuson et al, 2018) . Here, we show in a genetically-defined, autochthonous mouse model of lung adenocarcinoma that loss of T reg -specific ST2 function is sufficient to impair tumor development without provoking systemic autoimmunity.…”

Section: Discussionmentioning

confidence: 99%

Longitudinal single cell profiling of regulatory T cells identifies IL-33 as a driver of tumor immunosuppression

Canner

et al. 2019

Preprint

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Regulatory T cells (T regs ) can impair anti-tumor immune responses and are associated with poor prognosis in multiple cancer types. T regs in human tumors span diverse transcriptional states distinct from those of peripheral T regs , but their contribution to tumor development remains unknown. Here, we used single cell RNA-Seq to longitudinally profile conventional CD4 + T cells (T conv ) and T regs in a genetic mouse model of lung adenocarcinoma. Tissue-infiltrating and peripheral CD4 + T cells differed, highlighting divergent pathways of activation during tumorigenesis. Longitudinal shifts in T reg heterogeneity suggested increased terminal differentiation and stabilization of an effector phenotype over time. In particular, effector T regs had enhanced expression of the interleukin 33 receptor ST2. T reg -specific deletion of ST2 reduced effector T regs , increased infiltration of CD8 + T cells into tumors, and decreased tumor burden. Our study shows that ST2 plays a critical role in T reg -mediated immunosuppression in cancer, highlighting new potential paths for therapeutic intervention.

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Section: Discussionmentioning

confidence: 99%

Longitudinal single cell profiling of regulatory T cells identifies IL-33 as a driver of tumor immunosuppression

Canner

et al. 2019

Preprint

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“…In NSCLC patients, expression of IL33 and IL1RL1 was found to be increased in tumor tissue compared to adjacent non-tumor tissue, and this expression was associated with disease clinical stage (43). However, another study reports downregulation of IL33 and IL1RL1 in human lung cancer tissue and cells, compared to normal tissue and cells.…”

Section: Main Review Textmentioning

confidence: 99%

“…In addition, engagement of IL-33/ST2 signaling in NSCLC cells was found to increase the membrane expression of glucose transporter 1 (GLUT1) and thereby enhance their glucose uptake and lactate production. Finally, knockdown of SLC2A1/GLUT1 in NSCLC cells diminished their IL-33-mediated proliferation as well as their metastatic potential, in vitro (43). …”

Section: Main Review Textmentioning

confidence: 99%

The Role of IL-33-Dependent Inflammation in the Tumor Microenvironment

Wasmer

Krebs

2017

Front. Immunol.

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There is compelling evidence that inflammation contributes to tumorigenesis. Inflammatory mediators within the tumor microenvironment can either promote an antitumor immune response or support tumor pathogenesis. Therefore, it is critical to determine the relative contribution of tumor-associated inflammatory pathways to cancer development. Interleukin-33 (IL-33) is a member of the IL-1 family of cytokines that is released upon tissue stress or damage to operate as an alarmin. IL-33 has been primarily implicated in the induction of type-2 immune responses. However, recent findings have shown a role of IL-33 in several cancers where it may exert multiple functions. In this review, we will present the current knowledge on the role of IL-33 in the microenvironment of different tumors. We will highlight which cells produce and which cells are activated by IL-33 in cancer. Furthermore, we will explain how IL-33 modulates the tumor-associated inflammatory microenvironment to restrain or promote tumorigenesis. Finally, we will discuss the issues to be addressed first before potentially targeting the IL-33 pathway for cancer therapy.

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“…In patients with lung cancer, an inverse association of the levels of IL‐33 in plasma or in tissue specimen with advanced tumor stage has been reported . However, it has also been revealed that expression of IL‐33 in human lung tumor tissues is positively correlated with tumor progression . In addition, Barrera and associates have reported that circulating level of IL‐33 is not associated with pathological outcomes in lung cancer patients .…”

Section: Discussionmentioning

confidence: 99%

“…41,42 However, it has also been revealed that expression of IL-33 in human lung tumor tissues is positively correlated with tumor progression. 43,44 In addition, Barrera and associates have reported that circulating level of IL-33 is not associated with pathological outcomes in lung cancer patients. 45 This clearly reflects the diversity and complexity of the role of IL-33 in tumor progression.…”

Section: Discussionmentioning

confidence: 99%

Rab37 in lung cancer mediates exocytosis of soluble ST2 and thus skews macrophages toward tumor‐suppressing phenotype

Tzeng

Chang

et al. 2018

Intl Journal of Cancer

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Interplay between cancer epithelial cells and the surrounding immune cells shape the tumor microenvironment to promote cancer progression. Tumor-associated macrophages are well recognized for their roles in cancer progression. Accumulating evidence also indicates implication of Rab small GTPase-mediated exocytosis in tumorigenesis. However, the mechanism for Rab-mediated exocytosis in regulation of macrophage polarization is not clear. We have previously identified Rab37 as a metastasis suppressor in lung cancer. In our study, we identified a novel Rab37 trafficking cargo soluble ST2 (sST2), which skewed macrophage polarization toward anti-tumoral M1-like phenotype in vitro. We further demonstrated that Rab37-mediated sST2 secretion significantly increased the ratio of M1 vs. M2 in xenografts and thus reduced tumor growth. Moreover, lung cancer patients with low Rab37, low sST2 and low ratio of M1 vs. M2 macrophages expression profile correlated with worse overall survival examined by Kaplan-Meier survival analysis. Multivariate Cox regression analysis showed that this Rab37-sST2-M1/M2 expression profile predicted poor prognosis. Our findings reveal a novel regulation of cancerous Rab37 in microenvironmental macrophages polarization, which preferentially shifts to anti-tumoral phenotype and thereby suppresses lung tumor growth.

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IL-33 signaling fuels outgrowth and metastasis of human lung cancer

Cited by 66 publications

References 29 publications

Longitudinal single cell profiling of regulatory T cells identifies IL-33 as a driver of tumor immunosuppression

Longitudinal single cell profiling of regulatory T cells identifies IL-33 as a driver of tumor immunosuppression

The Role of IL-33-Dependent Inflammation in the Tumor Microenvironment

Rab37 in lung cancer mediates exocytosis of soluble ST2 and thus skews macrophages toward tumor‐suppressing phenotype

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