Type 2 Innate Lymphocytes Actuate Immunity Against Tumours and Limit Cancer Metastasis

Saranchova, Iryna; Han, Jeffrey S.; Zaman, Rysa; Arora, Hitesh; Huang, Hui; Fenninger, Franz; Choi, Kyung Bok; Munro, Lonna; Pfeifer, Cheryl G.; Welch, Ian; Takei, Fumio; Jefferies, Wilfred A.

doi:10.1038/s41598-018-20608-6

Cited by 82 publications

(115 citation statements)

References 53 publications

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“…IL-33-induced ILC2s can amplify inflammatory immune responses during immune-mediated hepatitis (58). It is also reported that ILC2s play a fundamental role in enhancing anticancer immunity and controlling tumor metastasis (62). We observed significant increase of ILC2s in liver of the IL-33 group during HCC development ( Supplemental Fig.…”

Section: Discussionsupporting

confidence: 54%

IL-33 Released in the Liver Inhibits Tumor Growth via Promotion of CD4+ and CD8+ T Cell Responses in Hepatocellular Carcinoma

Jin

Lei

Lin

et al. 2018

The Journal of Immunology

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IL-33 released by epithelial cells and immune cells functions as an alarmin and can induce both type 1 and type 2 immune responses. However, the role of IL-33 release in tumor development is still not clear. In this study, we examined the function of released IL-33 in murine hepatocellular carcinoma (HCC) models by hydrodynamically injecting either IL-33–expressing tumor cells or IL-33–expressing plasmids into the liver of tumor-bearing mice. Tumor growth was greatly inhibited by IL-33 release. This antitumor effect of IL-33 was dependent on suppression of tumorigenicity 2 (ST2) because it was diminished in ST2−/− mice. Moreover, HCC patients with high IL-33 expression have prolonged overall survival compared with the patients with low IL-33 expression. Further study showed that there were increased percentages and numbers of activated and effector CD4+ and CD8+ T cells in both spleen and liver in IL-33–expressing tumor-bearing mice. Moreover, IFN-γ production of the CD4+ and CD8+ T cells was upregulated in both spleen and liver by IL-33. The cytotoxicity of CTLs from IL-33–expressing mice was also enhanced. In vitro rIL-33 treatment could preferentially expand CD8+ T cells and promote CD4+ and CD8+ T cell activation and IFN-γ production. Depletion of CD4+ and CD8+ T cells diminished the antitumor activity of IL-33, suggesting that the antitumor function of released IL-33 was mediated by both CD4+ and CD8+ T cells. Taken together, we demonstrated in murine HCC models that IL-33 release could inhibit tumor development through its interaction with ST2 to promote antitumor CD4+ and CD8+ T cell responses.

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Section: Discussionsupporting

confidence: 54%

IL-33 Released in the Liver Inhibits Tumor Growth via Promotion of CD4+ and CD8+ T Cell Responses in Hepatocellular Carcinoma

Jin

Lei

Lin

et al. 2018

The Journal of Immunology

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“…In subsequent studies, Gao et al [ 77 ] showed that over-expression of IL-33 in B16 melanoma and 4T1 breast cancer cells inhibited tumor growth and metastasis by increasing the numbers and IFN-γ production of CD8 + T and NK cells in tumor tissues, creating a TME that favored the eradication of tumors [ 77 ]. More recent studies showed that IL-33 can regulate cytokines to mobilize Type 2 innate lymphoid cells (ILC2) from the lung and other tissues into tumor beds where they orchestrate tumor immune-surveillance in cooperation with dendritic cells to promote cytolytic T cell responses, thereby enhancing anti-cancer immunity and controlling metastasis [ 98 ].…”

Section: The Role Of Il33/st2 In Tumorigenesismentioning

confidence: 99%

The Role of IL-33/ST2 Pathway in Tumorigenesis

Larsen

Minaya

Vaish

et al. 2018

IJMS

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Cancer is initiated by mutations in critical regulatory genes; however, its progression to malignancy is aided by non-neoplastic cells and molecules that create a permissive environment known as the tumor stroma or microenvironment (TME). Interleukin 33 (IL-33) is a dual function cytokine that also acts as a nuclear factor. IL-33 typically resides in the nucleus of the cells where it is expressed. However, upon tissue damage, necrosis, or injury, it is quickly released into extracellular space where it binds to its cognate receptor suppression of tumorigenicity 2 (ST2)L found on the membrane of target cells to potently activate a T Helper 2 (Th2) immune response, thus, it is classified as an alarmin. While its role in immunity and immune-related disorders has been extensively studied, its role in tumorigenesis is only beginning to be elucidated and has revealed opposing roles in tumor development. The IL-33/ST2 axis is emerging as a potent modulator of the TME. By recruiting a cohort of immune cells, it can remodel the TME to promote malignancy or impose tumor regression. Here, we review its multiple functions in various cancers to better understand its potential as a therapeutic target to block tumor progression or as adjuvant therapy to enhance the efficacy of anticancer immunotherapies.

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“…Indeed, their tissue-repair function can induce cholangiocarcinoma and liver metastasis ( 121 ). ILC2s can also be mobilized from the lung and other tissues thanks to IL-33, to penetrate tumors, mediate immune-surveillance with DC, and promote adaptive cytolytic T cell responses and attraction ( 122 , 123 ).…”

Section: Direct or Indirect Effects Of Il-33 As A Tumor Suppressormentioning

confidence: 99%

The Pro-tumorigenic IL-33 Involved in Antitumor Immunity: A Yin and Yang Cytokine

Fournié

Poupot

2018

Front. Immunol.

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Interleukin-33 (IL-33), considered as an alarmin released upon tissue stress or damage, is a member of the IL-1 family and binds the ST2 receptor. First described as a potent initiator of type 2 immune responses through the activation of T helper 2 (TH2) cells and mast cells, IL-33 is now also known as an effective stimulator of TH1 immune cells, natural killer (NK) cells, iNKT cells, and CD8 T lymphocytes. Moreover, IL-33 was shown to play an important role in several cancers due to its pro and anti-tumorigenic functions. Currently, IL-33 is a possible inducer and prognostic marker of cancer development with a direct effect on tumor cells promoting tumorigenesis, proliferation, survival, and metastasis. IL-33 also promotes tumor growth and metastasis by remodeling the tumor microenvironment (TME) and inducing angiogenesis. IL-33 favors tumor progression through the immune system by inducing M2 macrophage polarization and tumor infiltration, and upon activation of immunosuppressive cells such as myeloid-derived suppressor cells (MDSC) or regulatory T cells. The anti-tumor functions of IL-33 also depend on infiltrated immune cells displaying TH1 responses. This review therefore summarizes the dual role of this cytokine in cancer and suggests that new proposals for IL-33-based cancer immunotherapies should be considered with caution.

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Type 2 Innate Lymphocytes Actuate Immunity Against Tumours and Limit Cancer Metastasis

Cited by 82 publications

References 53 publications

IL-33 Released in the Liver Inhibits Tumor Growth via Promotion of CD4+ and CD8+ T Cell Responses in Hepatocellular Carcinoma

IL-33 Released in the Liver Inhibits Tumor Growth via Promotion of CD4+ and CD8+ T Cell Responses in Hepatocellular Carcinoma

The Role of IL-33/ST2 Pathway in Tumorigenesis

The Pro-tumorigenic IL-33 Involved in Antitumor Immunity: A Yin and Yang Cytokine

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