IL-33 restricts tumor growth and inhibits pulmonary metastasis in melanoma-bearing mice through eosinophils

Lucarini, Valeria; Ziccheddu, Giovanna; Macchia, Iole; Sorsa, Valentina La; Peschiaroli, Francesca; Buccione, Carla; Sistigu, Antonella; Sanchez, Massimo; Andreone, Sara; D’Urso, Maria Teresa; Spada, Massimo; Macchia, Daniele; Afferni, Claudia; Mattei, Fabrizio; Schiavoni, Giovanna

doi:10.1080/2162402x.2017.1317420

Cited by 157 publications

(204 citation statements)

References 61 publications

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“…Therefore, the suppressing effect on tumor growth, which we observed, may be related, in part, to the presence of eosinophils. Concordantly with this hypothesis, Lucarini et al (2017) reported that both B16F10 melanoma growth and metastasis formation were enhanced upon in vivo depletion of eosinophils using an anti-Siglec-F antibody. Eosinophils have also been found to enable T cell responses through the normalization of the tumor vasculature (Carretero et al, 2016).…”

Section: Discussionsupporting

confidence: 59%

Tumor-Derived Lactic Acid Contributes to the Paucity of Intratumoral ILC2s

et al. 2020

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Graphical AbstractHighlights d ILC2s are involved in eosinophil-associated antitumor responses in melanoma d Lactic acid inhibits function and decreases survival of ILC2s d Tumors with decreased lactic acid production exhibit increased infiltration of ILC2s SUMMARY Group 2 innate lymphoid cells (ILC2s) are abundant in non-lymphoid tissues and increase following infectious and inflammatory insults. In solid tumors, however, ILC2s constitute a relatively small proportion of immune cells. Here, we show, using melanoma as a model, that while the IL-33/IL C2/eosinophil axis suppresses tumor growth, tumor-derived lactate attenuates the function and survival of ILC2s. Melanomas with reduced lactate production (LDHA low ) are growth delayed and typified by an increased number of ILC2s compared with control tumors. Upon IL-33 stimulation, ILC2s accompanied by eosinophils more effectively restrain the growth of LDHA low tumors than control melanomas. Furthermore, database analysis reveals a negative correlation between the expression of LDHA and markers associated with ILC2s and the association of high expression of IL33 and an eosinophil marker SIGLEC8 with better overall survival in human cutaneous melanoma patients. This work demonstrates that the balance between the IL-33/ILC2/eosinophil axis and lactate production by tumor cells regulates melanoma growth.

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Section: Discussionsupporting

confidence: 59%

Tumor-Derived Lactic Acid Contributes to the Paucity of Intratumoral ILC2s

et al. 2020

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“…Given the important role of NK cells in inhibiting the growth of metastatic tumor in mouse model, we explored whether IL‐33 inhibited the development of metastatic tumor in 4T1‐Luc mouse model in an NK cell‐dependent manner. By depleting NK cells using an anti‐AsGM1 antibody (Supporting Information Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Given the important role of NK cells in inhibiting the growth of metastatic tumor in mouse model, 23 we explored whether Fig. S4a), the tumor growth inhibitory activity of IL-33 was completely abolished (Fig.…”

Section: Nk Cells Play a Dominant Role In The Il-33-mediated Suppressmentioning

confidence: 99%

“…12,24 In addition to NK cells, eosinophils and CD8 + T cells may also participate in the IL-33-mediated inhibition of metastatic tumor development. 12,23 Although the proportion and cell number of eosinophils were greatly increased (both in the lung and the spleen of 4T1-bearing mice) when treated with IL-33, but suppression of their expansion by administration anti-IL-5 antibody had no effect on the inhibition of metastatic tumor development ( Figs. 3d and 3e, Supporting Information Fig.…”

Section: Nk Cells Play a Dominant Role In The Il-33-mediated Suppressmentioning

confidence: 99%

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Interleukin‐33 activates and recruits natural killer cells to inhibit pulmonary metastatic cancer development

Zhang

Miao

et al. 2019

Intl Journal of Cancer

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Increasing evidence suggests that IL‐33 plays an important role in regulating tumor development. However, conflicting results, obtained from numerous studies, have highlighted the divergent functions of IL‐33. The detailed mechanisms by which IL‐33 modulates tumor development merit further investigation. Here, we report that IL‐33 administration can effectively inhibit the development of pulmonary metastasis of breast cancer in a mouse. In our model, IL‐33 promotes the production of TNF‐α by macrophages, which increases IL‐33 specific receptor (ST2) expression on natural killer (NK) cells and is pivotal in IL‐33‐induced NK cell activation. IL‐33 treatment also facilitates the production of CCL5 in the lung by eosinophils and CD8+ T cells, which mediates the recruitment of NK cells to the tumor microenvironment. The systemic activation and local recruitment of NK cells result in potent tumor rejection in the lung. Our study reports a novel mechanism for the IL‐33‐meditated suppression of metastatic cancer and provides potential therapeutic strategies for targeting metastatic tumor.

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“…Many endothelial cells and tumors express both ST2L and sST2 mRNA [15, 16]. A large body of data has confirmed that the IL-33/ST2 axis affects the progression of many tumors, either through regulation of the immune system or by acting directly on tumor cells [17-23]. …”

Section: Introductionmentioning

confidence: 99%

IL-33/ST2 Axis Regulates Vasculogenic Mimicry via ERK1/2-MMP-2/9 Pathway in Melanoma

et al. 2019

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Background: Melanoma, an extremely malignant form of cancer, poses a significant health risk. Vasculogenic mimicry (VM), blood vessels formed by tumor cells instead of endothelial cells, is an important factor for the rapid progression of melanoma. Interleukin (IL)-33 is an inflammatory factor commonly found in the tumor microenvironment and plays an important role in the progression of many tumors. IL-33 acts on immune cells and tumor cells through its receptor ST2. This study hypothesized that IL-33 directly affects the progression of melanoma. Objectives: This study was designed to investigate the effect of IL-33 on VM of melanoma and its potential mechanism of action. Methods: The expression of ST2 was evaluated in 66 cases of melanoma collected from human patients, and the differences were analyzed. In vitro experiments were conducted to study the effects of the IL-33/ST2 axis on cell migration and invasion and to elucidate possible mechanisms. Results: ST2 expression is associated with that of matrix metalloproteinase (MMP)-2 and VM in melanoma of patients. IL-33 increases the abilities of proliferation, migration and invasion of melanoma cells and VM tube formation through ST2. IL-33 induces the production of MMP-2/9 via ERK1/2 phosphorylation. Conclusion: IL-33 can directly act on melanoma cells and promote its development.

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IL-33 restricts tumor growth and inhibits pulmonary metastasis in melanoma-bearing mice through eosinophils

Cited by 157 publications

References 61 publications

Tumor-Derived Lactic Acid Contributes to the Paucity of Intratumoral ILC2s

Tumor-Derived Lactic Acid Contributes to the Paucity of Intratumoral ILC2s

Interleukin‐33 activates and recruits natural killer cells to inhibit pulmonary metastatic cancer development

IL-33/ST2 Axis Regulates Vasculogenic Mimicry via ERK1/2-MMP-2/9 Pathway in Melanoma

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