IL-33-mediated mast cell activation promotes gastric cancer through macrophage mobilization

Moritz F. Eissmann; Christine Dijkstra; Andrew Jarnicki; Toby Phesse; Jamina Brunnberg; Ashleigh R. Poh; Nima Etemadi; Evelyn Tsantikos; Stefan Thiem; Nicholas D. Huntington; Margaret L. Hibbs; Alex Boussioutas; Michele A. Grimbaldeston; Michael Buchert; Robert J.J. O’Donoghue; Frederick Masson; Matthias Ernst

doi:10.1038/s41467-019-10676-1

IL-33-mediated mast cell activation promotes gastric cancer through macrophage mobilization

Moritz F. Eissmann, Christine Dijkstra, Andrew Jarnicki, Toby Phesse, Jamina Brunnberg, Ashleigh R. Poh, Nima Etemadi, Evelyn Tsantikos, Stefan Thiem, Nicholas D. Huntington, Margaret L. Hibbs, Alex Boussioutas, Michele A. Grimbaldeston, Michael Buchert, Robert J.J. O’Donoghue, Frederick Masson, Matthias Ernst

Immunology Alfred Hospital

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Abstract

The contribution of mast cells in the microenvironment of solid malignancies remains controversial. Here we functionally assess the impact of tumor-adjacent, submucosal mast cell accumulation in murine and human intestinal-type gastric cancer. We find that genetic ablation or therapeutic inactivation of mast cells suppresses accumulation of tumor-associated macrophages, reduces tumor cell proliferation and angiogenesis, and diminishes tumor burden. Mast cells are activated by interleukin (IL)-33, an alarmin produced by the tumor epithelium in response to the inflammatory cytokine IL-11, which is required for the growth of gastric cancers in mice. Accordingly, ablation of the cognate IL-33 receptor St2 limits tumor growth, and reduces mast cell-dependent production and release of the macrophage-attracting factors Csf2, Ccl3, and Il6. Conversely, genetic or therapeutic macrophage depletion reduces tumor burden without affecting mast cell abundance. Therefore, tumor-derived IL-33 sustains a mast cell and macrophage-dependent signaling cascade that is amenable for the treatment of gastric cancer.

Original language	English
Article number	2735
Number of pages	16
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-10676-1
Publication status	Published - 1 Dec 2019

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278026293-oaFinal published version, 2.69 MBLicence: CC BY

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Eissmann, M. F., Dijkstra, C., Jarnicki, A., Phesse, T., Brunnberg, J., Poh, A. R., Etemadi, N., Tsantikos, E., Thiem, S., Huntington, N. D., Hibbs, M. L., Boussioutas, A., Grimbaldeston, M. A., Buchert, M., O’Donoghue, R. J. J., Masson, F., & Ernst, M. (2019). IL-33-mediated mast cell activation promotes gastric cancer through macrophage mobilization. Nature Communications, 10(1), Article 2735. https://doi.org/10.1038/s41467-019-10676-1

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title = "IL-33-mediated mast cell activation promotes gastric cancer through macrophage mobilization",

abstract = "The contribution of mast cells in the microenvironment of solid malignancies remains controversial. Here we functionally assess the impact of tumor-adjacent, submucosal mast cell accumulation in murine and human intestinal-type gastric cancer. We find that genetic ablation or therapeutic inactivation of mast cells suppresses accumulation of tumor-associated macrophages, reduces tumor cell proliferation and angiogenesis, and diminishes tumor burden. Mast cells are activated by interleukin (IL)-33, an alarmin produced by the tumor epithelium in response to the inflammatory cytokine IL-11, which is required for the growth of gastric cancers in mice. Accordingly, ablation of the cognate IL-33 receptor St2 limits tumor growth, and reduces mast cell-dependent production and release of the macrophage-attracting factors Csf2, Ccl3, and Il6. Conversely, genetic or therapeutic macrophage depletion reduces tumor burden without affecting mast cell abundance. Therefore, tumor-derived IL-33 sustains a mast cell and macrophage-dependent signaling cascade that is amenable for the treatment of gastric cancer.",

author = "Eissmann, {Moritz F.} and Christine Dijkstra and Andrew Jarnicki and Toby Phesse and Jamina Brunnberg and Poh, {Ashleigh R.} and Nima Etemadi and Evelyn Tsantikos and Stefan Thiem and Huntington, {Nicholas D.} and Hibbs, {Margaret L.} and Alex Boussioutas and Grimbaldeston, {Michele A.} and Michael Buchert and O{\textquoteright}Donoghue, {Robert J.J.} and Frederick Masson and Matthias Ernst",

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Eissmann, MF, Dijkstra, C, Jarnicki, A, Phesse, T, Brunnberg, J, Poh, AR, Etemadi, N, Tsantikos, E, Thiem, S, Huntington, ND , Hibbs, ML , Boussioutas, A, Grimbaldeston, MA, Buchert, M, O’Donoghue, RJJ, Masson, F & Ernst, M 2019, 'IL-33-mediated mast cell activation promotes gastric cancer through macrophage mobilization', Nature Communications, vol. 10, no. 1, 2735. https://doi.org/10.1038/s41467-019-10676-1

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AU - Eissmann, Moritz F.

AU - Dijkstra, Christine

AU - Jarnicki, Andrew

AU - Phesse, Toby

AU - Brunnberg, Jamina

AU - Poh, Ashleigh R.

AU - Etemadi, Nima

AU - Tsantikos, Evelyn

AU - Thiem, Stefan

AU - Huntington, Nicholas D.

AU - Hibbs, Margaret L.

AU - Boussioutas, Alex

AU - Grimbaldeston, Michele A.

AU - Buchert, Michael

AU - O’Donoghue, Robert J.J.

AU - Masson, Frederick

AU - Ernst, Matthias

PY - 2019/12/1

Y1 - 2019/12/1

N2 - The contribution of mast cells in the microenvironment of solid malignancies remains controversial. Here we functionally assess the impact of tumor-adjacent, submucosal mast cell accumulation in murine and human intestinal-type gastric cancer. We find that genetic ablation or therapeutic inactivation of mast cells suppresses accumulation of tumor-associated macrophages, reduces tumor cell proliferation and angiogenesis, and diminishes tumor burden. Mast cells are activated by interleukin (IL)-33, an alarmin produced by the tumor epithelium in response to the inflammatory cytokine IL-11, which is required for the growth of gastric cancers in mice. Accordingly, ablation of the cognate IL-33 receptor St2 limits tumor growth, and reduces mast cell-dependent production and release of the macrophage-attracting factors Csf2, Ccl3, and Il6. Conversely, genetic or therapeutic macrophage depletion reduces tumor burden without affecting mast cell abundance. Therefore, tumor-derived IL-33 sustains a mast cell and macrophage-dependent signaling cascade that is amenable for the treatment of gastric cancer.

AB - The contribution of mast cells in the microenvironment of solid malignancies remains controversial. Here we functionally assess the impact of tumor-adjacent, submucosal mast cell accumulation in murine and human intestinal-type gastric cancer. We find that genetic ablation or therapeutic inactivation of mast cells suppresses accumulation of tumor-associated macrophages, reduces tumor cell proliferation and angiogenesis, and diminishes tumor burden. Mast cells are activated by interleukin (IL)-33, an alarmin produced by the tumor epithelium in response to the inflammatory cytokine IL-11, which is required for the growth of gastric cancers in mice. Accordingly, ablation of the cognate IL-33 receptor St2 limits tumor growth, and reduces mast cell-dependent production and release of the macrophage-attracting factors Csf2, Ccl3, and Il6. Conversely, genetic or therapeutic macrophage depletion reduces tumor burden without affecting mast cell abundance. Therefore, tumor-derived IL-33 sustains a mast cell and macrophage-dependent signaling cascade that is amenable for the treatment of gastric cancer.

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IL-33-mediated mast cell activation promotes gastric cancer through macrophage mobilization

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Control of gastrointestinal tumour progression by therapeutic interference with myeloid derived cells

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IL-33-mediated mast cell activation promotes gastric cancer through macrophage mobilization

Abstract

UN SDGs

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Control of gastrointestinal tumour progression by therapeutic interference with myeloid derived cells

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