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

Eissman, Moritz F, Dijkstra, Christine, Jarnicki, Andrew, Phesse, Toby, Brunnberg, Jamina, Poh, Ashleigh R, Etemadi, Nima, Tsantikos, Evelyn, Thiem, Stefan, Huntington, Nicholas H, Hibbs, Margaret L, Boussioutas, Alex, Grimbaldeston, Michele A, Buchert, Michael, O'Donoghue, Robert J J, Masson, Frederick and Ernst, Matthias 2019. IL-33 mediated mast cell activation promotes gastric cancer through macrophage mobilization. Nature Communications 10 , 2735. 10.1038/s41467-019-10676-1

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Publisher: Nature Publishing Group
ISSN: 2041-1723
Date of First Compliant Deposit: 22 May 2019
Date of Acceptance: 22 May 2019
Last Modified: 08 Jul 2019 10:38

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