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

Eissman, Moritz F, Dijkstra, Christine, Jarnicki, Andrew, Phesse, Toby ORCID: https://orcid.org/0000-0001-9568-4916, 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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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences European Cancer Stem Cell Research Institute (ECSCRI)
Publisher:	Nature Publishing Group
ISSN:	2041-1723
Date of First Compliant Deposit:	22 May 2019
Date of Acceptance:	22 May 2019
Last Modified:	11 Oct 2023 21:59
URI:	https://orca.cardiff.ac.uk/id/eprint/122783

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