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

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

doi:10.1038/s41467-019-10676-1

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.

Highlights

The contribution of mast cells in the microenvironment of solid malignancies remains controversial
In order to characterize the role of mast cells in gastric cancer, we initially investigated the mast cell frequency in gp130FF mice, a preclinically validated model for spontaneously occurring intestinal-type gastric cancer[37,38]
Gastric tumors in gp130FF mice, which harbor a knock in germline mutation in the shared IL-6/IL-11 receptor subunit gp[130], arise from excessive IL-6/IL11 dependent STAT3 activity; these tumors remain associated with chronic inflammation and immune cell infiltration

Summary

Introduction

The contribution of mast cells in the microenvironment of solid malignancies remains controversial. 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. Tumor-derived IL-33 sustains a mast cell and macrophage-dependent signaling cascade that is amenable for the treatment of gastric cancer. Walter and Eliza Hall Institute of Medical Research, and Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia. Predicting the outcome of IL-33/ST2 signaling in malignancies remains uncertain with both tumor promoting as well as tumor restricting activities being reported in knockout mouse models[33,34,35,36]

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Results

Conclusion