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

Nat Commun. 2019 Jun 21;10(1):2735. doi: 10.1038/s41467-019-10676-1.

Authors

Moritz F Eissmann¹, Christine Dijkstra¹, Andrew Jarnicki², Toby Phesse^{1

3}, Jamina Brunnberg^{1

4}, Ashleigh R Poh¹, Nima Etemadi^{1

5}, Evelyn Tsantikos⁶, Stefan Thiem¹, Nicholas D Huntington⁷, Margaret L Hibbs⁶, Alex Boussioutas⁸, Michele A Grimbaldeston^{9

10}, Michael Buchert¹, Robert J J O'Donoghue^{1

2}, Frederick Masson^{1

11}, Matthias Ernst¹²

Affiliations

¹ Cancer and Inflammation Laboratory, Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Heidelberg, VIC, 3084, Australia.
² Department of Pharmacology and Therapeutics, University of Melbourne, Melbourne, VIC, 3010, Australia.
³ Cell Signaling and Cancer Laboratory, European Cancer Stem Cell Research Institute and Cardiff University, Cardiff, CF24 4HQ, UK.
⁴ Institute of Biochemistry, Goethe University Frankfurt, Frankfurt am Main, 60438, Frankfurt, Germany.
⁵ Cell Signalling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, and Department of Medical Biology, University of Melbourne, Melbourne, VIC, 3052, Australia.
⁶ Department of Immunology and Pathology, Monash University, Melbourne, VIC, 3004, Australia.
⁷ Molecular Immunology Division, The Walter and Eliza Hall Institute of Medical Research, and Department of Medical Biology, University of Melbourne, Melbourne, VIC, 3052, Australia.
⁸ Department of Medicine, University of Melbourne, Melbourne, VIC, 3050, Australia.
⁹ Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, 5000, Australia.
¹⁰ OMNI-Biomarker Development, Genentech Inc., South San Francisco, CA, 94080, USA.
¹¹ Team 5, Centre of Physiopathology Toulouse-Purpan, INSERM UMR 1043/CNRS UMR 5282, University Toulouse III, CHU Purpan, 31024, Toulouse, France.
¹² Cancer and Inflammation Laboratory, Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Heidelberg, VIC, 3084, Australia. [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aminopyridines / administration & dosage
Animals
Cell Degranulation / drug effects
Cell Degranulation / immunology
Cromolyn Sodium / administration & dosage
Disease Models, Animal
Epithelium / immunology
Epithelium / pathology
Female
Gastric Mucosa / cytology
Gastric Mucosa / immunology
Gastric Mucosa / pathology
Humans
Interleukin-1 Receptor-Like 1 Protein / immunology
Interleukin-1 Receptor-Like 1 Protein / metabolism
Interleukin-33 / immunology*
Interleukin-33 / metabolism
Macrophages / immunology*
Male
Mast Cells / immunology*
Mice
Mice, Transgenic
Pyrroles / administration & dosage
Signal Transduction / drug effects
Signal Transduction / immunology
Stomach Neoplasms / genetics
Stomach Neoplasms / immunology*
Stomach Neoplasms / mortality
Stomach Neoplasms / pathology
Tissue Array Analysis
Tumor Microenvironment / immunology

Substances

Aminopyridines
IL1RL1 protein, human
IL33 protein, human
Il1rl1 protein, mouse
Il33 protein, mouse
Interleukin-1 Receptor-Like 1 Protein
Interleukin-33
Pyrroles
pexidartinib
Cromolyn Sodium

Abstract

Publication types

MeSH terms

Substances

Grants and funding