IL-33 promotes gastric tumour growth in concert with activation and recruitment of inflammatory myeloid cells
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Chau P. Tran1, Michelle Scurr1, Louise O’Connor1, Jon N. Buzzelli2, Garrett Z. Ng3, Sharleen Chung Nien Chin1, Lincon A. Stamp4, Toshinari Minamoto5, Andrew S. Giraud1,2, Louise M. Judd2, Philip Sutton2,3,* and Trevelyan R. Menheniott1,2,3,*
1 Tumour Immunology Group, Murdoch Children’s Research Institute, Melbourne, Victoria, Australia
2 Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia
3 Mucosal Immunology Group, Murdoch Children’s Research Institute, Melbourne, Victoria, Australia
4 Department of Anatomy and Physiology, The University of Melbourne, Victoria, Australia
5 Division of Translational and Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
* Co-senior authors
|Trevelyan R. Menheniott,||email:||firstname.lastname@example.org|
Keywords: IL-33; gastric cancer; tumorigenesis; mast cells; macrophages
Received: April 06, 2022 Accepted: May 07, 2022 Published: June 01, 2022
Interleukin-33 (IL-33) is an IL-1 family cytokine known to promote T-helper (Th) type 2 immune responses that are often deregulated in gastric cancer (GC). IL-33 is overexpressed in human gastric tumours suggesting a role in driving GC progression although a causal link has not been proven. Here, we investigated the impact of IL-33 genetic deficiency in the well-characterized gp130F/F mouse model of GC. Expression of IL-33 (and it’s cognate receptor, ST2) was increased in human and mouse GC progression. IL-33 deficient gp130F/F/Il33−/− mice had reduced gastric tumour growth and reduced recruitment of pro-tumorigenic myeloid cells including key mast cell subsets and type-2 (M2) macrophages. Cell sorting of gastric tumours revealed that IL-33 chiefly localized to gastric (tumour) epithelial cells and was absent from tumour-infiltrating immune cells (except modest IL-33 enrichment within CD11b+ CX3CR1+CD64+MHCII+ macrophages). By contrast, ST2 was absent from gastric epithelial cells and localized exclusively within the (non-macrophage) immune cell fraction together with mast cell markers, Mcpt1 and Mcpt2. Collectively, we show that IL-33 is required for gastric tumour growth and provide evidence of a likely mechanism by which gastric epithelial-derived IL-33 drives mobilization of tumour-promoting inflammatory myeloid cells.
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