Oncotarget

Research Papers:

IL-33 promotes gastric tumour growth in concert with activation and recruitment of inflammatory myeloid cells

Chau P. Tran, Michelle Scurr, Louise O’Connor, Jon N. Buzzelli, Garrett Z. Ng, Sharleen Chung Nien Chin, Lincon A. Stamp, Toshinari Minamoto, Andrew S. Giraud, Louise M. Judd, Philip Sutton and Trevelyan R. Menheniott _

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Abstract

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

Correspondence to:

Trevelyan R. Menheniott, email: trevelyan.menheniott@unimelb.edu.au

Keywords: IL-33; gastric cancer; tumorigenesis; mast cells; macrophages

Received: April 06, 2022     Accepted: May 07, 2022     Published: June 01, 2022

Copyright: © 2022 Tran et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

ABSTRACT

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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