A tuft cell - ILC2 signaling circuit provides therapeutic targets to inhibit gastric metaplasia and tumor development

Ryan N. O’Keefe, Annalisa L. E. Carli, David Baloyan, David Chisanga, Wei Shi, Shoukat Afshar-Sterle, Moritz F. Eissmann, Ashleigh R. Poh, Bhupinder Pal, Cyril Seillet, Richard M. Locksley, Matthias Ernst and Michael Buchert ()
Additional contact information
Ryan N. O’Keefe: Olivia Newton-John Cancer Research Institute
Annalisa L. E. Carli: Olivia Newton-John Cancer Research Institute
David Baloyan: Olivia Newton-John Cancer Research Institute
David Chisanga: Olivia Newton-John Cancer Research Institute
Wei Shi: Olivia Newton-John Cancer Research Institute
Shoukat Afshar-Sterle: Olivia Newton-John Cancer Research Institute
Moritz F. Eissmann: Olivia Newton-John Cancer Research Institute
Ashleigh R. Poh: Olivia Newton-John Cancer Research Institute
Bhupinder Pal: Olivia Newton-John Cancer Research Institute
Cyril Seillet: Walter and Eliza Hall Institute of Medical Research
Richard M. Locksley: University of California San Francisco
Matthias Ernst: Olivia Newton-John Cancer Research Institute
Michael Buchert: Olivia Newton-John Cancer Research Institute

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract Although gastric cancer is a leading cause of cancer-related deaths, systemic treatment strategies remain scarce. Here, we report the pro-tumorigenic properties of the crosstalk between intestinal tuft cells and type 2 innate lymphoid cells (ILC2) that is evolutionarily optimized for epithelial remodeling in response to helminth infection. We demonstrate that tuft cell-derived interleukin 25 (IL25) drives ILC2 activation, inducing the release of IL13 and promoting epithelial tuft cell hyperplasia. While the resulting tuft cell - ILC2 feed-forward circuit promotes gastric metaplasia and tumor formation, genetic depletion of tuft cells or ILC2s, or therapeutic targeting of IL13 or IL25 alleviates these pathologies in mice. In gastric cancer patients, tuft cell and ILC2 gene signatures predict worsening survival in intestinal-type gastric cancer where ~40% of the corresponding cancers show enriched co-existence of tuft cells and ILC2s. Our findings suggest a role for ILC2 and tuft cells, along with their associated cytokine IL13 and IL25 as gatekeepers and enablers of metaplastic transformation and gastric tumorigenesis, thereby providing an opportunity to therapeutically inhibit early-stage gastric cancer through repurposing antibody-mediated therapies.

Date: 2023
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DOI: 10.1038/s41467-023-42215-4

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