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bioRxiv · 10.1101/2022.02.16.480779

Inhibition of the tuft cell/ILC2 axis reduces gastric tumor development in mice

O'Keefe, R. N.·Carli, A.·Baloyan, D.·Sterle, S.·Eissmann, M. F.·Poh, A. R.·Seillet, C.·Locksley, R. M.·Ernst, M. M.·Buchert, M.
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Abstract

Although gastric cancer is a leading cause of cancer-related deaths, systemic treatment strategies remain scarce. Here we explore a metabolite-triggered circuit between epithelial tuft cells and innate lymphoid type 2 cells (ILC2) that is evolutionarily optimized for intestinal remodeling in response to helminth infection. We demonstrate that tuft cell-derived interleukin 25 (IL25) acts as an alarmin on ILC2s to induce the release of IL13 as a growth factor for tuft cells, and propose that this model drives early metaplastic remodeling and gastric tumor formation. Genetic ablation of tuft cells, ILC2s or antibody-mediated neutralization of IL13 or IL25 reduces the growth of established tumors. Thus, the tuft cell/ILC2 axis provides an opportunity to therapeutically inhibit preneoplastic lesions and early-stage gastric cancer through repurposing of antibody-mediated therapies. One-Sentence SummaryTuft cells and type 2 innate lymphoid cells offer a new therapeutic target in gastric disease.

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O'Keefe, R. N., Carli, A., Baloyan, D., Sterle, S., Eissmann, M. F., Poh, A. R., Seillet, C., Locksley, R. M., Ernst, M. M., Buchert, M.. 2022-02-18. Inhibition of the tuft cell/ILC2 axis reduces gastric tumor development in mice. https://doi.org/10.1101/2022.02.16.480779

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