Gastric cancer is the third leading cause of cancer-related deaths, and accounts for 800,000 deaths annually. Tuft cells are a rare subset of mucosal epithelial cells that are significantly increased during gastric tumorigenesis, and serve as a major source of IL25 within the tumour microenvironment. The production of IL25 promotes the activation of type 2 Innate Lymphoid Cells (ILC2s), and results in a feed-forward loop that promotes tuft cell development through the IL25/IL13 signal transduction pathway. Here we assess the role of tuft cells and ILC2s in gastric cancer development and the therapeutic potential of blocking this pathway.
To better understand the role of tuft cells and ILC2s in gastric tumour progression, we utilized the Gp130F/F mouse model of spontaneous intestinal-type gastric cancer. We observed a significant increase in tuft cells and ILC2s in the blood and within gastric tumours of Gp130F/F mice compared to wild-type (WT) controls. These results were consistent with increased ILC2 and tuft cell gene expression, Il13 and Il25 respectively, in Gp130F/F tumours compared to unaffected WT tissue. Accordingly, tuft cell ablation significantly impaired tumour growth and ILC2s in Gp130F/F mice, and reduced Il13 and Il25 gene expression within tumours.
Likewise, anti-IL25 and anti-IL13 treatment in Gp130F/F mice lead to significantly smaller tumours and reduced tuft cell numbers in these mice. In vitro analysis of gastric tumour organoids similarly demonstrated that treatment with anti-IL25 suppressed tumour organoid growth, while stimulation with IL13 enhanced organoid growth.
Together, our results suggest that tuft cells and ILC2s form a positive feed-forward loop that drives gastric tumour development through an IL25/IL13 signaling cascade. Inhibition of this pathway therefore provides a promising therapeutic approach for the treatment of gastric cancer.