In-person Oral Presentation 34th Lorne Cancer Conference 2022

Targeting the Tuft cells-Type 2 Innate Lymphoid Cell cytokine circuit in Gastric Cancer (#25)

Ryan O'Keefe 1 , Shoukat Sterle 1 , Cyril Seillet 2 , Richard Locksley 3 , Matthias Ernst 1 , Michael Buchert 1
  1. Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia
  2. Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
  3. Department of Medicine (Infectious Diseases), University of California Regents, Oakland, California, United States

Gastric cancer is the third leading cause of cancer-related deaths, and accounts for 900,000 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.

 

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 gastric tumours of Gp130F/F mice compared to wild-type (WT) controls. These results were consistent with increased Il13 and Il25 gene expression in Gp130F/F tumours compared to unaffected WT tissue. Accordingly, tuft cell ablation significantly impaired tumour growth and iILC2s in Gp130F/F mice, and reduced Il13 and Il25 gene expression within tumours.

 

To assess the therapeutic benefit of targeting the interaction between tuft cells and ILC2s, we treated Gp130F/F mice with either anti-IL25 or anti-IL13 blocking antibodies and observed significantly smaller tumours and reduced tuft cell numbers and ILC2s 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.

 

Finally we performed single cell RNA sequencing, demonstrating the strong similarities between the tuft cell and ILC2 feed-forward loop within our Gp130F/F mice and the progression of human gastric disease.

 

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.