Abstract 1403: The role of Dclk1-expression cells in normal pancreas and in pancreatic tumor progression
Authors: Valenti Giovanni , Laise Pasquale , Wu Feijing , Kobayashi Hiroki , Waterbury Quin T. , Takahashi Ryota , Ruan Tuo , Jiang Zhengyu , Ochiai Yosuke , Zamechek Leah B. , Wang Timothy C. 
Published: March 2024

Background: Tuft cells, marked by Doublecortin-like kinase-1 (Dclk1), are rare in the healthy pancreas but increase markedly during pancreatic tumorigenesis. While Group 2 innate lymphoid cells (ILC2s) are known to modulate inflammation and immunity, their specific roles in cancer-related immunity and immunotherapy interactions with pancreatic tuft cells remain unknown.

Methods: To investigate tuft cells during early pancreatic neoplasia, we used a Dclk1 reporter mouse model and single-cell RNA-seq to study Dclk1-expressing cells in normal pancreas and neoplasia using Mist1/Kras mouse. We treated mice with IL-13 peptides and anti-IL-13 antibodies to explore the IL-13-ILC2 axis in tuft cell regulation.

Results: Within the normal pancreas, Dclk1 expression marked several specialized epithelial cell types, including tuft-like cells, neuroendocrine cells, and a small number of acinar progenitor cells. A notable increase in Dclk1-expressing cells was observed at the onset of early PanIN lesions, with a subsequent decline in advanced PanIN stages and PDAC. Using flow cytometric analysis, we observed an increase in ILC2 cells in the Mist1/Kras pancreas in response to IL33 produced by pancreatic cancer-associated fibroblasts (CAFs). Blocking ILC2 activation with anti-IL33 antibodies reduced Dclk1 cell hyperplasia during PanIN progression. Given the known association between tuft cells, ILC2 cells, and the IL13/IL4 signaling pathways in the intestine, we discovered that Dclk1-expressing cells highly expressed the IL4 receptor (IL4ra). IL-13 levels increased during PanIN progression, and we found that ILC2s comprised the primary source of IL-13 within pancreatic tumors. In vitro, studies showed that the presence of IL-13 maintained the expansion of Dclk1-expressing tuft-like cells in pancreatic organoids derived from Dclk1-DTR-ZsGreen mice. Correspondingly, the in vivo administration of anti-IL-13 resulted in reduced Dclk1 expression.

Conclusion: Previous studies have shown that pancreatic tuft cells inhibit pancreatic cancer progression. Our study reveals a novel regulatory mechanism wherein IL-13 secreted by ILC2s modulates Dclk1 tuft cell expression during pancreatic tumorigenesis. The IL13-ILC2 axis appears to be a potential therapeutic target to regulate Dclk1 cell activity, which could influence the course of pancreatic tumorigenesis. Future investigations will further explore the interaction between the IL13/ILC2 axis and Dclk1 in pancreatic cancer development.

Citation Format: Giovanni Valenti, Pasquale Laise, Feijing Wu, Hiroki Kobayashi, Quin T. Waterbury, Ryota Takahashi, Tuo Ruan, Zhengyu Jiang, Yosuke Ochiai, Leah B. Zamechek, Timothy C. Wang. The role of Dclk1-expression cells in normal pancreas and in pancreatic tumor progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1403.