Abstract 2341: Group 2 innate lymphoid cells influence pancreatic stromal cell composition in homeostasis and pancreatic cancer

Abstract Background: Group 2 Innate Lymphoid Cells (ILC2s) are tissue-resident innate immune cells critical in orchestrating type-2 immune responses. Cancer-associated fibroblasts are increasingly recognized as having important pro- and anti-tumorigenic roles. While type-2 immunity has been linked to fibrosis and tumor development, how ILC2s influence the stromal microenvironment in these settings is poorly understood. Here, we investigated the role of ILC2s on pancreatic stromal cell (PSC) behavior in healthy and tumor-bearing mice. Methods: Naive, inflamed, and tumor-bearing pancreata of WT or ILC2-deficient mice were profiled by flow cytometry, histology, or multiplex immunofluorescence imaging. We assessed two-way communication between ILC2s and stromal cells using in silico analysis of single-cell RNAseq or in vitro coculture transcriptomic data. Putative crosstalk mechanisms were tested with in vitro and in vivo assays. Additionally, we performed two-photon microscopy of reporter mice pancreata and multiplex immunofluorescent imaging of tumor sections. Results: Imaging studies show that ILC2s co-localize with IL-33+ stromal cells in the naïve, inflamed and tumor-bearing pancreas. In vivo and in vitro studies indicate that ILC2s are critical mediators of stromal cell proliferation and density in homeostatic and inflamed conditions, while influencing stromal cell-driven immune modulation in cancer. Single-cell transcriptomic analysis reveal distinct Il33+ and Il33- stromal cell clusters, which may engage in different crosstalk mechanisms with ILC2s, as determined by in silico inferential analysis, in vitro co-culture and in vivo studies. Conclusion: ILC2s strongly influence stromal cell composition in both the healthy pancreas and pancreatic tumors. Given the importance attributed to the characteristic desmoplasia of pancreatic tumors, ILC2-driven modulation of the stromal compartment may affect tumor progression. Citation Format: Thomas Yip, Sheng Lee, Julie Stockis, Celine Garcia, Shwetha Raghunathan, Bram Lim, Silvain Pinaud, Shaun Png, Timotheus Halim. Group 2 innate lymphoid cells influence pancreatic stromal cell composition in homeostasis and pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2341.