Abstract C007: Identifying the role of Interleukin-17 signaling in intestinal stem cells during pancreatic cancer
Authors: Haoyue Liu, Vidhi Chandra, Le Li, Olivereen Le Roux, Virginia Tahan, Florencia McAllister
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC), the most aggressive type of pancreatic cancer, is predicted to become the second leading cause of cancer related deaths by 2030. Interleukin 17 (IL-17) signaling can promote tumor growth. In pancreatic cancer, IL-17 signaling in cancer cells is capable of triggering the formation of neutrophil extracellular traps (NETs) which is detrimental to the anti-tumor effect of immunotherapy. IL-17 signaling has been shown to have critical roles in maintaining gut homeostasis. Intestinal epithelial cells directly interact with the gut microbiome and are actively involved in infection control, injury repair, immune responses, and the production of antimicrobial peptides and cytokines, and need to be constantly replenished by intestinal stem cells (ISCs). Our lab’s study has previously shown that deletion of Interleukin 17 receptor A (IL-17RA) in the entire gut epithelium induces pro-tumorigenic IL-17 signaling due to the disruption of gut homeostasis, suggesting that immune responses induced by gut IL-17/IL-17RA signaling can affect the behavior of distant tumors. However, the mechanism of IL-17 signaling within specific gut epithelial compartments such as ISCs, enterocytes, secretory cells, etc. and their role in maintaining gut homeostasis and cancer risk are not well-studied until now. Thus, we aimed to identify the importance of IL-17 signaling in ISCs during pancreatic cancer. We hypothesized that disruption of IL-17/IL-17RA signaling within ISCs impacts tumor growth. Our preliminary data shows that IL-17 signaling in enterocytes maintains intestinal homeostasis and disruption of this axis triggers systemic increase in B cells that promotes tumor growth by increasing IL-17 levels in circulation. To identify the function of IL-17/IL-17RA signaling in ISCs, we utilized Leucine-rich-repeat-containing G-protein-coupled receptor 5 (Lgr5), a lineage marker for ISCs, to drive Cre enzyme tissue specific expression to specifically knockout Il17ra in gut ISCs - an inducible transgenic mouse model Il17ra fl/fl ;Lgr5- EGFP-CreERT2 (cKO). We used multiplex staining and imaging to validate the cell type specific loss of IL-17RA expression in tamoxifen treated cKO mice. We used implantable pancreatic tumor models and performed immunoprofiling using flow cytometry. We found that the pancreatic tumor growth was altered by the remote signal from gut ISCs in cKO mice. Furthermore, we performed RNAseq in both tumor and gut tissue which identified that the major changes in gene expression were associated with both innate and adaptive immune pathways, especially B cell activation. We conclude that the IL-17/IL-17RA signaling in gut ISCs changes intestinal immune responses locally that can affect distant tumor immunity. Citation Format: Haoyue Liu, Vidhi Chandra, Le Li, Olivereen Le Roux, Virginia Tahan, Florencia McAllister. Identifying the role of Interleukin-17 signaling in intestinal stem cells during pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C007.