When gut stem cells talk to the immune system: impacts on remote tumor 2240442

Introduction Pancreatic cancer is predicted to be the second leading cause of cancer deaths by 2030. Interleukin 17 (IL-17) signaling in pancreatic cancer cells can trigger neutrophil extracellular traps that impair immunotherapy efficacy. IL-17 signaling also maintains gut homeostasis. Intestinal epithelial cells interact with the gut microbiome, participate in injury repair, and are replenished by intestinal stem cells (ISCs). Our lab showed that deletion of IL-17 receptor A (IL-17RA) in the gut epithelium induces pro-tumorigenic IL-17 signaling due to the disruption of gut homeostasis, suggesting that gut IL-17/IL-17RA—mediated immune responses affect distant tumors. However, the role of IL-17 in specific epithelial compartments and its impact on gut homeostasis and cancer risk remain unclear. We hypothesized that disruption of IL-17/IL-17RA signaling within ISCs impacts tumor growth. Methods We utilized a lineage marker of ISCs, Lgr5, to drive Cre enzyme tissue specific expression to knock out Il17ra in gut ISCs (cKO mice). We used implantable pancreatic tumor models and performed immunoprofiling. Results We found that the pancreatic tumor growth was altered by the remote signal from gut ISCs in cKO mice. Furthermore, we identified that major transcriptomic changes were associated with innate and adaptive immune pathways, especially B cell activation. Conclusion We conclude that IL-17/IL-17RA signaling in gut ISCs changes intestinal immune responses locally that can affect distant tumor immunity.