Abstract B102: Remote effects of gut stem cell IL-17 signaling on pancreatic tumor behavior

Abstract

Pancreatic cancer is predicted to be the second leading cause of cancer deaths by 2030. Interleukin 17 (IL-17) signaling has been recognized as a classic pro-tumorigenic factor to tumor formation. 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. Preliminary data from our laboratory suggest that distinct epithelial compartments contribute to these effects, which led us to investigate how ISC IL-17/IL-17RA signalling shapes host-microbiome interactions and contributes to immune responses in pancreatic cancer. We propose a key hypothesis that disruption of IL-17/IL-17RA signaling in ISCs lineage is associated with gut epithelial transcriptomic reprograming that can change gut microbiota composition and systemic immune responses that ultimately impacts remote tumor growth. We utilized a lineage marker of ISCs, Lgr5, to drive inducible Cre enzyme tissue specific expression to knock out Il17ra in gut ISCs (cKO mice). Multiplex immunofluorescence staining confirmed the loss of IL-17RA expression in the ISC lineage cells following tamoxifen treatment. We used implantable murine pancreatic tumor models and performed immunoprofiling. We found that the pancreatic tumor growth was altered by the remote signal from gut ISCs in cKO mice, companioned by a shift of tumor-infiltrating CD8 T cells. To investigate the underlying mechanisms, we performed multiplex imaging, single-cell RNA sequencing, and spatial transcriptomic analyses of intestinal tissues. We found that the Paneth cells undergo major transcriptomic changes in responding to the disruption of IL-17/IL-17RA signaling in ISCs lineage, the anti-microbial functions were specifically enhanced in the cKO mice. Using 16S rRNA sequencing, we identified alterations in gut microbial composition following the genetic deletion of Il17ra. We conclude that the disruption of IL-17/IL-17RA signaling in ISC lineage is capable of reshaping gut epithelial program and alters host-microbiome interactions, which ultimately affects systemic immune responses in pancreatic cancer.