KRAS-Dependent IL17 Signaling Promotes Pancreatic Neoplasia

Immune cell infiltration and fibrocellular stromal expansion are hallmarks of KRAS-driven and chronic inflammation-associated pancreatic cancer, but the cellular mechanisms governing these effects are ill-defined. McAllister and colleagues found increased levels of RORγt, a transcription factor that induces differentiation of interleukin-17 (IL17)-producing T cells, in the stroma surrounding acinar-ductal metaplasia (ADM) and early and advanced pancreatic intraepithelial neoplasia (PanIN) lesions in human pancreatic preneoplastic tissue. Although IL17 receptor A (IL17RA) was not expressed in normal human acinar tissue or in ADMs, high levels were found in PanINs. In a murine model of pancreatic cancer, pancreatic Kras^G12D activation and cerulein-induced chronic pancreatitis synergized to induce IL17 expression in T_H17 and γδ T cells. In addition, IL17RA was significantly upregulated in PanIN epithelial cells as a result of Kras^G12D induction. Either depletion of helper T cells or elimination of IL17 in hematopoietic cells via transplantation of Il17-null bone marrow into lethally irradiated recipients resulted in the delay or near complete ablation of PanIN formation, respectively. Conversely, adenoviral overexpression of IL17A in the pancreas markedly increased PanIN and ADM formation as well as stromal expansion, further demonstrating a role of IL17 signaling in pancreatic neoplasia. Pharmacologic inhibition of IL17 signaling via antibody-based neutralization of IL17RA and IL17, a therapeutic strategy currently being evaluated in autoimmune diseases, resulted in a reduction of both early and advanced PanINs in association with gene expression changes characteristic of IL17 signaling loss such as downregulation of Il6 and associated STAT3 phosphorylation. These studies indicate that a KRAS-dependent IL17 signaling axis driven by the recruitment and infiltration of T_H17 and γδ T cells and upregulation of epithelial IL17RA expression is critical for PanIN formation and may be therapeutically tractable.

McAllister F, Bailey JM, Alsina J, Nirschl CJ, Sharma R, Fan H, et al. Oncogenic Kras activates a hematopoietic-to-epithelial IL-17 signaling axis in preinvasive pancreatic neoplasia. Cancer Cell 2014;25:621–37.