Abstract A76: Influence of IL-17-secreting immune cells on pancreatic cancer stemness

Little is known about how the immune system influences pancreatic cancer stemness. Using a murine model of pancreatic intraepithelial neoplasia (PanIN), we have previously reported that KrasG12D induces expression of IL-17 receptors (IL-17RA) on emerging PanINs, as well as pancreatic infiltration by IL-17-producing CD4+ and gamma-delta-T cells. Forced IL-17 over-expression dramatically accelerates PanIN initiation and progression, while inhibition of IL-17 signaling using either genetic or pharmacologic techniques effectively prevents PanIN formation. When IL-17 signaling was blocked using monoclonal antibodies on transgenic mice harboring PanINs, transcriptional analysis of Kras-mutated epithelial cells revealed significant down-regulation of multiple stemness-related genes: doublecortin-like kinase 1 (Dclk1) [2], Trefoil factor 1 (Tff1)[3], Sonic Hedgehog (SHH) [4], and others. Dclk1 has been recently described as a marker of tumor initiating cells and its functional role in cancer initiation and development is currently being studied. We found that adenovirus mediated-IL-17 overexpression in the murine pancreas harvesting Kras mutation results in PanINs with significantly higher number of Dclk1+ cells that PanINs generated in the presence of a luciferase control virus. Reversely, the genetic ablation of IL-17 in the hematopoietic compartment of the same type of mice resulted in PanINs with significantly lower number of Dclk1+ cells when compared with PanINs from mice trans...
Source: Cancer Research - Category: Cancer & Oncology Authors: Tags: Immune Drug Development Source Type: research