Abstract 2968: TH17 cells in early pancreatic tumorigenesis

Abstract

Abstract Activating Kras mutations have been detected in 30% of pancreatic intraepithelial neoplasias (PanIN), increasing to 100% in advanced pancreatic ductal adenocarcinoma (PDAC). Chronic pancreatitis is a risk factor for PDAC and cigarette smoking, the most important single risk factor for PDAC, has been recently associated with chronic pancreatic inflammation. The central hypothesis guiding our work is that inflammatory cells recruited to the pancreas in response to chronic injury can interact with epithelial cells harboring activated KrasG12D, affecting the progression of PanIN lesions. Further understanding of this interaction would be fundamental to generate effective chemopreventive strategies in high risk populations. To test this hypothesis, we have used the Mist1:CreERT2; LSL-KrasG12D mice in which the LSL KrasG12D allele is activated specifically in the acinar compartment of adult mice, leading to the rapid formation of PanIN with a classic “ductal” phenotype. We have established a model of chronic inflammation- induced pancreatic tumorigenesis that results in significant acceleration in the initiation and progression of PanIN lesions at 4 weeks after the activation of Kras. We have found that TH17 cells, a subtype of CD4+ T-helper cells known to play an active role in other models of inflammation- induced tumorigenesis, are rapidly recruited to the pancreas after Kras activation and are further increased in the presence of concomitant chronic pancreatic inflammation induced by cerulein injections. The differentiation of CD4+T cells into TH17 requires IL-6 and TGF-B, and both factors are increased in the pancreatic tumor microenvironment. Finally, Stat3, a key transcription factor that determines the differentiation of Th17 lineage, is activated in cells infiltrating early PanIN lesions. We are currently evaluating both genetic ablation of TH17 cells and neutralizing antibodies against IL-17 as novel therapeutics strategies in murine PanIN. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2968. doi:1538-7445.AM2012-2968