Abstract 2867: TH17 cells promote early pancreatic tumorigenesis.

Abstract

Abstract Chronic pancreatitis increases by 16 fold the risk of developing pancreatic ductal adenocarcinoma (PDAC), one of the deadliest human cancers. Activating Kras mutations have been detected in 30% of early pancreatic intraepithelial neoplasias (PanINs), increasing to 100% in advanced pancreatic ductal adenocarcinoma (PDAC). We hypothesize that inflammatory cells recruited to the pancreas in response to chronic injury can interact with epithelial cells harboring activated KrasG12D and affect the progression of PanIN lesions. To test this hypothesis, we have used the inducible transgenic Mist1:CreERT2; LSL-KrasG12D (KCiMist1) adult mice in which the LSL KrasG12D allele is activated specifically in the acinar compartment. This model leads to rapid formation of PanINs with a classic "ductal" phenotype and the progression of lesions is further accelerated with the induction of chronic pancreatitis (CP) generated by recurrent injections of cerulein. 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 recruited to the pancreas during chronic pancreatitis and further increased upon KrasG12D activation. The differentiation of CD4+T cells into TH17 requires IL-6 and TGF-B, factors that are increased in the pancreatic tumor microenvironment. Finally, Stat3, a key transcription factor that determines the differentiation of TH17 lineage, is activated in the pancreatic dysplastic epithelium as well as in the stromal infiltrating cells. We have discovered that PanINs from KCiMist1 mice overexpress the IL-17RA by immunofluorescence and furthermore we confirmed this finding on human PanIN tissue arrays. Intrapancreatic injections of adenovirus encoding IL-17A, the main cytokine produced by TH17 cells, into transgenic mice after KrasG12D activation led to an increase in the progression of PanIN lesions by 6 weeks when compared with mice injected with luciferase-adenovirus. We showed a decrease in initiation and progression of PanINs in KCiMist1/CP mice that have received neutralizating antibodies against IL-17RA, IL-17A and IL-17F for 6 weeks after Kras activation. Finally, we transplanted IL-17A KO bone marrow into KCiMist1 mice and showed a significant decrease in metaplasia and PanINs formation when compared with mice transplanted with WT bone marrow. In conclusion, we have shown through three functional murine experiments that TH17 cells, recruited to the pancreas in the presence of chronic pancreatitis, can accelerate the progression of early pancreatic tumorigenesis, setting the basis for future translational studies targeting TH17 cells. This work has been supported by the training grant: NIGMS T32GMO66691. Citation Format: Florencia McAllister, Jennifer M. Bailey, Janivette Alsina, Chris Nirschl, Rachana Lankapalli, Jeffrey Roeser, Elizabeth Jaffee, Cynthia Sears, Jay K. Kolls, Charles G. Drake, Drew M. Pardoll, Steven D. Leach. TH17 cells promote early pancreatic tumorigenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2867. doi:10.1158/1538-7445.AM2013-2867