The Role of Dendritic Cells in Pancreatic Fibrosis and the Development of Pancreatic Neoplasia

Pancreatic cancer (PC) is one of ten most common cancers in the United States and is lethal in more than 95% of cases. On a cellular level, pancreatic cancer is composed largely of stromal and desmoplastic elements interspersed with islands of neoplastic epithelium. PC and Chronic Pancreatitis (CP) have long been thought to be linked since both are accompanied by fibrosis and have a huge cellular immune infiltrate. Activation of the Pancreatic Stellate Cells (PSC) is perhaps common to both disorders since activated PSC are highly fibrogenic.  However, the contribution of the cellular immunofibrotic infiltrate in the progression of disease from CP to PC is not known. In fact, whether such a link exists remains largely unexplored. Dendritic cells (DC) are the primary professional antigen presenting cell (APC) of the immune system. Our recent work has shown that (i) DC regulate the hepatic inflammatory milieu in organ fibrosis and that (ii) in murine experimental models of pancreatic cancer, DC expand in the liver enabling metastases. For the present proposal we examined the effect of DC expansion on murine pancreata. Surprisingly, we found: (a) Desmoplastic changes in the pancreatic parenchyma upon adoptive transfer of DC by intrperitoneal injection resulting in the formation of ductal Pancreatic Epithelial Neoplasia (PanINs). Further, (b) On primary co-culture of DC with PSC from fibrotic murine pancreas, we found that DCactivate PSC by increasing their inflammatory chemokine production, migration ability, and that (c) Toll likereceptors on PSC and (d) I-CAM1 receptor on DC are required for this DC-mediated PSC activation which appearsto proceed via TNFα production in the PSC. We wish to explore whether DC mediated PSC activation is a mechanism for the development of the observed pancreatic neoplasia. In pancreatic disease, our preliminary work suggests that (i) inflammation and fibrosis in chronic pancreatitis is exacerbated manifold by DC infiltration and (ii) adoptive transfer of DC in fibro-inflammatory pancreatic disease results in dysplasia of the pancreatic ductal epithelia and intense surrounding fibro-inflammatory desmoplasia. We postulate that DC drive chronic pancreatitis to pancreatic cancer by promoting inflammation, activation of PSC and stromal proliferation.