Role of immune cells and immune-based therapies in pancreatitis and pancreatic ductal adenocarcinoma

Abstract

Immune cells are important in the pathogenesis of acute pancreatitis and determine disease severity. Results from cytokine-based clinical trials for acute pancreatitis have been disappointing, so strategies that target and alter the behavior of infiltrating immune cells require consideration. Recurrent acute pancreatitis can progress to chronic pancreatitis, which is a well-described risk factor for pancreatic ductal adenocarcinoma (PDA). However, most patients with chronic pancreatitis do not develop PDA, and most patients with PDA do not have a history of pancreatitis. Interestingly, chronic pancreatitis and PDA tissues have similarities in their desmoplasia and inflammatory infiltrates, indicating overlapping inflammatory responses. Further studies are needed to determine the differences and similarities of these responses, improve our understanding of PDA pathogenesis, and develop specific immune-based therapies. Immune cells in PDA produce immunosuppressive signals that allow tumors to evade the immune response. Unlike single therapeutic agent studies that block immunosuppressive mechanisms, studies of combination therapies that include therapeutic vaccines have provided promising results.

Figure 1. Immune cell involvement in pancreatic ductal adenocarcinoma, acute and chronic pancreatitis

Recurrent and continued pancreatic injury can lead to chronic pancreatitis (CP). CP can progress to pancreatic ductal adenocarcinoma (PDA), although most PDA likely arises independent of pancreatitis. Cytotoxic T lymphocyte (CTL), polysaccharide (LPS), myeloid derived suppressor cells (MDSC), natural killer cells (NK), pancreatic stellate cells (PSCs), platelet derived growth factor (PDGF), reactive oxygen species (ROS), regulatory T cells (Tregs), T helper cells (Th).

Figure 2. Immune cell infiltrates during pancreatic tumor progression

Infiltration by immune cells with immunosuppressive activities allows for an environment that fosters tumor growth and progression. Sequential acquisition of mutations in proto-oncogene K-RAS and the tumor suppressors INK4A, TP53, DPC4, BRCA2, and over-expression of cyclin D1 and mesothelin lead to pancreatic tumor progression. Effector T cells (Teff), myeloid derived suppressor cells (MDSC), natural killer cells (NK), pancreatic ductal adenocarcinoma (PDA), pancreatic intraepithelial neoplasia (PanIN), regulatory T cells (Tregs), T helper cells (Th).