Biology of the PancreasReviewRole of Immune Cells and Immune-Based Therapies in Pancreatitis and Pancreatic Ductal Adenocarcinoma
Section snippets
Adaptive and Innate Immune Cells and Their Roles in AP
In AP, the initial inflammatory process leads to migration of monocytes and neutrophils into the pancreas, mediated by a multistep process that involves adhesion molecules.21 Hyperstimulation with caerulein leads to up-regulation of intracellular adhesion molecule–1 (ICAM-1) in the pancreas, which mediates adhesion of neutrophils to the site of inflammation.22 Neutrophils have been proposed to have important roles in the early phase of disease development, contributing to activation of
Roles for Adaptive and Innate Immune Cells in CP
Our understanding of fibrogenesis in the pancreas of patients with CP improved with the finding that pancreatic stellate cells (PSCs) regulate synthesis and degradation of the extracellular matrix proteins that comprise fibrous tissue.56 Under homeostatic conditions, PSCs are quiescent. However, PSCs are activated by toxic factors, such as ethanol and its metabolites, or by inflammatory cytokines and chemokines (Figure 1), which are up-regulated in pancreatic tissues of patients with CP. Such
Innate and Adaptive Immune Cells in PDA Development
Genetically engineered mouse models of pancreatic cancer have facilitated evaluation of inflammatory factors within the developing tumor microenvironment.66 This is a relatively new area of study, but a number of different immune cell types, innate and the adaptive, have been found to contribute to the progressive inflammatory changes that lead to PDA (Table 1). The activities of these cells, and their roles in immune regulation during tumor development, have not been completely elucidated.
Immunopathogenesis of PDA
Many of the immune components of the PDA microenvironment are inflammatory cells or factors. However, these do not support anti-tumor immunity. Instead, these inflammatory components (which include macrophages, neutrophils, and mast cells) promote tumor growth and invasion. These cell types have been observed in low-grade premalignant lesions, and their numbers increase when the low-grade premalignant lesions progress into high-grade lesions and invasive PDAs. Many of these cell types are also
Immune-Based Therapeutic Strategies
For many years, researchers believed that human PDAs were poorly immunogenic. However, our current understanding of the role of inflammation in development of PanINs and progression to PDA contradicts this concept. PDAs evade the immune response by sending immunosuppressive signals to the microenvironment, and inflammation promotes formation of early, premalignant lesions and their progression. The inflammatory response in PanINs resembles that observed in patients with CP (Table 2).
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Conflicts of interest The authors disclose no conflicts.
Funding This work was supported in part by National Institutes of Health Grant R01 DK092421 (A.H.), K23 CA148964-01 (L.Z.), Digestive Disease Center grants DK56339 (Stanford University), The Robert Wood Johnson Foundation (A.H.), Johns Hopkins School of Medicine Clinical Scientist Award (L.Z.), The National Pancreas Foundation (L.Z.), Lefkofsky Family Foundation (L.Z.), the NCI SPORE in Gastrointestinal Cancers P50 CA062924-14 (E.M.J. and L.Z.), Lustgarten Foundation (E.M.J. and L.Z.), Viragh Foundation and the Skip Viragh Pancreatic Cancer Center at Johns Hopkins (E.M.J. and L.Z), and the Sol Goldman Pancreatic Cancer Center (L.Z.). Dr Jaffee is the first recipient of the Dana and Albert “Cubby” Broccoli Endowed Professorship.