Role of Immune Cells and Immune-Based Therapies in Pancreatitis and Pancreatic Ductal Adenocarcinoma

doi:10.1053/j.gastro.2012.12.042

Gastroenterology

Volume 144, Issue 6, May 2013, Pages 1230-1240

https://doi.org/10.1053/j.gastro.2012.12.042 Get rights and content

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.

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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Cited by (244)

Circulating immune signatures in chronic pancreatitis with and without preceding acute pancreatitis: A pilot study
2024, Pancreatology
To investigate profiles of circulating immune signatures in healthy controls and chronic pancreatitis patients (CP) with and without a preceding history of acute pancreatitis (AP).
We performed a phase 1, cross-sectional analysis of prospectively collected serum samples from the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translation StuDies (PROCEED) study. All samples were collected during a clinically quiescent phase. CP subjects were categorized into two subgroups based on preceding episode(s) of AP. Healthy controls were included for comparison. Blinded samples were analyzed using an 80-plex Luminex assay of cytokines, chemokines, and adhesion molecules. Group and pairwise comparisons of analytes were performed between the subgroups.
In total, 133 patients with CP (111 with AP and 22 without AP) and 50 healthy controls were included. Among the 80 analytes studied, CP patients with a history of AP had significantly higher serum levels of pro-inflammatory cytokines (interleukin (IL)-6, IL-8, IL-1 receptor antagonist, IL-15) and chemokines (Cutaneous T-Cell Attracting Chemokine (CTACK), Monokine induced Gamma Interferon (MIG), Macrophage-derived Chemokine (MDC), Monocyte Chemoattractant Protein-1 (MCP-1)) compared to CP without preceding AP and controls. In contrast, CP patients without AP had immune profiles characterized by low systemic inflammation and downregulation of anti-inflammatory mediators, including IL-10.
CP patients with a preceding history of AP have signs of systemic inflammatory activity even during a clinically quiescent phase. In contrast, CP patients without a history of AP have low systemic inflammatory activity. These findings suggest the presence of two immunologically diverse subtypes of CP.
Multistate Model of the Natural History of Inflammatory Pancreatic Diseases: A Nationwide Population-based Cohort Study
2023, Gastroenterology
Understanding the nature of inflammatory pancreatic diseases is essential for planning health care system requirements and interventions. The aim of this study was to quantify the trajectories of inflammatory pancreatic diseases and their association with pancreatic cancer in a population-based setting.
National health registries were used to identify all Danish residents (18 years or older) in the period from 2000 through 2018 with incident cases of acute pancreatitis (AP), recurrent acute pancreatitis (RAP), chronic pancreatitis (CP), and pancreatic cancer. We used a multistate model to examine transitions from a healthy state to intermediate states of acute pancreatic inflammation (AP and RAP) to chronic states (CP and pancreatic cancer) and, ultimately, death. Results were reported as transition incidence rates per 1000 person-years with 95% CIs.
There were 4,663,864 individuals included (mean age, 46 years; 51% were women). During a mean follow-up of 16.8 years, 31,396 individuals were diagnosed with incident AP, 5546 with RAP, 8898 with CP, and 18,182 with pancreatic cancer. The cumulative incidence of pancreatitis (acute and chronic) during the study period was 0.80% (95% CI, 0.79%–0.80%). The transition incidence rates to CP were 12.1 (95% CI, 8.1–18.1) from AP, 46.8 (95% CI, 31.6–69.3) from RAP, and 0.07 (95% CI, 0.04–0.13) from a healthy state. Similar patterns were observed for transitions to pancreatic cancer. Most patients diagnosed with CP (64.2%) and pancreatic cancer (96.4%) transitioned directly from a healthy state. Among patients with pancreatitis, 41.0% (95% CI, 40.5%–41.5%) died during follow-up.
The study findings revealed an increased risk of CP and pancreatic cancer in patients with a history of AP. However, most patients with CP and pancreatic cancer transitioned directly from a healthy state.
Optimal timing of free total rhubarb anthraquinones on immune regulation in rats with severe acute pancreatitis
2023, Journal of Ethnopharmacology
Rhubarb is the peeled and dried root of Rheum palmatum L., Rheum tanguticum Maxim. ex Balf. or Rheum officinale Baill. Free total rhubarb anthraquinones (FTRAs) isolated and extracted from rhubarb display the beneficial effects of anti-inflammation and immunological modulation. The timing of immune regulation is a major problem in the immunotherapy for severe acute pancreatitis (SAP). several studies reported that FTRAs could reduce systemic inflammatory responses by inhibiting early immune overactivity in the gut in rats with SAP. But, the optimal timing of rhubarb and FTRAs administration is not clear in clinical practice. Therefore, the time window for the best efficacy of rhubarb and FTRAs in the treatment of SAP patients should be further elucidated.
The main purpose of the present study was to evaluate the efficacy and optimal timing of immune modulation with FTRAs in the treatment of SAP in rats. Materials and methods: FTRAs (22.5, 45 and 90 mg/kg), Rhubarb (RHU) (900 mg/kg, positive control) or normal saline (vehicle control) were initiated at 0 (immediately), 48 and 72 h every 12 h for three times in total. The therapeutic effects of FTRAs and RHU on pancreas and intestinal tissues injury, secondary infection with pseudomonas aeruginosa (PA), amylase, lipase, D-lactic acid (DLA), endotoxin (ET), proinflammatory and anti-inflammatory cytokines, macrophages, dendritic cells and regulatory T cells (Tregs) in the blood, small intestine and/or mesenteric lymph node (MLN) were determined in rats with SAP after treatment.
The results showed that administration of FTRAs at 0 h was superior to 48 h and 72 h, which significantly protected the injury of pancreas and intestinal tissues, reduced the mortality induced by secondary infection with PA, decreased the levels of amylase, lipase, DLA, ET, tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), IL-6, IL-8, IL-18 and Tregs, and increased the levels of IL-4, sTNF-αR, macrophages and dendritic cells, secretary immunoglobulin A (SIgA) in the blood and/or small intestinal tissues in rats with SAP.
In conclusion, our studies indicate that the treatment window of FTRAs for SAP is within 48 h of development, administration of FTRAs at the early stage (0 h, immune overreaction period) was the optimal time and superior to that of 48 h and 72 h for its therapeutic efficacy. The earlier the administration of FTRAs, the better the therapeutic efficacy. Therefore, our data may provide a scientific rationale for the clinical application and optimal timing of FTRAs in the treatment of SAP.
Biochanin A ameliorates caerulein-induced acute pancreatitis and associated intestinal injury in mice by inhibiting TLR4 signaling
2023, Journal of Nutritional Biochemistry
Acute pancreatitis (AP) is an acute inflammatory abdominal disease frequently associated with intestinal barrier dysfunction. Biochanin A (BCA), a dietary isoflavone, has gained increasing interest with its pronounced biological activities. However, its potential beneficial effects on AP have not been demonstrated. Herein, we explored the protective effect of BCA on caerulein-induced AP in BALB/c mice and underlying mechanisms. BCA alleviated AP as evidenced by reduced serum amylase and lipase levels, pancreatic edema, pancreatic myeloperoxidase activity, and improved pancreatic morphology. Amelioration of pancreatic damage by BCA was associated with reduced levels of tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and monocyte chemotactic protein-1 in both pancreas and colon. Moreover, BCA attenuated AP-associated barrier damage by upregulating the expression of tight junction proteins zonulin occluding (ZO)-1, ZO-2, occludin, and claudin-1. Concomitantly, the translocation of pathogenic bacteria Escherichia coli (E. coli) to pancreas was reduced by BCA. More importantly, reduction of E. coli dissemination by BCA inhibited the TLR4-MAPK/NF-κB signaling and NLRP3 inflammasome activation, thereby protecting against AP and related intestinal injury. Consistently, TLR4 inhibition by TAK-242 pre-treatment counteracted the anti-inflammatory effects of BCA in acinar cells. Taken together, our study extends beneficial effects of BCA to AP prevention, and dietary BCA supplement may be a potential strategy to safeguard AP.
Interplay between MAP kinases and tumor microenvironment: Opportunity for immunotherapy in pancreatic cancer
2023, Advances in Cancer Research
Pancreatic Ductal Adenocarcinoma (PDAC), commonly called pancreatic cancer, is aggressive cancer usually detected at a late stage, limiting treatment options with modest clinical responses. It is projected that by 2030, PDAC will be the second most common cause of cancer-related mortality in the United States. Drug resistance in PDAC is common and significantly affects patients' overall survival (OS). Oncogenic KRAS mutations are nearly uniform in PDAC, affecting over 90% of patients. However, effective drugs directed to target prevalent KRAS mutants in pancreatic cancer are not in clinical practice. Accordingly, efforts are continued on identifying alternative druggable target(s) or approaches to improve patient outcomes with PDAC. In most PDAC cases, the KRAS mutations turn-on the RAF-MEK-MAPK pathways, leading to pancreatic tumorigenesis. The MAPK signaling cascade (MAP4K → MAP3K → MAP2K → MAPK) plays a central role in the pancreatic cancer tumor microenvironment (TME) and chemotherapy resistance. The immunosuppressive pancreatic cancer TME is another unfavorable factor affecting the therapeutic efficacy of chemotherapy and immunotherapy. The immune checkpoint proteins (ICPs), including CTLA-4, PD-1, PD-L1, and PD-L2, are critical players in T cell dysfunction and pancreatic tumor cell growth. Here, we review the activation of MAPKs, a molecular trait of KRAS mutations and their impact on pancreatic cancer TME, chemoresistance, and expression of ICPs that could influence the clinical outcomes in PDAC patients. Therefore, understanding the interplay between MAPK pathways and TME could help to design rational therapy combining immunotherapy and MAPK inhibitors for pancreatic cancer treatment.
Metabolic reprogramming of immune cells in pancreatic cancer progression
2023, Biomedicine and Pharmacotherapy
Abnormal intracellular metabolism not only provides nutrition for tumor occurrence and development, but also sensitizes the function of various immune cells in the immune microenvironment to promote tumor immune escape. This review discusses the emerging role of immune cells in the progress of pancreatic cancer, acrossing metabolic reprogramming and key metabolic pathways present in different immune cell types. At present, the hotspots of metabolic reprogramming of immune cells in pancreatic cancer progression mainly focuses on glucose metabolism, lipid metabolism, tricarboxylic acid cycle and amino acid metabolism, which affect the function of anti-tumor immune cells and immunosuppressive cells in the microenvironment, such as macrophages, dendritic cells, T cells, myeloid-derived suppressor cells, neutrophils and B cells by a series of key metabolic signaling pathways, such as PI3K/AKT, mTOR, AMPK, HIF-1α, c-Myc and p53. Drugs that target the tumor metabolism pathways for clinical treatment of pancreatic cancer are also systematically elaborated, which may constitute food for others' projects involved in clinical anti-cancer research.

View all citing articles on Scopus

: 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.

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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

Roles for Adaptive and Innate Immune Cells in CP

Innate and Adaptive Immune Cells in PDA Development

Immunopathogenesis of PDA

Immune-Based Therapeutic Strategies

Lancet

Gastroenterology

Curr Opin Pharmacol

Best Pract Res Clin Gastroenterol

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Lancet

Human Immunol

Immunity

Gastroenterology

Am J Gastroenterol

Gastroenterology

Am J Gastroenterol

Am J Pathol

Gastroenterology

Pancreatology

Gastroenterology

Gastroenterology

Gastroenterology

Biochim Biophys Acta

Semin Cancer Biol

J Surg Res

Eur J Cell Biol

Cancer Cell

Cancer Cell

Mod Pathol

Surgery

Am J Pathol

J Surg Res

Cancer Cell

Cancer Cell

Cancer Cell

Protease activation during in vivo pancreatitis is dependent on calcineurin activation

Ame J Physiol Gastrointest Liver Physiol

Secretagogue-induced digestive enzyme activation and cell injury in rat pancreatic acini

Am J Physiol

A novel role for leucocytes in determining the severity of acute pancreatitis

Gut

Long-term follow-up after the first episode of acute alcoholic pancreatitis: time course and risk factors for recurrence

Scand J Gastroenterol

Natural history of acute pancreatitis: a long-term population-based study

Am J Gastroenterol

Progression from acute to chronic pancreatitis: prognostic factors, mortality, and natural course

Pancreas

Long-term prognosis of acute pancreatitis in Japan

Clin Gastroenterol Hepatol

Natural history following the first attack of acute pancreatitis

Am J Gastroenterol

Alcoholic nonprogressive chronic pancreatitis: prospective long-term study of a large cohort with alcoholic acute pancreatitis (1976–1992)

Pancreas

Prognosis of acute and chronic pancreatitis—a 30-year follow-up of a Danish cohort

Danish Med Bull

The role of inflammatory cells in fostering pancreatic cancer cell growth and invasion

Front Physiol

Pancreatic ductal adenocarcinoma: a review of immunologic aspects

J Investig Med

Stromal biology and therapy in pancreatic cancer

Gut

Chronic pancreatitis, pancreatic adenocarcinoma and the black box in-between

Cell Res

Hereditary pancreatitis and secondary screening for early pancreatic cancer

Rocz Akad Med Bialymst

Biology of the Pancreas
Review
Role of Immune Cells and Immune-Based Therapies in Pancreatitis and Pancreatic Ductal Adenocarcinoma