Semi Mature Blood Dendritic Cells Exist in Patients with Ductal Pancreatic Adenocarcinoma Owing to Inflammatory Factors Released from the Tumor

Abstract

BackgroundMuch evidence exists regarding the fact that blood DCs, both myeloid DCs (MDCs) and plasmacytoid DCs (PDCs), are negatively affected in different types of cancer, with both reduced numbers and impaired functionality. Functional impairment of DCs in patients with pancreatic ductal adenocarcinoma (PDAC), may contribute to the poor clinical outcome. The aim of this study was to examine the effects PDAC had on blood DCs and elucidate the underlying mechanism responsible for the DC impairment.Methodology/Principal FindingsWe examined the systemic influence PDAC exerted on blood DCs by ex vivo measuring numerous activation and maturation markers expressed on these cells. Furthermore, the effect patient plasma and the inflammatory factors CXCL8 and PGE2 had on purified MDCs and PDCs from healthy donors was assessed and compared to the DCs existing in PDAC patients. We found a partial maturation of the blood MDCs and PDCs in PDAC patients with significantly enhanced expression of CD83, CD40, B7H3, PDL-1, CCR6, and CCR7 and decreased expression of ICOSL, and DCIR. These changes lead to impairment in their immunostimulatory function. Furthermore, chronic pancreatitis gave rise to DCs with similar semi-mature phenotype as seen in PDAC. Low expression of ICOSL was associated with poor prognosis. We found that the mechanism underlying this semi-maturation of DCs was inflammatory factors existing in the PDAC patients' plasma. Of note, PGE2, which is elevated PDAC patient plasma, was one contributing factor to the changes seen in MDCs and PDCs phenotype.Conclusion/SignificanceOur findings point to a role for the systemic inflammation in transforming blood MDCs and PDCs into semi-mature cells in PDAC patients and we show a correlation between maturation status and clinical outcome. Thus, means to preserve a functional blood DC compartment in PDAC patients by diminishing the inflammation could facilitate their ability to control the disease and improve survival.

p53MVA Therapy in Patients with Refractory Gastrointestinal Malignancies Elevates p53-Specific CD8+ T-cell Responses

“…The primary ligand, PDL-1, has been detected on tumor cells, hence the PD-1/PDL-1 pathway can hamper anti-tumor immune responses (42). In addition, blood DC express elevated levels of PD-L1 in cancer patients (43). This could reduce the effectiveness of viral based vaccines, which require uptake and expression within DC.…”

Role of immune cells in pancreatic cancer from bench to clinical application

“…1D). [57,58] When DCs and tumor interact, levels of cytokines and chemokines responsible for DCs suppression, such as IL-10, TGF-β, and granulocyte-macrophage colony-stimulating factor (GM-CSF), are increased, but those for DCs activation are inhibited mainly through activation of signal transducer and activator of transcription 3 (STAT3). [59] STAT3 ablation can lead to maturation of DCs and restore DC functions in tumor-bearing mice.…”

Antitumor immune response of dendritic cells (DCs) expressing tumor‐associated antigens derived from induced pluripotent stem cells: In comparison to bone marrow‐derived DCs

“…An additional problem is that the number of DCs is reduced in the peripheral blood and the function of DCs is impaired in cancer patients. 9,10 Therefore, obtaining a sufficient number of functional DCs remains a serious problem for the application of DC vaccine therapy.…”