Pancreatic adenocarcinoma exerts systemic effects on the peripheral blood myeloid and plasmacytoid dendritic cells: an indicator of disease severity?

Abstract

BackgroundDendritic cells (DCs) isolated from tumor bearing animals or from individuals with solid tumors display functional abnormalities and the DC impairment has emerged as one mechanism for tumor evasion from the control of the immune system. Ductal pancreatic adenocarcinoma (PDAC), the most common pancreatic cancer, is recognized as a very aggressive cancer type with a mortality that almost matches the rate of incidence.MethodsWe examined the systemic influence ductal pancreatic adenocarcinoma (PDAC) exerted on levels of peripheral blood DCs and inflammatory mediators in comparison to the effects exerted by other pancreatic tumors, chronic pancreatitis, and age-matched controls.ResultsAll groups examined, including PDAC, had decreased levels of myeloid DCs (MDC) and plasmacytoid DCs (PDC) and enhanced apoptosis in these cells as compared to controls. We found elevated levels of PGE2 and CXCL8 in subjects with PDAC, and chronic pancreatitis. Levels of these inflammatory factors were in part restored in PDAC after tumor resection, whereas the levels of DCs were impaired in the majority of these patients ~12 weeks after tumor removal. Our results prove that solid pancreatic tumors, including PDAC, systemically affect blood DCs. The impairments do not seem to be tumor-specific, since similar results were obtained in subjects with chronic pancreatitis. Furthermore, we found that PDAC patients with a survival over 2 years had significant higher levels of blood DCs compared to patients with less than one year survival.ConclusionsOur findings points to the involvement of inflammation in the destruction of the blood MDCs and PDCs. Furthermore, the preservation of the blood DCs compartment in PDAC patients seems to benefit their ability to control the disease and survival.

Quantitative and Functional Alterations of Plasmacytoid Dendritic Cells Contribute to Immune Tolerance in Ovarian Cancer

“…In our study, we found that blood pDC and mDC were significantly decreased compared with HDs, consistent with prior studies in breast (13) and pancreatic cancer (18) Figure 7. Ovarian tumor microenvironment inhibits IFN-a production by healthy pDC through TGF-b and TNF-a cooperation.…”

“…Several types of cancers are characterized by impaired function and numbers of pDC (13,16), but correlations of pDC frequency with disease progression in cancer remain poorly studied. Infiltration of primary breast carcinomas by pDC is variable and their presence at high density is associated with poor clinical outcome (17) and their depletion in the blood of pancreatic cancer patients is correlated with reduced survival (18).…”

slanDCs selectively accumulate in carcinoma-draining lymph nodes and marginate metastatic cells

“…We also observed that the uptake of tumour-cell-derived apoptotic bodies by slanDCs is Dectin-1/CLEC7A-and CD18-independent, and that IFNg-activated slanDCs cultured with fluorescent-labelled, alive HT29 cells contained intracellular apoptotic bodies likely derived from the slanDC-mediated killing of HT29 cells, as previously shown 16 . Circulating mDCs and pDCs from cancer patients are frequently reduced in number and functionally defective [30][31][32][33][34] . Recent works have proved the prognostic significance of the immune response to colon carcinomas (CCR) 35,36 .…”

Hepatitis B and C virus infections as possible risk factor for pancreatic adenocarcinoma

“…[244][245][246] Inactivation and/or epigenetic modification of many tumour suppressor genes, including p16INK4A via HCV-core, NS5A and NS4A proteins [244,213] MICRO-RNA perturbations in pancreatic and liver tissues PAC HBV-related hepatitis/HCC HCV-related HCC of cancer-specific effector T cells with protective properties and the presence of MDCS has been observed. Several mediators, released in this complex stromal microenvironment, exert an immunosuppressive activity and affect several mechanisms, which are involved in development of a proper and effective response of immune system.…”

“…PAC HBV HCV Serum Interleukin-6 (IL-6) Increased [135,136,142] Increased (enhancement of cellular transcription factor NF-IL6 production and HBV-DNA replication) [199] Increased (enhancement of cellular transcription factor NFIL6production) [213] Serum Interleukin-8 (IL- 8) Increased (promotion of neoangiogenesis,neoplastic cell proliferation and invasion) [146] Increased (enhancement of viral replication) [202] Increased (enhancement of viral replication via interferon effect inhibition) [201] Prostaglandin-E2 (PGE2) Cyclooxygenase-2 (COX-2)…”