Abstract
BackgroundBlood and spleen expansion of immature myeloid cells (IMCs) might compromise the immune response to cancer. We studied in vivo circulating and splenic T lymphocyte and IMC subsets in patients with benign and malignant pancreatic diseases. We ascertained in vitro whether pancreatic adenocarcinoma (PDAC)-associated IMC subsets are induced by tumor-derived soluble factors and whether they are immunosuppressive focusing on the inhibitory co-stimulatory molecules PDL1 and CTLA4.Methodology and Principal Findings103 pancreatic and/or splenic surgical patients were enrolled including 52 PDAC, 10 borderline and 10 neuroendocrine tumors (NETs). Lymphocytes and IMCs were analysed by flow cytometry in blood, in spleen and in three PDAC cell conditioned (CM) or non conditioned PBMC. PDL1 and CTLA4 were studied in 30 splenic samples, in control and conditioned PBMC. IMCs were FACS sorted and co-coltured with allogenic T lymphocytes. In PDAC a reduction was found in circulating CD8+ lymphocytes (p = 0.004) and dendritic cells (p = 0.01), which were reduced in vitro by one PDAC CM (Capan1; p = 0.03). Blood myeloid derived suppressive cells (MDSCs) CD33+CD14−HLA-DR− were increased in PDAC (p = 0.022) and were induced in vitro by BxPC3 CM. Splenic dendritic cells had a higher PDL1 expression (p = 0.007), while CD33+CD14+HLA-DR− IMCs had a lower CTLA4 expression (p = 0.029) in PDAC patients. In vitro S100A8/A9 complex, one of the possible inflammatory mediators of immune suppression in PDAC, induced PDL1 (p = 0.018) and reduced CTLA4 expression (p = 0.028) among IMCs. IMCs not expressing CTLA4 were demonstrated to be immune suppressive.ConclusionIn PDAC circulating dendritic and cytotoxic T cells are reduced, while MDSCs are increased and this might favour tumoral growth and progression. The reduced CTLA4 expression found among splenic IMCs of PDAC patients was demonstrated to characterize an immune suppressive phenotype and to be consequent to the direct exposure of myeloid cells to pancreatic cancer derived products, S100A8/A9 complex in particular.
Highlights
IntroductionMetastases to distant organs, invasion of adjacent organs and angioinvasion characterize exocrine and endocrine pancreatic tumors [1,2], the metastatic switch depending on the accumulation of genetic and epigenetic alterations within the tumor cells, which detach from the primary site and migrate into the circulatory system to become embedded in a secondary site [3]
The reduced CTLA4 expression found among splenic immature myeloid cells (IMCs) of pancreatic adenocarcinoma (PDAC) patients was demonstrated to characterize an immune suppressive phenotype and to be consequent to the direct exposure of myeloid cells to pancreatic cancer derived products, S100A8/A9 complex in particular
Metastases to distant organs, invasion of adjacent organs and angioinvasion characterize exocrine and endocrine pancreatic tumors [1,2], the metastatic switch depending on the accumulation of genetic and epigenetic alterations within the tumor cells, which detach from the primary site and migrate into the circulatory system to become embedded in a secondary site [3]
Summary
Metastases to distant organs, invasion of adjacent organs and angioinvasion characterize exocrine and endocrine pancreatic tumors [1,2], the metastatic switch depending on the accumulation of genetic and epigenetic alterations within the tumor cells, which detach from the primary site and migrate into the circulatory system to become embedded in a secondary site [3]. Inadequate immune response to cancer cells, a widely debated issue phenomenon, may enable primary tumor growth and metastasis [3] This failure may depend on the ability of tumors, including pancreatic ductal adenocarcinoma (PDAC), the fourth leading cause of cancer-related death in the US [6], to escape immune recognition and destruction through the loss or downregulation of the antigen presenting MHC molecules [7], or through the reduction in the capacity of the MHC to complex with antigenic peptides [8]. We ascertained in vitro whether pancreatic adenocarcinoma (PDAC)-associated IMC subsets are induced by tumor-derived soluble factors and whether they are immunosuppressive focusing on the inhibitory costimulatory molecules PDL1 and CTLA4
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