Pancreatic tumors and immature immunosuppressive myeloid cells in blood and spleen: role of inhibitory co-stimulatory molecules PDL1 and CTLA4. An in vivo and in vitro study

Autor: Dania Bozzato, Stefania Moz, Cosimo Sperti, Eliana Greco, Domenico Tamburrino, Massimo Falconi, Sara Teolato, Elisa Fadi, Gianpietro Semenzato, Daniela Basso, Elisa Gnatta, Carlo Federico Zambon, Paolo Pederzoli, Michela Pelloso, Paola Fogar, Mario Plebani, Giuseppe Basso, Sergio Pedrazzoli, Giuseppe De Franchis, Filippo Navaglia, Claudio Pasquali, Monica Facco, Andrea Padoan, Chiara Frasson
Přispěvatelé: Basso, D, Fogar, P, Falconi, Massimo, Fadi, E, Sperti, C, Frasson, C, Greco, E, Tamburrino, D, Teolato, S, Moz, S, Bozzato, D, Pelloso, M, Padoan, A, De Franchis, G, Gnatta, E, Facco, M, Zambon, Cf, Navaglia, F, Pasquali, C, Basso, G, Semenzato, G, Pedrazzoli, S, Pederzoli, P, Plebani, M.
Jazyk: angličtina
Rok vydání: 2013
Předmět:
Male
Myeloid
endocrine system diseases
Epidemiology
CD33
REGULATORY T-CELLS
SUPPRESSOR-CELLS
DENDRITIC CELLS
IMMUNE EVASION
CLINICAL-SIGNIFICANCE
CARCINOMA CELLS
CANCER
MICROENVIRONMENT
DIFFERENTIATION
ADENOCARCINOMA
lcsh:Medicine
Cell Separation
B7-H1 Antigen
Gastrointestinal Cancers
Basic Cancer Research
Cytotoxic T cell
CTLA-4 Antigen
Endocrine Tumors
lcsh:Science
Immune Response
Aged
80 and over
Multidisciplinary
T Cells
Chemistry
Middle Aged
Flow Cytometry
medicine.anatomical_structure
Oncology
Medicine
Female
Cancer Epidemiology
Research Article
Adult
Immune Cells
CD14
Immunology
Spleen
Gastroenterology and Hepatology
In Vitro Techniques
Immunophenotyping
Young Adult
Pancreatic Cancer
Immune system
Pancreatic cancer
Gastrointestinal Tumors
medicine
Humans
Biology
Pancreas
Aged
DNA Primers
Base Sequence
lcsh:R
Cancers and Neoplasms
medicine.disease
Pancreatic Neoplasms
Pancreatitis
Cancer research
Clinical Immunology
lcsh:Q
CD8
Zdroj: PLoS ONE, Vol 8, Iss 1, p e54824 (2013)
PLoS ONE
Popis: Background Blood 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 findings 103 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. Conclusion In 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.
Databáze: OpenAIRE
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