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

Daniela Basso, Paola Fogar, Massimo Falconi, Elisa Fadi, Cosimo Sperti, Chiara Frasson, Eliana Greco, Domenico Tamburrino, Sara Teolato, Stefania Moz, Dania Bozzato, Michela Pelloso, Andrea Padoan, Giuseppe de Franchis, Elisa Gnatta, Monica Facco, Carlo Federico Zambon, Filippo Navaglia, Claudio Pasquali, Giuseppe BassoGianpietro Semenzato, Sergio Pedrazzoli, Paolo Pederzoli, Mario Plebani

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Article numbere54824
JournalPLoS One
Volume8
Issue number1
DOIs
Publication statusPublished - Jan 30 2013

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immunosuppressive agents
T-cells
Myeloid Cells
Immunosuppressive Agents
blood cells
splenocytes
in vitro studies
Tumors
Blood
Spleen
Lymphocytes
immatures
HLA-DR Antigens
Molecules
neoplasms
Neoplasms
Flow cytometry
cells
T-Lymphocytes
Dendritic Cells

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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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. / Basso, Daniela; Fogar, Paola; Falconi, Massimo; Fadi, Elisa; Sperti, Cosimo; Frasson, Chiara; Greco, Eliana; Tamburrino, Domenico; Teolato, Sara; Moz, Stefania; Bozzato, Dania; Pelloso, Michela; Padoan, Andrea; de Franchis, Giuseppe; Gnatta, Elisa; Facco, Monica; Zambon, Carlo Federico; Navaglia, Filippo; Pasquali, Claudio; Basso, Giuseppe; Semenzato, Gianpietro; Pedrazzoli, Sergio; Pederzoli, Paolo; Plebani, Mario.

In: PLoS One, Vol. 8, No. 1, e54824, 30.01.2013.

Research output: Contribution to journalArticle

Basso, D, Fogar, P, Falconi, M, 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 2013, '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', PLoS One, vol. 8, no. 1, e54824. https://doi.org/10.1371/journal.pone.0054824
Basso, Daniela ; Fogar, Paola ; Falconi, Massimo ; Fadi, Elisa ; Sperti, Cosimo ; Frasson, Chiara ; Greco, Eliana ; Tamburrino, Domenico ; Teolato, Sara ; Moz, Stefania ; Bozzato, Dania ; Pelloso, Michela ; Padoan, Andrea ; de Franchis, Giuseppe ; Gnatta, Elisa ; Facco, Monica ; Zambon, Carlo Federico ; Navaglia, Filippo ; Pasquali, Claudio ; Basso, Giuseppe ; Semenzato, Gianpietro ; Pedrazzoli, Sergio ; Pederzoli, Paolo ; Plebani, Mario. / 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. In: PLoS One. 2013 ; Vol. 8, No. 1.
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abstract = "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.",
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T1 - Pancreatic Tumors and Immature Immunosuppressive Myeloid Cells in Blood and Spleen

T2 - Role of Inhibitory Co-Stimulatory Molecules PDL1 and CTLA4. An In Vivo and In Vitro Study

AU - Basso, Daniela

AU - Fogar, Paola

AU - Falconi, Massimo

AU - Fadi, Elisa

AU - Sperti, Cosimo

AU - Frasson, Chiara

AU - Greco, Eliana

AU - Tamburrino, Domenico

AU - Teolato, Sara

AU - Moz, Stefania

AU - Bozzato, Dania

AU - Pelloso, Michela

AU - Padoan, Andrea

AU - de Franchis, Giuseppe

AU - Gnatta, Elisa

AU - Facco, Monica

AU - Zambon, Carlo Federico

AU - Navaglia, Filippo

AU - Pasquali, Claudio

AU - Basso, Giuseppe

AU - Semenzato, Gianpietro

AU - Pedrazzoli, Sergio

AU - Pederzoli, Paolo

AU - Plebani, Mario

PY - 2013/1/30

Y1 - 2013/1/30

N2 - 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.

AB - 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.

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