Identification of a new subset of myeloid suppressor cells in peripheral blood of melanoma patients with modulation by a granulocyte-macrophage colony-stimulation factor-based antitumor vaccine

Paola Filipazzi, Roberta Valenti, Veronica Huber, Lorenzo Pilla, Paola Canese, Manuela Iero, Chiara Castelli, Luigi Mariani, Giorgio Parmiani, Licia Rivoltini

Research output: Contribution to journalArticle

Abstract

Purpose: Phenotypic and functional features of myeloid suppressor cells (MSC), which are known to serve as critical regulators of antitumor T-cell responses in tumor-bearing mice, are still poorly defined in human cancers. Here, we analyzed myeloid subsets with suppressive activity present in peripheral blood of metastatic melanoma patients and evaluated their modulation by a granulocyte-macrophage colony-stimulating factor (GM-CSF) -based antitumor vaccine. Patients and Methods: Stage IV metastatic melanoma patients (n = 16) vaccinated with autologous tumor-derived heat shock protein peptide complex gp96 (HSPPC-96) and low-dose GM-CSF provided pre- and post-treatment whole blood specimens. Peripheral-blood mononuclear cells (PBMCs) were analyzed by flow cytometry, separated into cellular subsets, and used for in vitro proliferation assays. PBMCs from stage-matched metastatic melanoma patients (n = 12) treated with non-GM-CSF-based vaccines (ie, HSPPC-96 alone or interferon alfa/melanoma-derived peptides) or sex- and age-matched healthy donors (n = 16) were also analyzed for comparison. Results: The lack of or low HLA-DR expression was found to identify a CD14+ cell subset highly suppressive of lymphocyte functions. CD14+HLA-DR-/lo cells were significantly expanded in all metastatic melanoma patients, whereas they were undetectable in healthy donors. Suppressive activity was mediated by transforming growth factor beta (TGF-β), whereas no involvement of the arginase and inducible nitric oxide synthase pathways could be detected. CD14+HLA-DR-/lo cells, as well as spontaneous ex vivo release and plasma levels of TGF-β, were augmented after administration of the HSPPC-96/GM-CSF vaccine. No enhancement of the CD14+-mediated suppressive activity was found in patients receiving non-GM-CSF-based vaccines. Conclusion: CD14+HLA-DR-/lo cells exerting TGF-β-mediated immune suppression represent a new subset of MSC potentially expandable by the administration of GM-CSF-based vaccines in metastatic melanoma patients.

Original languageEnglish
Pages (from-to)2546-2553
Number of pages8
JournalJournal of Clinical Oncology
Volume25
Issue number18
DOIs
Publication statusPublished - Jun 20 2007

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Myeloid Cells
Granulocytes
Melanoma
Vaccines
Macrophages
HLA-DR Antigens
Granulocyte-Macrophage Colony-Stimulating Factor
Heat-Shock Proteins
Transforming Growth Factor beta
Peptides
Macrophage Colony-Stimulating Factor
Blood Cells
Tissue Donors
Arginase
Neoplasms
Nitric Oxide Synthase Type II
Interferon-alpha
Flow Cytometry
Lymphocytes
T-Lymphocytes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Identification of a new subset of myeloid suppressor cells in peripheral blood of melanoma patients with modulation by a granulocyte-macrophage colony-stimulation factor-based antitumor vaccine. / Filipazzi, Paola; Valenti, Roberta; Huber, Veronica; Pilla, Lorenzo; Canese, Paola; Iero, Manuela; Castelli, Chiara; Mariani, Luigi; Parmiani, Giorgio; Rivoltini, Licia.

In: Journal of Clinical Oncology, Vol. 25, No. 18, 20.06.2007, p. 2546-2553.

Research output: Contribution to journalArticle

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abstract = "Purpose: Phenotypic and functional features of myeloid suppressor cells (MSC), which are known to serve as critical regulators of antitumor T-cell responses in tumor-bearing mice, are still poorly defined in human cancers. Here, we analyzed myeloid subsets with suppressive activity present in peripheral blood of metastatic melanoma patients and evaluated their modulation by a granulocyte-macrophage colony-stimulating factor (GM-CSF) -based antitumor vaccine. Patients and Methods: Stage IV metastatic melanoma patients (n = 16) vaccinated with autologous tumor-derived heat shock protein peptide complex gp96 (HSPPC-96) and low-dose GM-CSF provided pre- and post-treatment whole blood specimens. Peripheral-blood mononuclear cells (PBMCs) were analyzed by flow cytometry, separated into cellular subsets, and used for in vitro proliferation assays. PBMCs from stage-matched metastatic melanoma patients (n = 12) treated with non-GM-CSF-based vaccines (ie, HSPPC-96 alone or interferon alfa/melanoma-derived peptides) or sex- and age-matched healthy donors (n = 16) were also analyzed for comparison. Results: The lack of or low HLA-DR expression was found to identify a CD14+ cell subset highly suppressive of lymphocyte functions. CD14+HLA-DR-/lo cells were significantly expanded in all metastatic melanoma patients, whereas they were undetectable in healthy donors. Suppressive activity was mediated by transforming growth factor beta (TGF-β), whereas no involvement of the arginase and inducible nitric oxide synthase pathways could be detected. CD14+HLA-DR-/lo cells, as well as spontaneous ex vivo release and plasma levels of TGF-β, were augmented after administration of the HSPPC-96/GM-CSF vaccine. No enhancement of the CD14+-mediated suppressive activity was found in patients receiving non-GM-CSF-based vaccines. Conclusion: CD14+HLA-DR-/lo cells exerting TGF-β-mediated immune suppression represent a new subset of MSC potentially expandable by the administration of GM-CSF-based vaccines in metastatic melanoma patients.",
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T1 - Identification of a new subset of myeloid suppressor cells in peripheral blood of melanoma patients with modulation by a granulocyte-macrophage colony-stimulation factor-based antitumor vaccine

AU - Filipazzi, Paola

AU - Valenti, Roberta

AU - Huber, Veronica

AU - Pilla, Lorenzo

AU - Canese, Paola

AU - Iero, Manuela

AU - Castelli, Chiara

AU - Mariani, Luigi

AU - Parmiani, Giorgio

AU - Rivoltini, Licia

PY - 2007/6/20

Y1 - 2007/6/20

N2 - Purpose: Phenotypic and functional features of myeloid suppressor cells (MSC), which are known to serve as critical regulators of antitumor T-cell responses in tumor-bearing mice, are still poorly defined in human cancers. Here, we analyzed myeloid subsets with suppressive activity present in peripheral blood of metastatic melanoma patients and evaluated their modulation by a granulocyte-macrophage colony-stimulating factor (GM-CSF) -based antitumor vaccine. Patients and Methods: Stage IV metastatic melanoma patients (n = 16) vaccinated with autologous tumor-derived heat shock protein peptide complex gp96 (HSPPC-96) and low-dose GM-CSF provided pre- and post-treatment whole blood specimens. Peripheral-blood mononuclear cells (PBMCs) were analyzed by flow cytometry, separated into cellular subsets, and used for in vitro proliferation assays. PBMCs from stage-matched metastatic melanoma patients (n = 12) treated with non-GM-CSF-based vaccines (ie, HSPPC-96 alone or interferon alfa/melanoma-derived peptides) or sex- and age-matched healthy donors (n = 16) were also analyzed for comparison. Results: The lack of or low HLA-DR expression was found to identify a CD14+ cell subset highly suppressive of lymphocyte functions. CD14+HLA-DR-/lo cells were significantly expanded in all metastatic melanoma patients, whereas they were undetectable in healthy donors. Suppressive activity was mediated by transforming growth factor beta (TGF-β), whereas no involvement of the arginase and inducible nitric oxide synthase pathways could be detected. CD14+HLA-DR-/lo cells, as well as spontaneous ex vivo release and plasma levels of TGF-β, were augmented after administration of the HSPPC-96/GM-CSF vaccine. No enhancement of the CD14+-mediated suppressive activity was found in patients receiving non-GM-CSF-based vaccines. Conclusion: CD14+HLA-DR-/lo cells exerting TGF-β-mediated immune suppression represent a new subset of MSC potentially expandable by the administration of GM-CSF-based vaccines in metastatic melanoma patients.

AB - Purpose: Phenotypic and functional features of myeloid suppressor cells (MSC), which are known to serve as critical regulators of antitumor T-cell responses in tumor-bearing mice, are still poorly defined in human cancers. Here, we analyzed myeloid subsets with suppressive activity present in peripheral blood of metastatic melanoma patients and evaluated their modulation by a granulocyte-macrophage colony-stimulating factor (GM-CSF) -based antitumor vaccine. Patients and Methods: Stage IV metastatic melanoma patients (n = 16) vaccinated with autologous tumor-derived heat shock protein peptide complex gp96 (HSPPC-96) and low-dose GM-CSF provided pre- and post-treatment whole blood specimens. Peripheral-blood mononuclear cells (PBMCs) were analyzed by flow cytometry, separated into cellular subsets, and used for in vitro proliferation assays. PBMCs from stage-matched metastatic melanoma patients (n = 12) treated with non-GM-CSF-based vaccines (ie, HSPPC-96 alone or interferon alfa/melanoma-derived peptides) or sex- and age-matched healthy donors (n = 16) were also analyzed for comparison. Results: The lack of or low HLA-DR expression was found to identify a CD14+ cell subset highly suppressive of lymphocyte functions. CD14+HLA-DR-/lo cells were significantly expanded in all metastatic melanoma patients, whereas they were undetectable in healthy donors. Suppressive activity was mediated by transforming growth factor beta (TGF-β), whereas no involvement of the arginase and inducible nitric oxide synthase pathways could be detected. CD14+HLA-DR-/lo cells, as well as spontaneous ex vivo release and plasma levels of TGF-β, were augmented after administration of the HSPPC-96/GM-CSF vaccine. No enhancement of the CD14+-mediated suppressive activity was found in patients receiving non-GM-CSF-based vaccines. Conclusion: CD14+HLA-DR-/lo cells exerting TGF-β-mediated immune suppression represent a new subset of MSC potentially expandable by the administration of GM-CSF-based vaccines in metastatic melanoma patients.

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