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.

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-beta), 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-beta, 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-beta-mediated immune suppression represent a new subset of MSC potentially expandable by the administration of GM-CSF-based vaccines in metastatic melanoma patients.

• Authors: Paola Filipazzi, Roberta Valenti, Veronica Huber, Lorenzo Pilla, Paola Canese, Manuela Iero, Chiara Castelli, Luigi Mariani, Giorgio Parmiani, Licia Rivoltini
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 25 Issue 18 Pg. 2546-53 (Jun 20 2007) ISSN: 1527-7755 [Electronic] United States
• PMID: 17577033 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cancer Vaccines
• HLA-DR Antigens
• Heat-Shock Proteins
• Granulocyte-Macrophage Colony-Stimulating Factor

Topics

• Adult
• Cancer Vaccines (immunology)
• Enzyme-Linked Immunosorbent Assay
• Female
• Flow Cytometry
• Granulocyte-Macrophage Colony-Stimulating Factor (immunology)
• HLA-DR Antigens (immunology)
• Heat-Shock Proteins (immunology)
• Humans
• Male
• Melanoma (immunology, pathology, prevention & control)
• Myeloid Cells (immunology)
• Neoplasm Metastasis
• Phenotype
• T-Lymphocytes, Regulatory (immunology)
• Treatment Outcome