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

• Published in: Journal of clinical oncology Vol. 25; no. 18; pp. 2546 - 2553
• Main Authors: FILIPAZZI, Paola, VALENTI, Roberta, HUBER, Veronica, PILLA, Lorenzo, CANESE, Paola, LERO, Manuela, CASTELLI, Chiara, MARIANI, Luigi, PARMIANI, Giorgio, RIVOLTINI, Licia
• Format: Journal Article
• Language: English
• Published: Baltimore, MD American Society of Clinical Oncology 20.06.2007; Lippincott Williams & Wilkins
• Subjects: Adult; Biological and medical sciences; Cancer Vaccines - immunology; Dermatology; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Granulocyte-Macrophage Colony-Stimulating Factor - immunology; Heat-Shock Proteins - immunology; HLA-DR Antigens - immunology; Humans; Male; Medical sciences; Melanoma - immunology; Melanoma - pathology; Melanoma - prevention & control; Myeloid Cells - immunology; Neoplasm Metastasis; Phenotype; T-Lymphocytes, Regulatory - immunology; Treatment Outcome; Tumors; Tumors of the skin and soft tissue. Premalignant lesions; Antineoplastic agent; Human; Granulocyte; Stimulation; Vaccine; Malignant tumor; Myeloid cell; Blood cell; Cancerology; Modulation; Malignant melanoma; Suppressor; Macrophage
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2006.08.5829

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. 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. 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. 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.