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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

From the Unit of Immunotherapy of Human Tumors and Unit of Medical Statistics and Biometry, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Tumori, Milan, Italy

Address reprint requests to Licia Rivoltini, MD, Unit of Immunotherapy of Human Tumors, Istituto Nazionale per lo Studio e la Cura dei Tumori, Via Venezian 1, 20133, Milan, Italy; e-mail: licia.rivoltini{at}istitutotumori.mi.it

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

Supported by grants from the Italian Association for Cancer Research, Program No. 518234 from European Community, and Grant No. 530/F-A17 the Italy-USA Project. R.V. is a scholarship holder of the Italian Foundation for Cancer Research (Milan, Italy).

Presented in part at the 20th Annual Meeting of the International Society of Biological Therapy, November 10-13, 2005, Alexandria, VA, and the Keystone Symposium on Advances in the Understanding and Treatment of Melanoma, January 18-23, 2006, Santa Fe, NM.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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