title: IFN-alpha skews monocytes into CD56+-expressing dendritic cells with potent functional activities in vitro and in vivo.
abstract: The antitumor effect of IFN-alpha is mediated by the activation of CTLs, NK cells, and the generation of highly potent Ag-presenting dendritic cells (IFN-DCs). In this study, we show that IFN-DCs generated in vitro from monocytes express CD56 on their surface, a marker which has been thought to be specific for NK cells. FACS analyses of CD56(+) and CD56(-) IFN-DCs showed a nearly identical pattern for most of the classical DC markers. Importantly, however, only CD56(+) IFN-DCs exhibited cytolytic activity up to 24% that could almost completely be blocked (-81%) after coincubation with anti-TRAIL. Intracytoplasmatic cytokine staining revealed that the majority of IFN-DCs independently of their CD56 expression were IFN-gamma positive as well. In contrast, CD56(+) IFN-DCs showed stronger capacity in stimulating allogenic T cells compared with CD56(-) IFN-DC. Based on these results, five patients with metastasized medullary thyroid carcinoma were treated for the first time with monocyte-derived tumor Ag-pulsed IFN-DCs. After a long term follow-up (in mean 37 mo) all patients are alive. Immunohistochemical analyses of delayed-type hypersensitivity skin reaction showed a strong infiltration with CD8(+) cells. In two patients no substantial change in tumor morphology was detected. Importantly, by analyzing PBMCs, these patients also showed an increase of Ag-specific IFN-gamma-secreting T cells. In summary, we here describe for the first time that cytotoxic activity of IFN-DCs is mainly mediated by an IFN-DC subset showing partial phenotypic and functional characteristics of NK cells. These cells represent another mechanism of the antitumor effect induced by IFN-alpha.
authors.affiliation: Endocrine Cancer Center, Department of Endocrinology, Diabetes, and Rheumatology, University Hospital, Moorenstrasse 5, Duesseldorf, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Papewalis
authors.forename: Benedikt
authors.initials: B
authors.lastname: Jacobs
authors.forename: Margret
authors.initials: M
authors.lastname: Wuttke
authors.forename: Evelyn
authors.initials: E
authors.lastname: Ullrich
authors.forename: Thomas
authors.initials: T
authors.lastname: Baehring
authors.forename: Roland
authors.initials: R
authors.lastname: Fenk
authors.forename: Holger S
authors.initials: HS
authors.lastname: Willenberg
authors.forename: Sven
authors.initials: S
authors.lastname: Schinner
authors.forename: Mathias
authors.initials: M
authors.lastname: Cohnen
authors.forename: Jochen
authors.initials: J
authors.lastname: Seissler
authors.forename: Kai
authors.initials: K
authors.lastname: Zacharowski
authors.forename: Werner A
authors.initials: WA
authors.lastname: Scherbaum
authors.forename: Matthias
authors.initials: M
authors.lastname: Schott
mesh_terms: D000938:Antigen-Presenting Cells / Q000276:immunology; D019002:CD56 Antigen / Q000032:analysis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D018276:Carcinoma, Medullary / Q000628:therapy*; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation*; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000276:immunology; D016898:Interferon-alpha / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000628:therapy*; D014611:Vaccination
chemical_list: D019002:CD56 Antigen; D016898:Interferon-alpha; D053221:TNF-Related Apoptosis-Inducing Ligand