IFN-alpha skews monocytes into CD56+-expressing dendritic cells with potent functional activities in vitro and in vivo.
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.
Papewalis
Claudia
C
Endocrine Cancer Center, Department of Endocrinology, Diabetes, and Rheumatology, University Hospital, Moorenstrasse 5, Duesseldorf, Germany.
Jacobs
Benedikt
B
Wuttke
Margret
M
Ullrich
Evelyn
E
Baehring
Thomas
T
Fenk
Roland
R
Willenberg
Holger S
HS
Schinner
Sven
S
Cohnen
Mathias
M
Seissler
Jochen
J
Zacharowski
Kai
K
Scherbaum
Werner A
WA
Schott
Matthias
M
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
D019002:CD56 Antigen; D016898:Interferon-alpha; D053221:TNF-Related Apoptosis-Inducing Ligand