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Skews Monocytes into CD56+-Expressing Dendritic Cells with Potent Functional Activities In Vitro and In Vivo1
* Endocrine Cancer Center, Department of Endocrinology, Diabetes, and Rheumatology, University Hospital, Duesseldorf, Germany;
Unité 805, Institut National de la Santé et de la Recherche Médicale, Institute Gustave Roussy, Villejuif, France;
Department of Haematology, Oncology, and Clinical Immunology, University Hospital, Duesseldorf, Germany;
Department of Radiology, University Hospital, Duesseldorf, Germany;
¶ Department of Internal Medicine, Ludwig-Maximilians-University, Munich, Germany; and
|| Department of Anaesthesia, Bristol Royal Infirmary, Bristol, United Kingdom
The antitumor effect of IFN-
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-
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--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-.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Deutsche Forschungsgemeinschaft (DFG; Scho 781/4-1), the American Thyroid Association (ThyCa), and by grant given by the Medical Faculty of Heinrich-Heine-University (Duesseldorf, Germany). E.U. received a fellowship from the DFG.
2 C.P. and B.J. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Matthias Schott, Endocrine Cancer Center, Department of Endocrinology, Diabetes, and Rheumatology, University Hospital, Moorenstrasse 5, 40225 Duesseldorf, Germany. E-mail address: matthias.schott{at}uni-duesseldorf.de
4 Abbreviations used in this paper: pDC, plasmacytoid dendritic cell; IKDC, IFN-producing killer DC; MTC, medullary thyroid carcinoma; CT, computed tomography; DTH, delayed-type hypersensitivity; IFN-DC, IFN- generated DC.
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