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-Producing Human Invariant NKT Cells Promote Tumor-Associated Antigen-Specific Cytotoxic T Cell Responses1
* Department of Pathology,
Department of Obstetrics and Gynecology, and
Department of Medical Oncology of the VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands.
CD1d-restricted invariant NKT (iNKT) cells can enhance immunity to cancer or prevent autoimmunity, depending on the cytokine profile secreted. Antitumor effects of the iNKT cell ligand 
-galactosylceramide (GC) and iNKT cell adoptive transfer have been demonstrated in various tumor models. Together with reduced numbers of iNKT cells in cancer patients, which have been linked to poor clinical outcome, these data suggest that cancer patients may benefit from therapy aiming at iNKT cell proliferation and activation. Herein we present results of investigations on the effects of human iNKT cells on Ag-specific CTL responses. iNKT cells were expanded using GC-pulsed allogeneic DC derived from the acute myeloid leukemia cell line MUTZ-3, transduced with CD1d to enhance iNKT cell stimulation, and with IL-12 to stimulate type 1 cytokine production. Enhanced activation and increased IFN-
production was observed in iNKT cells, irrespective of CD4 expression, upon stimulation with IL-12-overexpressing dendritic cells. IL-12-stimulated iNKT cells strongly enhanced the MART-1 (melanoma Ag recognized by T cell 1)-specific CD8+ CTL response, which was dependent on iNKT cell-derived IFN-. Furthermore, autologous IL-12-overexpressing dendritic cells, loaded with Ag as well as GC, was superior in stimulating both iNKT cells and Ag-specific CTL. This study shows that IL-12-overexpressing allogeneic dendritic cells expand IFN--producing iNKT cells, which may be more effective against tumors in vivo. Furthermore, the efficacy of autologous Ag-loaded DC vaccines may well be enhanced by IL-12 overexpression and loading with GC.
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 Dutch Cancer Society Grant VU2002-2607.
2 Current address: Nijmegen Center for Molecular Life Sciences (NCMLS), PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
3 Current address: Department of Woman and Baby, Division of Surgical and Oncological Gynaecology, University Medical Center Utrecht, Utrecht, The Netherlands.
4 Address correspondence and reprint requests to Dr. H. J. Bontkes, Department of Hematology, VU University Medical Center, De Boelelaan 1117, 1081HV Amsterdam, The Netherlands. E-mail address: hj.bontkes{at}vumc.nl
5 Abbreviations used in this paper: iNKT, invariant NKT cells; GC, -galactosylceramide; DC, dendritic cell; iNKTIL-12, IL-12-stimulated iNKT cells; IRES, internal ribosome entry site; MART-1, melanoma Ag recognized by T cell 1; MoDC, monocyte-derived dendritic cell; MUTZ-3 (M3), CD1d-transduced M3; M3CD1d, CD1d-transduced M3; M312CD1d, IL-12 and CD1d double-transduced M3; NGFR, nerve growth factor receptor; TAA, tumor-associated Ag; Tm, tetramer.
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