title: IFN-gamma-producing human invariant NKT cells promote tumor-associated antigen-specific cytotoxic T cell responses.
abstract: 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 alpha-galactosylceramide (alphaGC) 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 alphaGC-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-gamma 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-gamma. Furthermore, autologous IL-12-overexpressing dendritic cells, loaded with Ag as well as alphaGC, was superior in stimulating both iNKT cells and Ag-specific CTL. This study shows that IL-12-overexpressing allogeneic dendritic cells expand IFN-gamma-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 alphaGC.
authors.affiliation: Department of Pathology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands.
authors.forename: María
authors.initials: M
authors.lastname: Moreno
authors.forename: Johan W
authors.initials: JW
authors.lastname: Molling
authors.forename: Silvia
authors.initials: S
authors.lastname: von Mensdorff-Pouilly
authors.forename: René H M
authors.initials: RH
authors.lastname: Verheijen
authors.forename: Erik
authors.initials: E
authors.lastname: Hooijberg
authors.forename: Duco
authors.initials: D
authors.lastname: Kramer
authors.forename: Anneke W
authors.initials: AW
authors.lastname: Reurs
authors.forename: Alfons J M
authors.initials: AJ
authors.lastname: van den Eertwegh
authors.forename: B Mary E
authors.initials: BM
authors.lastname: von Blomberg
authors.forename: Rik J
authors.initials: RJ
authors.lastname: Scheper
authors.forename: Hetty J
authors.initials: HJ
authors.lastname: Bontkes
mesh_terms: D000208:Acute Disease; D018949:Antigens, CD1 / Q000235:genetics / Q000276:immunology; D055610:Antigens, CD1d; D019496:Cancer Vaccines / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D006367:HeLa Cells; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D007951:Leukemia, Myeloid / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D008545:Melanoma / Q000276:immunology*; D012190:Retroviridae / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D014161:Transduction, Genetic
chemical_list: D018949:Antigens, CD1; D055610:Antigens, CD1d; C526877:CD1D protein, human; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D007371:Interferon-gamma