title: Non-glycosidic compounds can stimulate both human and mouse iNKT cells.
abstract: Invariant natural killer T (iNKT) cells recognize CD1d/glycolipid complexes and upon activation with synthetic agonists display immunostimulatory properties. We have previously described that the non-glycosidic CD1d-binding lipid, threitolceramide (ThrCer) activates murine and human iNKT cells. Here, we show that incorporating the headgroup of ThrCer into a conformationally more restricted 6- or 7-membered ring results in significantly more potent non-glycosidic analogs. In particular, ThrCer 6 was found to promote strong anti-tumor responses and to induce a more prolonged stimulation of iNKT cells than does the canonical α-galactosylceramide (α-GalCer), achieving an enhanced T-cell response at lower concentrations compared with α-GalCer both in vitro, using human iNKT-cell lines and in vivo, using C57BL/6 mice. Collectively, these studies describe novel non-glycosidic ThrCer-based analogs that have improved potency in iNKT-cell activation compared with that of α-GalCer, and are clinically relevant iNKT-cell agonists.
authors.affiliation: MRC Human Immunology Unit, Radcliffe Department of Medicine, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
authors.forename: John-Paul
authors.initials: JP
authors.lastname: Jukes
authors.affiliation: MRC Human Immunology Unit, Radcliffe Department of Medicine, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
authors.forename: Uzi
authors.initials: U
authors.lastname: Gileadi
authors.affiliation: MRC Human Immunology Unit, Radcliffe Department of Medicine, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
authors.forename: Hemza
authors.initials: H
authors.lastname: Ghadbane
authors.affiliation: School of Biosciences, University of Birmingham, Edgbaston, Birmingham, UK.|School of Chemistry, University of Birmingham, Edgbaston, Birmingham, UK.
authors.forename: Ting-Fong
authors.initials: TF
authors.lastname: Yu
authors.affiliation: MRC Human Immunology Unit, Radcliffe Department of Medicine, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
authors.forename: Dawn
authors.initials: D
authors.lastname: Shepherd
authors.affiliation: School of Chemistry, University of Birmingham, Edgbaston, Birmingham, UK.
authors.forename: Liam R
authors.initials: LR
authors.lastname: Cox
authors.affiliation: School of Biosciences, University of Birmingham, Edgbaston, Birmingham, UK.
authors.forename: Gurdyal S
authors.initials: GS
authors.lastname: Besra
authors.affiliation: MRC Human Immunology Unit, Radcliffe Department of Medicine, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cerundolo
mesh_terms: D000818:Animals; D055610:Antigens, CD1d / Q000276:immunology; D002518:Ceramides / Q000138:chemical synthesis / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology; D016207:Cytokines / Q000276:immunology; D005699:Galactosylceramides / Q000276:immunology / Q000494:pharmacology; D006801:Humans; D007167:Immunotherapy; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D055611:Natural Killer T-Cells / Q000187:drug effects / Q000276:immunology* / Q000502:physiology; D009369:Neoplasms / Q000276:immunology; D013402:Sugar Alcohols / Q000138:chemical synthesis / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology
chemical_list: D055610:Antigens, CD1d; C584692:CD1d antigen, mouse; D002518:Ceramides; D016207:Cytokines; D005699:Galactosylceramides; D013402:Sugar Alcohols; C493154:alpha-galactosylceramide; C003460:threitol
keywords: CD1d; Immunotherapy; Tumor; iNKT cell; α-Galactosylceramide