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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.

Original publication

DOI

10.1002/eji.201546114

Type

Journal article

Journal

Eur J Immunol

Publication Date

05/2016

Volume

46

Pages

1224 - 1234

Keywords

CD1d, Immunotherapy, Tumor, iNKT cell, α-Galactosylceramide, Animals, Antigens, CD1d, Ceramides, Cytokines, Galactosylceramides, Humans, Immunotherapy, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Natural Killer T-Cells, Neoplasms, Sugar Alcohols