Non-glycosidic compounds can stimulate both human and mouse iNKT cells

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• 作者：John-Paul Jukes ; Uzi Gileadi ; Hemza Ghadbane ; Ting-Fong Yu ; Dawn Shepherd ; Liam R. Cox ; Gurdyal S. Besra and Vincenzo Cerundolo
• 关键词：-Galactosylceramide ; CD1d ; Immunotherapy ; iNKT cell ; Tumor
• 刊名：European Journal of Immunology
• 出版年：2016
• 出版时间：May 2016
• 年：2016
• 卷：46
• 期：5
• 页码：1224-1234
• 全文大小：744K
• ISSN：1521-4141

文摘

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 -galactosylceramide (-GalCer), achieving an enhanced T-cell response at lower concentrations compared with -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 -GalCer, and are clinically relevant iNKT-cell agonists.