Non‐glycosidic compounds can stimulate both human and mouse i NKT cells

• Published in: European journal of immunology 2016-05, Vol.46 (5), p.1224-1234
• Main Authors: Jukes, John‐Paul, Gileadi, Uzi, Ghadbane, Hemza, Yu, Ting‐Fong, Shepherd, Dawn, Cox, Liam R., Besra, Gurdyal S., Cerundolo, Vincenzo
• Format: Article
• Language: English
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.201546114

Invariant natural killer T ( i NKT) 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 i NKT 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 i NKT 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 i NKT‐cell activation compared with that of α‐GalCer, and are clinically relevant i NKT‐cell agonists.