期刊
EUROPEAN JOURNAL OF IMMUNOLOGY
卷 46, 期 5, 页码 1224-1234出版社
WILEY-BLACKWELL
DOI: 10.1002/eji.201546114
关键词
alpha-Galactosylceramide; CD1d; Immunotherapy; iNKT cell; Tumor
类别
资金
- Wellcome Trust [084923/Z/08/Z, 084923/B/08/Z]
- Ludwig Institute for Cancer Research
- Medical Research Council
- Cancer Research UK [C399/A2291]
- BBSRC
- Royal Society Wolfson Research Merit Award
- Wellcome Trust
- Cancer Research UK [17722] Funding Source: researchfish
- Medical Research Council [MC_UU_12010/1, G1000800, G1000800e] Funding Source: researchfish
- MRC [MC_UU_12010/1, G1000800] Funding Source: UKRI
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 alpha-galactosylceramide (alpha-GalCer), achieving an enhanced T-cell response at lower concentrations compared with alpha-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 alpha-GalCer, and are clinically relevant iNKT-cell agonists.
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