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

Eur J Immunol. 2016 May;46(5):1224-34. doi: 10.1002/eji.201546114. Epub 2016 Mar 1.

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.

Keywords: CD1d; Immunotherapy; Tumor; iNKT cell; α-Galactosylceramide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD1d / immunology
  • Ceramides / chemical synthesis
  • Ceramides / chemistry
  • Ceramides / immunology*
  • Ceramides / pharmacology
  • Cytokines / immunology
  • Galactosylceramides / immunology
  • Galactosylceramides / pharmacology
  • Humans
  • Immunotherapy
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred C57BL
  • Natural Killer T-Cells / drug effects
  • Natural Killer T-Cells / immunology*
  • Natural Killer T-Cells / physiology
  • Neoplasms / immunology
  • Sugar Alcohols / chemical synthesis
  • Sugar Alcohols / chemistry
  • Sugar Alcohols / immunology*
  • Sugar Alcohols / pharmacology

Substances

  • Antigens, CD1d
  • CD1d antigen, mouse
  • Ceramides
  • Cytokines
  • Galactosylceramides
  • Sugar Alcohols
  • alpha-galactosylceramide
  • threitol