Targeted delivery of alpha-galactosylceramide to CD8alpha+ dendritic cells optimizes type I NKT cell-based antitumor responses.
Fiche publication
Date publication
juillet 2014
Auteurs
Membres identifiés du Cancéropôle Est :
Dr FRISCH Benoit
Tous les auteurs :
Macho-Fernandez E, Cruz LJ, Ghinnagow R, Fontaine J, Bialecki E, Frisch B, Trottein F, Faveeuw C
Lien Pubmed
Résumé
Immunotherapy aiming at enhancing innate and acquired host immunity is a promising approach for cancer treatment. The invariant NKT (iNKT) cell ligand alpha-galactosylceramide (alpha-GalCer) holds great promise in cancer therapy, although several concerns limit its use in clinics, including the uncontrolled response it promotes when delivered in a nonvectorized form. Therefore, development of delivery systems to in vivo target immune cells might be a valuable option to optimize iNKT cell-based antitumor responses. Using dendritic cell (DC)-depleted mice, DC transfer experiments, and in vivo active cell targeting, we show that presentation of alpha-GalCer by DCs not only triggers optimal primary iNKT cell stimulation, but also maintains secondary iNKT cell activation after challenge. Furthermore, targeted delivery of alpha-GalCer to CD8alpha(+) DCs, by means of anti-DEC205 decorated nanoparticles, enhances iNKT cell-based transactivation of NK cells, DCs, and gammadelta T cells. We report that codelivery of alpha-GalCer and protein Ag to CD8alpha(+) DCs triggers optimal Ag-specific Ab and cytotoxic CD8(+) T cell responses. Finally, we show that targeting nanoparticles containing alpha-GalCer and Ag to CD8alpha(+) DCs promotes potent antitumor responses, both in prophylactic and in therapeutic settings. Our data may have important implications in tumor immunotherapy and vaccine development.
Référence
J Immunol. 2014 Jul 15;193(2):961-9