Targeted Delivery of α-Galactosylceramide to CD8α+ Dendritic Cells Optimizes Type I NKT Cell-Based Antitumor Responses

Immunotherapy aiming at enhancing innate and acquired host immunity is a promising approach for cancer treatment. The invariant NKT (iNKT) cell ligand a-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 cellbased 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 a-GalCer to CD8 alpha(+) DCs, by means of anti-DEC205 decorated nanoparticles, enhances iNKT cell-based transactivation of NK cells, DCs, and gd T cells. We report that codelivery of a-GalCer and protein Ag to CD8 alpha+ DCs triggers optimal Ag-specific Ab and cytotoxic CD8 alpha(+) T cell responses. Finally, we show that targeting nanoparticles containing a-GalCer and Ag to CD8 alpha(+) DCs promotes potent antitumor responses, both in prophylactic and in therapeutic settings. Our data may have important implications in tumor immunotherapy and vaccine development.