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J Immunol. 2014 Jul 15;193(2):961-9. doi: 10.4049/jimmunol.1303029. Epub 2014 Jun 9.

Targeted delivery of α-galactosylceramide to CD8α+ dendritic cells optimizes type I NKT cell-based antitumor responses.

Author information

1
Institut Pasteur de Lille, Centre d'Infection et d'Immunité de Lille, F-59019 Lille, France; Université Lille Nord de France, F-59000 Lille, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8204, F-59021 Lille, France; INSERM, U1019, F-59019 Lille, France; Institut Fédératif de Recherche 142, F-59019 Lille, France;
2
Department of Endocrinology, Leiden University Medical Center, 2333 Leiden, The Netherlands; and.
3
Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7199, Université de Strasbourg, F-67401 Illkirch Cedex, France.
4
Institut Pasteur de Lille, Centre d'Infection et d'Immunité de Lille, F-59019 Lille, France; Université Lille Nord de France, F-59000 Lille, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8204, F-59021 Lille, France; INSERM, U1019, F-59019 Lille, France; Institut Fédératif de Recherche 142, F-59019 Lille, France; francois.trottein@pasteur-lille.fr.

Abstract

Immunotherapy aiming at enhancing innate and acquired host immunity is a promising approach for cancer treatment. The invariant NKT (iNKT) cell ligand α-galactosylceramide (α-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 α-GalCer by DCs not only triggers optimal primary iNKT cell stimulation, but also maintains secondary iNKT cell activation after challenge. Furthermore, targeted delivery of α-GalCer to CD8α(+) DCs, by means of anti-DEC205 decorated nanoparticles, enhances iNKT cell-based transactivation of NK cells, DCs, and γδ T cells. We report that codelivery of α-GalCer and protein Ag to CD8α(+) DCs triggers optimal Ag-specific Ab and cytotoxic CD8(+) T cell responses. Finally, we show that targeting nanoparticles containing α-GalCer and Ag to CD8α(+) DCs promotes potent antitumor responses, both in prophylactic and in therapeutic settings. Our data may have important implications in tumor immunotherapy and vaccine development.

PMID:
24913977
DOI:
10.4049/jimmunol.1303029
[Indexed for MEDLINE]
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