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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / chemistry
  • Antibodies / immunology
  • Antigen Presentation / immunology
  • Antigens, CD / immunology
  • CD8 Antigens / immunology*
  • CD8 Antigens / metabolism
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Cell Line, Tumor
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Drug Delivery Systems / methods
  • Galactosylceramides / administration & dosage
  • Galactosylceramides / chemistry
  • Galactosylceramides / immunology*
  • Lectins, C-Type / immunology
  • Lymphocyte Activation / immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Minor Histocompatibility Antigens
  • Nanoparticles / administration & dosage
  • Nanoparticles / chemistry
  • Natural Killer T-Cells / immunology*
  • Natural Killer T-Cells / metabolism
  • Neoplasms, Experimental / immunology*
  • Neoplasms, Experimental / pathology
  • Neoplasms, Experimental / therapy
  • Receptors, Antigen, T-Cell, gamma-delta / immunology
  • Receptors, Antigen, T-Cell, gamma-delta / metabolism
  • Receptors, Cell Surface / immunology
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • T-Lymphocytes, Cytotoxic / immunology
  • T-Lymphocytes, Cytotoxic / metabolism
  • Tumor Burden / immunology


  • Antibodies
  • Antigens, CD
  • CD8 Antigens
  • CD8 antigen, alpha chain
  • DEC-205 receptor
  • Galactosylceramides
  • Lectins, C-Type
  • Minor Histocompatibility Antigens
  • Receptors, Antigen, T-Cell, gamma-delta
  • Receptors, Cell Surface
  • alpha-galactosylceramide