Sustained activation and tumor targeting of NKT cells using a CD1d-anti-HER2-scFv fusion protein induce antitumor effects in mice

J Clin Invest. 2008 Mar;118(3):994-1005. doi: 10.1172/JCI33249.


Invariant NKT (iNKT) cells are potent activators of DCs, NK cells, and T cells, and their antitumor activity has been well demonstrated. A single injection of the high-affinity CD1d ligand alpha-galactosylceramide (alphaGalCer) leads to short-lived iNKT cell activation followed, however, by long-term anergy, limiting its therapeutic use. In contrast, we demonstrated here that when alphaGalCer was loaded on a recombinant soluble CD1d molecule (alphaGalCer/sCD1d), repeated injections led to sustained iNKT and NK cell activation associated with IFN-gamma secretion as well as DC maturation in mice. Most importantly, when alphaGalCer/sCD1d was fused to a HER2-specific scFv antibody fragment, potent inhibition of experimental lung metastasis and established s.c. tumors was obtained when systemic treatment was started 2-7 days after the injection of HER2-expressing B16 melanoma cells. In contrast, administration of free alphaGalCer at this time had no effect. The antitumor activity of the CD1d-anti-HER2 fusion protein was associated with HER2-specific tumor localization and accumulation of iNKT, NK, and T cells at the tumor site. Targeting iNKT cells to the tumor site thus may activate a combined innate and adaptive immune response that may prove to be effective in cancer immunotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD1 / pharmacology*
  • Antigens, CD1d
  • Antineoplastic Agents / pharmacology*
  • Cytotoxicity, Immunologic
  • Dendritic Cells / immunology
  • Female
  • Galactosylceramides / pharmacology*
  • Immunoglobulin Fragments / pharmacology*
  • Interferon-gamma / biosynthesis
  • Killer Cells, Natural / immunology*
  • Lung Neoplasms / prevention & control
  • Lung Neoplasms / secondary
  • Lymphocyte Activation*
  • Melanoma, Experimental / drug therapy
  • Melanoma, Experimental / pathology
  • Mice
  • Mice, Inbred C57BL
  • Receptor, ErbB-2 / antagonists & inhibitors*
  • Receptor, ErbB-2 / immunology
  • Recombinant Fusion Proteins / pharmacology*


  • Antigens, CD1
  • Antigens, CD1d
  • Antineoplastic Agents
  • Galactosylceramides
  • Immunoglobulin Fragments
  • Recombinant Fusion Proteins
  • alpha-galactosylceramide
  • immunoglobulin Fv
  • Interferon-gamma
  • Receptor, ErbB-2