Sustained activation and tumor targeting of NKT cells using a CD1d-anti-HER2-scFv fusion protein induce antitumor effects in mice.
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.
Stirnemann
Kathrin
K
Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
Romero
Jackeline F
JF
Baldi
Lucia
L
Robert
Bruno
B
Cesson
Valérie
V
Besra
Gurdyal S
GS
Zauderer
Maurice
M
Wurm
Florian
F
Corradin
Giampietro
G
Mach
Jean-Pierre
JP
Macdonald
H Robson
HR
Donda
Alena
A
D000818:Animals; D018949:Antigens, CD1 / Q000494:pharmacology*; D055610:Antigens, CD1d; D000970:Antineoplastic Agents / Q000494:pharmacology*; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D005699:Galactosylceramides / Q000494:pharmacology*; D007128:Immunoglobulin Fragments / Q000494:pharmacology*; D007371:Interferon-gamma / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology*; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D008213:Lymphocyte Activation; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*
D018949:Antigens, CD1; D055610:Antigens, CD1d; D000970:Antineoplastic Agents; D005699:Galactosylceramides; D007128:Immunoglobulin Fragments; D007371:Interferon-gamma; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; C493154:alpha-galactosylceramide; C055966:immunoglobulin Fv