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Sustained activation and tumor targeting of NKT cells using a CD1d–anti-HER2–scFv fusion protein induce antitumor effects in mice
Kathrin Stirnemann, … , H. Robson MacDonald, Alena Donda
Kathrin Stirnemann, … , H. Robson MacDonald, Alena Donda
Published February 7, 2008
Citation Information: J Clin Invest. 2008;118(3):994-1005. https://doi.org/10.1172/JCI33249.
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Research Article Oncology Article has an altmetric score of 4

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

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Abstract

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 α-galactosylceramide (αGalCer) leads to short-lived iNKT cell activation followed, however, by long-term anergy, limiting its therapeutic use. In contrast, we demonstrated here that when αGalCer was loaded on a recombinant soluble CD1d molecule (αGalCer/sCD1d), repeated injections led to sustained iNKT and NK cell activation associated with IFN-γ secretion as well as DC maturation in mice. Most importantly, when αGalCer/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 αGalCer 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.

Authors

Kathrin Stirnemann, Jackeline F. Romero, Lucia Baldi, Bruno Robert, Valérie Cesson, Gurdyal S. Besra, Maurice Zauderer, Florian Wurm, Giampietro Corradin, Jean-Pierre Mach, H. Robson MacDonald, Alena Donda

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Figure 5

iNKT cells are required for the antitumor effect and are characterized by a sustained activation with TH1 bias.

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iNKT cells are required for the antitumor effect and are characterized b...
(A) The antitumor activity is lost in the absence of iNKT cells. C57BL/6 or CD1d–/– mice were grafted on the left flank with 700,000 B16-HER2 cells, and systemic treatment with the αGalCer/sCD1d–anti-HER2 was started 2 days later (40 μg/i.v. injection every 3 days). For each mouse strain, a group was left untreated. Results represent the kinetic of s.c. tumor growth (in mm3) as the mean ± SD of 4 mice per group. (B) Ex vivo IFNγ production by liver iNKT cells after several injections of αGalCer/sCD1d–anti-HER2 fusion. Liver lymphocytes were isolated 20 minutes after the sixth injection of PBS (control), αGalCer, or sCD1d–anti-HER2 protein, and cultured for 1 h. Cells were stained with anti-NK1.1–PE and anti-CD3–FITC, and intracellularly with anti-IFNγ–APC. Graph shows percent of IFNγ-producing iNKT (gated on NK1.1+ CD3+ cells). (C) Sustained IFNγ production by liver iNKT cells after several i.v. injections as indicated, followed by in vitro rechallenge with the same stimuli as in vivo. Liver lymphocytes were isolated 3 days after the fifth injection and restimulated in vitro for 6 hours. Naive mice were tested with αGalCer or αGalCer/sCD1d–anti-HER2. Cells were stained as described in B and results are expressed as fold increase of IFNγ-producing liver iNKT cells compared with the nonstimulated iNKT fraction derived from the same mouse. White bar, no in vitro stimulation; gray bar, in vitro αGalCer; black bar, in vitro sCD1d–anti-HER2. Results show the mean ± SD of 3 different experiments. *P < 0.03, **P < 0.005.

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