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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 8

The αGalCer/sCD1d–anti-HER2 fusion protein redirects iNKT, NK, and T cells to HER2-expressing lung tumors and specifically localizes at the tumor site.

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The αGalCer/sCD1d–anti-HER2 fusion protein redirects iNKT, NK, and T cel...
To study tumor targeting, mice were grafted with 700,000 B16-HER2 cells i.v., and systemic treatment, as described in Figure 4, was started 10 days after the tumor graft. For BrdU-incorporation, mice were injected i.p. with 1 mg BrdU on day 10, and BrdU was added to the drinking water throughout the whole experiment. Two days after the third injection, mice were sacrificed, lymphocytes were isolated from lungs, spleen, and PBMCs and stained with anti-NK1.1–PE, anti-CD3–FITC, and anti-BrdU–APC. Proliferation of iNKT, NK, and CD3 T cells is shown as percent of BrdU-positive cells in the respective population. (A) Dot plots with numbers indicating the percent of BrdU-positive iNKT, NK, and T cells isolated from lung tissue and (B) graphs of BrdU-incorporation in iNKT, NK, and CD3 T cells from lungs, spleen, and PBMC expressed as fold increase of BrdU-positive cells compared with control group. (C) Biodistribution study with radiolabeled sCD1d molecules. Mice were grafted s.c. on each flank with 1 × 106 of either B16-HER2 or B16 wt cells. On day 8, 2 groups of mice were injected with equimolar amounts of either 125I-labeled αGalCer/sCD1d or αGalCer/sCD1d–anti-HER2. Twenty-four hours later, mice were sacrificed and radioactivity was measured in tumors and normal tissues. Results are expressed as percent of injected dose per gram of tissue. Mean ± SD of 3 mice per group. *P < 0.05 for αGalCer/sCD1d–anti-HER2 in B16-HER2 tumors versus B16 wt tumors; **P < 0.02 for αGalCer/sCD1d–anti-HER2 versus αGalCer/sCD1d in B16-HER2 tumors.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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