Enhanced antimetastatic effect of fetal liver kinase 1 extracellular domain and interferon-gamma fusion gene-modified dendritic cell vaccination
| Autor: | Axel Heiser, Dietrich Kabelitz, Jianping Pan, Matthias Marget, J Steinmann |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
Cytotoxicity
Immunologic Genetic enhancement Melanoma Experimental Biology CD8-Positive T-Lymphocytes Transfection Cancer Vaccines Fusion gene Carcinoma Lewis Lung Interferon-gamma Mice Immunity Antimetastatic Agent Genetics Extracellular medicine Vaccines DNA Animals Interferon gamma Neoplasm Metastasis Molecular Biology Immunity Cellular Neovascularization Pathologic Kinase Dendritic cell Dendritic Cells Neoplasms Experimental Vascular Endothelial Growth Factor Receptor-2 Cell biology Mice Inbred C57BL Electroporation Immunology Molecular Medicine Female Immunization medicine.drug Plasmids |
| Zdroj: | Gene therapy. 12(9) |
| ISSN: | 0969-7128 |
| Popis: | Antiangiogenic immunotherapy benefits from targeting antigens expressed on genetically stable endothelial cells and represents a novel modality for cancer treatment. Vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2, also known as flk1 in mouse) mediated VEGF signaling is the key rate-limiting step in angiogenesis. Blockade of the flk1 signaling pathway can significantly inhibit tumor cell-induced angiogenesis and lead to inhibition of tumor metastasis. Interferon-gamma (IFN-gamma) is a pleiotropic cytokine, which plays an important role in cell-mediated immunity. In this study, we tested the hypothesis that immunization of mice with soluble flk1 (sflk1) and IFN-gamma fusion gene-transfected dendritic cells (DC-sflk1-IFN-gamma) would induce a potent CTL response to flk1, leading to an inhibition of tumor-induced angiogenesis and metastasis. Our data show that immunization of mice with sflk1 gene-modified DC (DC-sflk1) could induce a CTL response to flk1, leading to profound inhibition of tumor-cell-induced angiogenesis and metastasis. However, more striking antimetastatic effects were achieved through induction of enhanced CTL response to flk1 and augmented inhibition of angiogenesis when mice were immunized with DC-sflk1-IFN-gamma. In vivo T-cell subset depletion experiments showed that CD8(+) T cells were mainly responsible for this antimetastatic effect. Our data extend the notion that DC-based active antiangiogenic immunotherapy is an effective modality for cancer treatment, and show that the antitumor efficacy of this strategy can be improved by combination with DC-based cytokine immunotherapy. |
| Databáze: | OpenAIRE |
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