Enhanced antimetastatic effect of fetal liver kinase 1 extracellular domain and interferon-gamma fusion gene-modified dendritic cell vaccination.
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.
Pan
J
J
Institute of Immunology, Zhejiang University, Hangzhou, People's Republic of China.
Heiser
A
A
Marget
M
M
Steinmann
J
J
Kabelitz
D
D
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology*; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000276:immunology / Q000556:secondary; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology; D018274:Electroporation; D005260:Female; D007111:Immunity, Cellular; D007114:Immunization / Q000379:methods; D007371:Interferon-gamma / Q000235:genetics* / Q000276:immunology; D008546:Melanoma, Experimental / Q000098:blood supply / Q000276:immunology / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000276:immunology; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000517:prevention & control*; D010957:Plasmids; D014162:Transfection; D019444:Vaccines, DNA / Q000276:immunology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics* / Q000276:immunology
D019496:Cancer Vaccines; D019444:Vaccines, DNA; D007371:Interferon-gamma; D040301:Vascular Endothelial Growth Factor Receptor-2