Abstract
The use of type I interferons (IFNs) in cancer therapy has been limited by ineffective dosing and significant toxicity. Here, we exploited the tumor-homing ability of proangiogenic Tie2-expressing monocytes (TEMs) to deliver IFN-alpha to tumors. By transplanting hematopoietic progenitors transduced with a Tie2 promoter/enhancer-driven Ifna1 gene, we turned TEMs into IFN-alpha cell vehicles that efficiently targeted the IFN response to orthotopic human gliomas and spontaneous mouse mammary carcinomas and obtained significant antitumor responses and near complete abrogation of metastasis. TEM-mediated IFN-alpha delivery inhibited tumor angiogenesis and activated innate and adaptive immune cells but did not impair myelopoiesis and wound healing detectably. These results illustrate the therapeutic potential of gene- and cell-based IFN-alpha delivery and should allow the development of IFN treatments that more effectively treat cancer.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Line, Tumor
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Cell Proliferation*
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Cells, Cultured
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Female
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Genetic Therapy / methods*
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Glioma / genetics
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Glioma / immunology
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Glioma / metabolism
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Glioma / pathology
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Glioma / therapy*
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Hematopoiesis
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Hematopoietic Stem Cell Transplantation*
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Hematopoietic Stem Cells / metabolism*
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Humans
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Immunity, Innate
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Interferon-alpha / genetics
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Interferon-alpha / metabolism*
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Mammary Neoplasms, Experimental / genetics
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Mammary Neoplasms, Experimental / immunology
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Mammary Neoplasms, Experimental / metabolism
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Mammary Neoplasms, Experimental / pathology
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Mammary Neoplasms, Experimental / prevention & control*
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Mice
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Mice, Nude
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Mice, Transgenic
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Monocytes / metabolism*
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Monocytes / transplantation
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Neoplasm Metastasis
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Neovascularization, Pathologic / immunology
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Neovascularization, Pathologic / metabolism
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Neovascularization, Pathologic / prevention & control
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Promoter Regions, Genetic
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Receptor, TIE-2 / genetics
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Receptor, TIE-2 / metabolism*
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Recombinant Fusion Proteins / metabolism
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Time Factors
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Transduction, Genetic
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Wound Healing
Substances
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Interferon-alpha
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Recombinant Fusion Proteins
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Receptor, TIE-2