Abstract
Emerging evidence suggests a link between tumor hypoxia and immune suppression. In this study, we investigated the role of hypoxia-induced Nanog, a stemness-associated transcription factor, in immune suppression. We observed that hypoxia-induced Nanog correlated with the acquisition of stem cell-like properties in B16-F10 cells. We further show that Nanog was selectively induced in hypoxic areas of B16-F10 tumors. Stable short hairpin RNA-mediated depletion of Nanog, combined with melanocyte differentiation Ag tyrosinase-related protein-2 peptide-based vaccination, resulted in complete inhibition of B16-F10 tumor growth. Nanog targeting significantly reduced immunosuppressive cells (regulatory T cells and macrophages) and increased CD8(+) T effector cells in tumor bed in part by modulating TGF-β1 production. Additionally, Nanog regulated TGF-β1 under hypoxia by directly binding the TGF-β1 proximal promoter. Collectively, our data establish a novel functional link between hypoxia-induced Nanog and TGF-β1 regulation and point to a major role of Nanog in hypoxia-driven immunosuppression.
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 Hypoxia / genetics*
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Cell Line, Tumor
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Gene Expression Regulation, Neoplastic*
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Genetic Therapy
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Homeodomain Proteins / antagonists & inhibitors
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Homeodomain Proteins / biosynthesis
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Homeodomain Proteins / genetics
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Homeodomain Proteins / physiology*
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Immunotherapy
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Intramolecular Oxidoreductases / immunology
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Lymphocytes, Tumor-Infiltrating / immunology*
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Lymphopoiesis
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Macrophages / immunology*
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Melanoma, Experimental / genetics
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Melanoma, Experimental / immunology*
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Melanoma, Experimental / metabolism
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Melanoma, Experimental / therapy
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Mice, Inbred C57BL
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Nanog Homeobox Protein
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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Neoplastic Stem Cells / cytology*
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Neoplastic Stem Cells / enzymology
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Neoplastic Stem Cells / immunology
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Peptide Fragments / immunology
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Promoter Regions, Genetic
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RNA Interference
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RNA, Small Interfering
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Spheroids, Cellular
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T-Lymphocytes, Regulatory / immunology*
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Transforming Growth Factor beta1 / biosynthesis
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Transforming Growth Factor beta1 / genetics
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Transforming Growth Factor beta1 / metabolism
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Transforming Growth Factor beta1 / physiology*
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Tumor Escape / genetics
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Tumor Escape / immunology*
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Tumor Microenvironment
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Up-Regulation
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Vaccination
Substances
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Homeodomain Proteins
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Nanog Homeobox Protein
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Nanog protein, mouse
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Neoplasm Proteins
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Peptide Fragments
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RNA, Small Interfering
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Transforming Growth Factor beta1
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Intramolecular Oxidoreductases
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dopachrome isomerase