Abstract
Immune cell infiltration varies widely between different glioblastomas (GBMs). The underlying mechanism, however, remains unknown. Here we show that TGF-beta regulates proliferation, migration, and tumorigenicity of mesenchymal GBM cancer stem cells (CSCs) in vivo and in vitro. In contrast, proneural GBM CSCs resisted TGF-beta due to TGFR2 deficiency. In vivo, a substantially increased infiltration of immune cells was observed in mesenchymal GBMs, while immune infiltrates were rare in proneural GBMs. On a functional level, proneural CSC lines caused a significantly stronger TGF-beta-dependent suppression of NKG2D expression on CD8(+) T and NK cells in vitro providing a mechanistic explanation for the reduced immune infiltration of proneural GBMs. Thus, the molecular subtype of CSCs TGF-beta-dependently contributes to the degree of immune infiltration.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Brain Neoplasms / immunology*
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Brain Neoplasms / pathology
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Cell Line, Tumor
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Cell Proliferation
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Gene Expression Regulation, Neoplastic
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Glioblastoma / immunology*
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Glioblastoma / pathology
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Humans
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Immunologic Factors / physiology
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Mice
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NK Cell Lectin-Like Receptor Subfamily K / genetics
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NK Cell Lectin-Like Receptor Subfamily K / metabolism
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Neoplasm Transplantation
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Neoplastic Stem Cells / immunology*
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Neoplastic Stem Cells / pathology
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Oligonucleotide Array Sequence Analysis
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Phosphorylation
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Protein Processing, Post-Translational
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Smad2 Protein / metabolism
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T-Lymphocytes, Cytotoxic / immunology*
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T-Lymphocytes, Cytotoxic / pathology
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Transcriptional Activation
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Transcriptome
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Transforming Growth Factor beta / physiology
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Tumor Burden / immunology
Substances
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Immunologic Factors
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NK Cell Lectin-Like Receptor Subfamily K
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SMAD2 protein, human
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Smad2 Protein
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Transforming Growth Factor beta