Abstract
The anatomic location and immunologic characteristics of brain tumors result in strong lymphocyte suppression. Consequently, conventional immunotherapies targeting CD8 T cells are ineffective against brain tumors. Tumor cells escape immunosurveillance by various mechanisms and tumor cell metabolism can affect the metabolic states and functions of tumor-infiltrating lymphocytes. Here, we discovered that brain tumor cells had a particularly high demand for oxygen, which affected γδ T cell-mediated antitumor immune responses but not those of conventional T cells. Specifically, tumor hypoxia activated the γδ T cell protein kinase A pathway at a transcriptional level, resulting in repression of the activatory receptor NKG2D. Alleviating tumor hypoxia reinvigorated NKG2D expression and the antitumor function of γδ T cells. These results reveal a hypoxia-mediated mechanism through which brain tumors and γδ T cells interact and emphasize the importance of γδ T cells for antitumor immunity against brain tumors.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis
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Brain Neoplasms / genetics
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Brain Neoplasms / immunology*
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Brain Neoplasms / metabolism
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Brain Neoplasms / pathology
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CD8 Antigens / genetics
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CD8 Antigens / metabolism
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Cell Line, Tumor
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Coculture Techniques
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Cyclic AMP-Dependent Protein Kinases / metabolism
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Cytotoxicity, Immunologic*
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Gene Expression Regulation, Neoplastic
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Genes, T-Cell Receptor delta
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Glioblastoma / genetics
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Glioblastoma / immunology*
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Glioblastoma / metabolism
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Glioblastoma / pathology
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Humans
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Intraepithelial Lymphocytes / immunology*
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Intraepithelial Lymphocytes / metabolism
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Intraepithelial Lymphocytes / pathology
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Lymphocytes, Tumor-Infiltrating / immunology*
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Lymphocytes, Tumor-Infiltrating / metabolism
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Lymphocytes, Tumor-Infiltrating / pathology
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Inbred NOD
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Mice, Knockout
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Mice, Nude
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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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Phenotype
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Signal Transduction
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Tumor Escape*
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Tumor Hypoxia
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Tumor Microenvironment*
Substances
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CD8 Antigens
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CD8 antigen, alpha chain
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KLRK1 protein, human
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NK Cell Lectin-Like Receptor Subfamily K
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Cyclic AMP-Dependent Protein Kinases