Abstract
Immune escape describes a critical event whereby tumor cells adopt an immunoresistant phenotype to escape adaptive surveillance. We show that expression of a pivotal negative regulator of T-cell function, B7-H1, correlates with PI(3) kinase activation in breast and prostate cancer patients. B7-H1-mediated immunoresistance can be attenuated by inhibitors of the PI(3) kinase pathway, and is dependent on S6K1-mediated translational regulation of B7-H1 protein. Breast and prostate carcinoma cells with activated PI(3) kinase lose the immunoresistant phenotype after treatment with B7-H1 siRNA. Conversely, breast and prostate carcinoma cells with minimal PI(3) kinase activation adopt an immunoresistant phenotype when engineered to overexpress B7-H1 protein. These observations describe a mechanism for immune escape from tumor dormancy in humans that relates to oncogenesis.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / enzymology*
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Adenocarcinoma / immunology
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Adenocarcinoma / pathology
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Antigens, CD / genetics
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Antigens, CD / physiology*
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B7-H1 Antigen
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Breast Neoplasms / enzymology*
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Breast Neoplasms / immunology
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Breast Neoplasms / pathology
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Cell Line, Tumor / drug effects
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Cell Line, Tumor / enzymology
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Cell Line, Tumor / immunology
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Female
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Gene Expression Regulation, Neoplastic
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Gene Knockdown Techniques
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Humans
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Male
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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PTEN Phosphohydrolase / physiology
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Phenotype
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Phosphatidylinositol 3-Kinases / physiology*
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Phosphoinositide-3 Kinase Inhibitors
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Prostatic Neoplasms / enzymology*
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Prostatic Neoplasms / immunology
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Prostatic Neoplasms / pathology
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Protein Kinase Inhibitors / pharmacology
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RNA, Small Interfering / pharmacology
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Recombinant Fusion Proteins / physiology
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Ribosomal Protein S6 Kinases / physiology
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T-Lymphocytes, Cytotoxic / immunology
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Tumor Escape / drug effects
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Tumor Escape / genetics
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Tumor Escape / immunology*
Substances
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Antigens, CD
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B7-H1 Antigen
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CD274 protein, human
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Neoplasm Proteins
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase Inhibitors
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RNA, Small Interfering
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Recombinant Fusion Proteins
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Ribosomal Protein S6 Kinases
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PTEN Phosphohydrolase
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PTEN protein, human