Abstract
Local immunosuppressive mechanisms shape the tumor microenvironment and contribute to carcinogenesis. In ovarian cancer such mechanisms have been shown to influence survival. Dendritic cells (DCs) are central immunity regulators and induce potent cytotoxic T-cell responses as well as peripheral tolerance depending on modulatory stimuli. Here, we show that ovarian cancer-derived glycodelin (Gd), a glycoprotein that physiologically modulates local immunity in early pregnancy, induces a tolerogenic DC phenotype. Gd was isolated with high performance liquid chromatography from the malignant ascites of ovarian cancer patients. DCs were generated from monocytes of healthy donors and exposed to Gd with or without an inflammatory stimulus (tumor necrosis factor-alpha and interleukin 1-beta). We investigated the effect of Gd on DC surface marker expression, endopinocytotic activity, cytokine profile, and lymphoproliferative activity. DCs that were exposed to Gd altered their phenotype as seen by a differential expression of costimulatory molecules, whereas expression of DC-specific intercellular adhesion molecule 3-grabbing nonintegrin, a marker of an immature phenotype, was increased. Functional data provided further evidence for the immature/tolerogenic properties of Gd-pretreated DCs. Antigen uptake was retained, production of interleukin-10 was increased, and lymphoproliferative activity was reduced. This effect was reversible by adding Gd-blocking antibodies. Gd, which is found in the malignant ascites of ovarian cancer patients, induces a tolerogenic phenotype in DC, thereby shaping an immunodeficient tumor micromilieu.
MeSH terms
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Antigen Presentation
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Antigens, CD / genetics
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Antigens, CD / immunology
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Antigens, CD / metabolism
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Antigens, Differentiation / genetics
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Antigens, Differentiation / immunology
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Antigens, Differentiation / metabolism
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Antigens, Neoplasm / immunology
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Antigens, Neoplasm / isolation & purification
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Antigens, Neoplasm / metabolism
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Cell Adhesion Molecules / genetics
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Cell Adhesion Molecules / immunology
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Cell Adhesion Molecules / metabolism
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Cell Differentiation / drug effects
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Cell Differentiation / immunology
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Cell Proliferation
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Cells, Cultured
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Chromatography, High Pressure Liquid
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Dendritic Cells / drug effects
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Dendritic Cells / immunology*
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Dendritic Cells / metabolism
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Dendritic Cells / pathology
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Female
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Gene Expression Regulation, Neoplastic*
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Glycodelin
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Glycoproteins / immunology*
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Glycoproteins / isolation & purification
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Glycoproteins / metabolism*
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Glycoproteins / pharmacology
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Humans
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Immune Tolerance
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Immunosuppressive Agents / immunology
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Immunosuppressive Agents / metabolism
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Immunosuppressive Agents / pharmacology
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Interferon-beta / metabolism
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Interleukin-10 / genetics
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Interleukin-10 / immunology
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Interleukin-10 / metabolism
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Leukocytes, Mononuclear / pathology
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Ovarian Neoplasms / genetics
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Ovarian Neoplasms / immunology
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Ovarian Neoplasms / metabolism*
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Ovarian Neoplasms / pathology
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Pregnancy
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Pregnancy Proteins / immunology*
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Pregnancy Proteins / isolation & purification
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Pregnancy Proteins / metabolism*
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Pregnancy Proteins / pharmacology
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Antigens, CD
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Antigens, Differentiation
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Antigens, Neoplasm
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Cell Adhesion Molecules
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Glycodelin
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Glycoproteins
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ICAM3 protein, human
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Immunosuppressive Agents
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PAEP protein, human
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Pregnancy Proteins
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Tumor Necrosis Factor-alpha
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Interleukin-10
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Interferon-beta