Abstract
Tumor-Associated Macrophages (TAMs) are abundantly present in the stroma of solid tumors and modulate several important biological processes, such as neoangiogenesis, cancer cell proliferation and invasion, and suppression of adaptive immune responses. Myeloid C-type lectin receptors (CLRs) constitute a large family of transmembrane carbohydrate-binding receptors that recognize pathogens as well as endogenous glycoproteins. Several lines of evidence demonstrate that some CLRs can inhibit the immune response. In this study we investigated TAM-associated molecules potentially involved in their immune suppressive activity. We found that TAMs isolated from human ovarian carcinoma samples predominantly express the CLRs Dectin-1, MDL-1, MGL, DCIR, and most abundantly the Mannose Receptor (MR). Components of carcinomatous ascites and purified tumoral mucins (CA125 and TAG-72) bound the MR and induced its internalization. MR engagement by tumoral mucins and by an agonist anti-MR antibody modulated cytokine production by TAM toward an immune-suppressive profile: increase of IL-10, absence of IL-12, and decrease of the Th1-attracting chemokine CCL3. This study highlights that tumoral mucin-mediated ligation of the MR on infiltrating TAM may contribute to their immune suppressive phenotype.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptive Immunity / drug effects
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Adaptive Immunity / immunology
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Antibodies / immunology
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Antibodies / pharmacology
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Antigens, Neoplasm / immunology
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Antigens, Neoplasm / metabolism
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CA-125 Antigen / genetics
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CA-125 Antigen / immunology
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CA-125 Antigen / metabolism
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Chemokine CCL3 / immunology
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Chemokine CCL3 / metabolism
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Endocytosis / immunology
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Enzyme-Linked Immunosorbent Assay
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Female
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Flow Cytometry
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Gene Expression Profiling
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Glycoproteins / immunology
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Glycoproteins / metabolism
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Humans
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Immunohistochemistry
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Interferon-gamma / pharmacology
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Interleukin-10 / immunology
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Interleukin-10 / metabolism
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Interleukin-10 / pharmacology
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Interleukin-12 / immunology
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Interleukin-12 / metabolism
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Lectins, C-Type / genetics
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Lectins, C-Type / immunology*
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Lectins, C-Type / metabolism
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Lipopolysaccharides / pharmacology
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Macrophages / drug effects
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Macrophages / immunology*
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Macrophages / metabolism
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Mannose Receptor
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Mannose-Binding Lectins / genetics
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Mannose-Binding Lectins / immunology*
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Mannose-Binding Lectins / metabolism
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Membrane Proteins / genetics
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Membrane Proteins / immunology
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Membrane Proteins / metabolism
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Mucins / immunology*
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Mucins / metabolism
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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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Receptors, Cell Surface / genetics
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Receptors, Cell Surface / immunology*
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Receptors, Cell Surface / metabolism
Substances
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Antibodies
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Antigens, Neoplasm
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CA-125 Antigen
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Chemokine CCL3
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Glycoproteins
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Lectins, C-Type
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Lipopolysaccharides
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MUC16 protein, human
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Mannose Receptor
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Mannose-Binding Lectins
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Membrane Proteins
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Mucins
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Receptors, Cell Surface
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tumor-associated antigen 72
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Interleukin-10
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Interleukin-12
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Interferon-gamma