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      Mixed-polarization phenotype of ascites-associated macrophages in human ovarian carcinoma: Correlation of CD163 expression, cytokine levels and early relapse

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          Abstract

          Ovarian cancer is typically accompanied by the occurrence of malignant ascites containing large number of macrophages. It has been suggested that these tumor-associated macrophages (TAMs) are skewed to alternative polarization (M2) and thereby play an essential role in therapy resistance and metastatic spread. In our study, we have investigated the nature, regulation and clinical correlations of TAM polarization in serous ovarian cancer. Macrophage polarization markers on TAMs and ascites cytokine levels were analyzed for 30 patients and associated with relapse-free survival (RFS) in a prospective study with 20 evaluable patients. Surface expression of the M2 marker CD163 on TAMs was inversely associated with RFS ( p < 0.01). However, global gene expression profiles determined for 17 of these patients revealed a mixed-polarization phenotype unrelated to the M1/M2 classification. CD163 surface expression also correlated with the ascites levels of IL-6 and IL-10 ( p < 0.05), both cytokines induced CD163 expression, and their ascites levels showed a clear inverse association with RFS ( p < 0.01). These findings define a subgroup of patients with high CD163 expression, high IL-6 and/or IL-10 levels and poor clinical outcome.

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          Most cited references32

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          Altered macrophage differentiation and immune dysfunction in tumor development.

          Tumors require a constant influx of myelomonocytic cells to support the angiogenesis and stroma remodeling needed for their growth. This is mediated by tumor-derived factors, which cause sustained myelopoiesis and the accumulation and functional differentiation of myelomonocytic cells, most of which are macrophages, at the tumor site. An important side effect of the accumulation and functional differentiation of these cells is that they can induce lymphocyte dysfunction. A complete understanding of the complex interplay between neoplastic and myelomonocytic cells might offer novel targets for therapeutic intervention aimed at depriving tumor cells of important growth support and enhancing the antitumor immune response.
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            Regulation of scavenger receptor CD163 expression in human monocytes and macrophages by pro- and antiinflammatory stimuli.

            CD163, also referred to as M130, a member of the scavenger receptor cysteine-rich family (SRCR) is exclusively expressed on cells of the monocyte lineage. In freshly isolated monocytes the CD14bright CD16+ monocyte subset revealed the highest expression of CD163 among all monocyte subsets. CD163 mRNA and protein expression is up-regulated during macrophage colony-stimulating factor (M-CSF)-dependent phagocytic differentiation of human blood monocytes. In contrast, monocytic cells treated with GM-CSF and interleukin-4 (IL-4) for dendritic differentiation down-regulate this antigen. CD163 expression is also suppressed by proinflammatory mediators like lipopolysaccharide (LPS), interferon-gamma (IFN-gamma), and tumor necrosis factor alpha, whereas IL-6 and the antiinflammatory cytokine interleukin-10 (IL-10) strongly up-regulate CD163 mRNA in monocytes and macrophages. The effects of the immunosuppressants dexamethasone, cyclosporin A (CA), and cortisol differ in their capacity to influence CD163 mRNA levels. Our results demonstrate that CD163 expression in monocytes/macrophages is regulated by proinflammatory and antiinflammatory mediators. This expression pattern implies a functional role of CD 163 in the antiinflammatory response of monocytes.
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              Tumor-associated leukemia inhibitory factor and IL-6 skew monocyte differentiation into tumor-associated macrophage-like cells.

              Tumor-associated macrophages (TAMs), the most abundant immunosuppressive cells in the tumor microenvironment, originate from blood monocytes and exhibit an IL-10(high)IL-12(low) M2 profile. The factors involved in TAM generation remain unidentified. We identify here leukemia inhibitory factor (LIF) and IL-6 as tumor microenvironmental factors that can promote TAM generation. Ovarian cancer ascites switched monocyte differentiation into TAM-like cells that exhibit most ovarian TAM functional and phenotypic characteristics. Ovarian cancer ascites contained high concentrations of LIF and IL-6. Recombinant LIF and IL-6 skew monocyte differentiation into TAM-like cells by enabling monocytes to consume monocyte-colony-stimulating factor (M-CSF). Depletion of LIF, IL-6, and M-CSF in ovarian cancer ascites suppressed TAM-like cell induction. We extended these observations to different tumor-cell line supernatants. In addition to revealing a new tumor-escape mechanism associated with TAM generation via LIF and IL-6, these findings offer novel therapeutic perspectives to subvert TAM-induced immunosuppression and hence improve T-cell-based antitumor immunotherapy efficacy.
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                Author and article information

                Journal
                Int J Cancer
                Int. J. Cancer
                ijc
                International Journal of Cancer. Journal International du Cancer
                BlackWell Publishing Ltd (Oxford, UK )
                0020-7136
                1097-0215
                01 January 2014
                19 July 2013
                : 134
                : 1
                : 32-42
                Affiliations
                [1 ]Clinic for Gynecology, Gynecological Oncology and Gynecological Endocrinology, Philipps University Marburg, Germany
                [2 ]Institute of Molecular Biology and Tumor Research (IMT), Philipps University Marburg, Germany
                Author notes
                Correspondence to: Dr. Sabine Müller-Brüsselbach or Dr. Rolf Müller, Institute of Molecular Biology and Tumor Research (IMT), Philipps University, Emil-Mannkopff-Straße 2, 35032 Marburg, Germany, E-mail: smb@ 123456imt.uni-marburg.de , rmueller@ 123456imt.uni-marburg.de
                [*]

                S.M.B. and R.M. shared senior authorship

                Grant sponsor: Wilhelm-Sander-Stiftung, UKGM

                Article
                10.1002/ijc.28335
                4232932
                23784932
                e60b896b-ef37-44b0-8af8-b5b4e5d55f2f
                © 2013 The Authors. Published by Wiley Periodicals, Inc. on behalf of UICC

                This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 06 May 2013
                : 03 June 2013
                Categories
                Cancer Cell Biology

                Oncology & Radiotherapy
                ovarian carcinoma,tumor-associated macrophages,cd163,il-6,il-10
                Oncology & Radiotherapy
                ovarian carcinoma, tumor-associated macrophages, cd163, il-6, il-10

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