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Ovarian Carcinoma Macrophages Associated with Human Defective Expression of the Monocyte Chemotactic Protein-1 Receptor CCR2 in Macrophages Associated with Human Ovarian Carcinoma This information is current as of September 24, 2021. Antonio Sica, Alessandra Saccani, Barbara Bottazzi, Sergio Bernasconi, Paola Allavena, Brancatelli Gaetano, Francesca Fei, Graig LaRosa, Chris Scotton, Frances Balkwill and Alberto Mantovani J Immunol 2000; 164:733-738; ; Downloaded from doi: 10.4049/jimmunol.164.2.733 http://www.jimmunol.org/content/164/2/733 http://www.jimmunol.org/ References This article cites 53 articles, 20 of which you can access for free at: http://www.jimmunol.org/content/164/2/733.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 24, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2000 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Defective Expression of the Monocyte Chemotactic Protein-1 Receptor CCR2 in Macrophages Associated with Human Ovarian Carcinoma1 Antonio Sica,2* Alessandra Saccani,* Barbara Bottazzi,* Sergio Bernasconi,* Paola Allavena,* Brancatelli Gaetano,† Francesca Fei,† Graig LaRosa,‡ Chris Scotton,§ Frances Balkwill,§ and Alberto Mantovani*¶ Monocyte chemotactic protein-1 (MCP-1, CCL2) is an important determinant of macrophage infiltration in tumors, ovarian carcinoma in particular. MCP-1 binds the chemokine receptor CCR2. Recent results indicate that proinflammatory and anti- inflammatory signals regulate chemokine receptor expression in monocytes. The present study was designed to investigate the expression of CCR2 in tumor-associated macrophages (TAM) from ovarian cancer patients. TAM isolated from ascitic or solid Downloaded from ovarian carcinoma displayed defective CCR2 mRNA (Northern blot and PCR) and surface expression and did not migrate in response to MCP-1. The defect was selective for CCR2 in that CCR1 and CCR5 were expressed normally in TAM. CCR2 gene expression and chemotactic response to MCP-1 were decreased to a lesser extent in blood monocytes from cancer patients. CCR2 mRNA levels and the chemotactic response to MCP-1 were drastically reduced in fresh monocytes cultured in the presence of tumor ascites from cancer patients. Ab against TNF-␣ restored the CCR2 mRNA level in monocytes cultured in the presence of ascitic fluid. The finding of defective CCR2 expression in TAM, largely dependent on local TNF production, is consistent with http://www.jimmunol.org/ previous in vitro data on down-regulation of chemokine receptors by proinflammatory molecules. Receptor inhibition may serve as a mechanism to arrest and retain recruited macrophages and to prevent chemokine scavenging by mononuclear phagocytes at sites of inflammation and tumor growth. In the presence of advanced tumors or chronic inflammation, systemic down-regulation of receptor expression by proinflammatory molecules leaking in the systemic circulation may account for defective chemotaxis and a defective capacity to mount inflammatory responses associated with advanced neoplasia. The Journal of Immunology, 2000, 164: 733–738. elective accumulation of leukocyte subpopulations is the esis (1) was coined to emphasize the dual potential of TAM to hallmark of pathological conditions, including allergic and influence tumor growth in opposite directions. by guest on September 24, 2021 S inflammatory reactions and tumors (1). In particular, the Macrophages represent a major component of the lymphoreticu- presence of macrophages in tumor tissues and/or their periphery lar infiltrate of tumors, and the percentage of TAM for each tumor has generated broad interest, and analysis of tumor-associated is usually maintained as a relatively stable “individual” property macrophages (TAM)3 suggests that these cells have the capacity to during tumor growth and upon transplantation in syngeneic hosts affect diverse aspects of the immunobiology of neoplastic tissues, (1, 5). The search for tumor-derived chemotactic factors, which including vascularization, growth rate and metastasis, stroma for- may account for recruitment of mononuclear phagocytes in neoplastic mation, and dissolution (1, 2). On the other hand, cells of the tissues, lead to the identification of the monocyte chemotactic pro- monocyte-macrophage lineage have the potential to express tu- tein-1 (MCP-1, CCL2) as well as of other chemokines (1, 2, 6–12). moricidal capacity and to elicit tumor-destructive reactions (3, 4). MCP-1 is a member of a superfamily of cytokines called che- Based on these observations, the “macrophages balance” hypoth- mokines. The hallmark of this family is a conserved cysteine res- idue motif (13–15). According to the relative position of the first two cysteines, it is possible to distinguish two main families: the *Istituto di Ricerche Farmacologiche “Mario Negri,” Milan, Italy; †Department of ␣ Obstetrics and Gynecology, S. Gerardo Hospital, Monza, Italy; ¶Department of Bio- CXC (or ) chemokines, which are active on neutrophils, T and B technology, University of Brescia, Brescia, Italy; ‡Receptor Pharmacology, Leuko- lymphocytes (13–15), and the CC (or ␤) chemokines that exert § site, Inc., Cambridge, MA; and Biological Therapy Laboratory, Imperial Cancer their action on multiple leukocyte populations, including mono- Research Fund, London, United Kingdom cytes, basophils, eosinophils, T lymphocytes, NK, and dendritic Received for publication June 15, 1999. Accepted for publication November 4, 1999. cells (13–18). A third type of protein (the C or ␥ chemokines) was The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance described, which is active on T lymphocytes and NK cells. This with 18 U.S.C. Section 1734 solely to indicate this fact. protein is characterized by the absence of the first and third cysteines, 1 This work was supported by Associazione Italiana Ricerca sul Cancro, Target but shows overall sequence identity with CC chemokines (19, 20). Project on Biotechnology, Consiglio Nazionale delle Ricerche, Contract More recently, fractalkine, CX3C (or ␦ motif), was described as che- 99.00119.PF49, Project Therapy of Tumors, and Ministero Universita’ Ricerca Sci- entifica e Tecnologica. Travel support for F.B. was provided by a special program motactic for monocytes, T cells, and NK cells (21, 22). from Consiglio Nazionale delle Ricerche. Chemokines, as well as classical chemotactic agonists, such as 2 Address correspondence and reprint requests to Dr. Antonio Sica, Istituto di formylated peptides (of which fMLP is the prototype) and C5a, Ricerche Farmacologiche “Mario Negri,” via Eritrea 62, 20157 Milan, Italy. E-mail bind to and activate a family of rhodopsin-like, GTP-binding pro- address: [email protected] tein-coupled seven-transmembrane domain receptors (23–25). 3 Abbreviations used in this paper: TAM, tumor-associated macrophages; MCP-1, monocyte chemotactic protein-1; MIP-1, macrophage inflammatory protein-1; Nine receptors for CC chemokines, now named CCR1 through 9, M-DM, monocyte-derived macrophage. have been identified and cloned (13, 14, 23–26). Copyright © 2000 by The American Association of Immunologists 0022-1767/00/$02.00 734 DEFECTIVE EXPRESSION OF CCR2 IN TUMOR-ASSOCIATED MACROPHAGES MCP-1 interacts with CCR2, of which two isoforms have been ted to the Department of Obstetrics and Gynecology, San Gerardo Hospital cloned and termed A and B (26). In monocytes and NK cells, (Monza, Italy). All patients had cancer classified as stage II, III, or IV. CCR2 is expressed predominantly as B isoform, with vanishingly Ascitic fluid was collected and centrifuged. Cell pellets were resuspended in RPMI 1640 medium without serum and layered on top of a Ficoll- low levels of A transcripts (27). In addition to MCP-1, CCR2 Hypaque cushion to prepare mononuclear cells. Purification of peritoneal recognizes MCP-2 and MCP-3 (28–30). Several lines of evidence, macrophages was further conducted by two subsequent adherence steps for including studies in gene-targeted mice, indicate that MCP-1 and 45 min, each in RPMI 1640 medium without serum. After adherence pro- CCR2 are important for monocyte recruitment at the site of in- cedures, cells were repeatedly washed with saline to remove all nonadher- ent cells. The adherent cells were cultured with complete medium over flammation (31, 32). There is also evidence that in a variety of night at 37°C to rest and then stimulated as indicated above. To purify murine and human tumors, including ovarian cancer, MCP-1 is a TAM by flow cytometry and sorting, ascitic fluids (four patients) were major determinant of the degree of macrophage infiltration in neo- incubated with anti-CD68 mAb. A total of 5 ϫ 107 cells was washed in plastic tissue (1, 2, 33–40). saline with 1% human serum and then incubated in 0.5 ml of anti-CD68 Recent results indicate
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