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The IL-18 Antagonist IL-18–Binding Protein Is Produced in the Human Ovarian Cancer Microenvironment

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The IL-18 Antagonist IL-18–Binding Protein Is Produced in the Human Ovarian Cancer Microenvironment Published OnlineFirst July 19, 2013; DOI: 10.1158/1078-0432.CCR-13-0568 Clinical Cancer Human Cancer Biology Research The IL-18 Antagonist IL-18–Binding Protein Is Produced in the Human Ovarian Cancer Microenvironment Grazia Carbotti1, Gaia Barisione1, Anna Maria Orengo1, Antonella Brizzolara1, Irma Airoldi3, Marina Bagnoli4, Patrizia Pinciroli4, Delia Mezzanzanica4, Maria Grazia Centurioni2, Marina Fabbi1, and Silvano Ferrini1 Abstract Purpose: Interleukin (IL)-18 is an immune-enhancing cytokine, which induces IFN-g production, T-helper 1 responses, and antitumor effects. In turn, IFN-g stimulates IL-18–binding protein production, which blocks IL-18 activity. In view of the potential use of IL-18 in epithelial ovarian cancer (EOC) immuno- therapy, here, we studied IL-18BP expression and its regulation by cytokines in EOC cells in vitro and in vivo. Experimental Design: Expression and production of IL-18BP in EOC cell lines, primary ovarian carcinomas, and the corresponding normal tissues, patients’ serum, and ascites were investigated by immunochemistry, ELISA, screening of gene expression profiles, and reverse-transcription PCR. Results: Analysis of gene expression profiles revealed that IL18BP mRNA is increased in EOC tumors compared with normal ovary cells. Release of IL-18BP was detectable in EOC sera and to a greater extent in the ascites, indicating production at the tumor site. Indeed, immunochemical analyses on cells isolated from the ascites and on tumor sections indicated that IL-18BP is expressed in both tumor cells À À À þ and tumor-associated leukocytes, which displayed a CD3 CD20 NKp46 CD13 CD14low phenotype. EOC cell lines do not constitutively express IL-18BP. However, its release is inducible both by IFN-g stimulation in vitro and by xenotransplantation of EOC cells in immune-deficient mice, suggesting a role for the microenvironment. In vitro experiments and immunochemistry indicated that IL-27 is also involved in IL-18BP upregulation in EOC cell lines and primary cells through STAT1 activation. Together, these data indicate that IL-18BP, which is produced in EOC in response to microenvironmental factors, may inhibit endogenous or exogenous IL-18 activity. Clin Cancer Res; 19(17); 1–10. Ó2013 AACR. Introduction and that T-cell–mediated immunity may have an impact on Epithelial ovarian cancer (EOC) represents 80% of all clinical course of EOC (3). However, similar to other ovarian malignancies, is frequently diagnosed at advanced tumors, EOC has the ability to escape from immune system stages, and has a poor 5-year survival rate (1). Evidence from control through several mechanisms (4, 5). several studies indicates that T lymphocytes capable of Several cytokines and chemokines were found to be ele- recognizing EOC cells are present at the tumor site (2, 3) vated in serum and in the ascites of patients with EOC and have been implicated in tumor development, angiogenesis (6, 7), progression (8), drug resistance (9), or immune Authors' Affiliations: Departments of 1Integrated Oncological Therapies suppression (10). Some of these cytokines have been con- 2 and Surgery, IRCCS AOU San Martino-IST Istituto Nazionale per la sidered as serologic biomarkers of EOC (11). Among them, Ricerca sul Cancro, and 3Laboratory of Oncology, IRCCS Istituto G. Gaslini, Genoa, Italy; and 4Department of Experimental Oncology and Molecular interleukin (IL)-18 was proposed as a potential biomarker by Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy gene expression profiling (12) and, indeed, IL-18 levels were Note: Supplementary data for this article are available at Clinical Cancer elevated in serum and ascites of patients with EOC (12, 13). Research Online (http://clincancerres.aacrjournals.org/). IL-18 is a proinflammatory and immune-enhancing cyto- kine, which induces IFN-g production by T cells and natural M. Fabbi and S. Ferrini contributed equally to this work. killer (NK) cells, mediates T-helper 1 cell (TH1) polariza- G. Carbotti is enrolled in the Doctorate School of Genetics, University of tion, and is involved in the defense from pathogens (14– Genoa, Italy. 16). IL-18 is synthesized as an inactive precursor (pro-IL- Corresponding Authors: Silvano Ferrini, UOC Terapia Immunologica, 18), which is converted to a mature form (mat-IL-18) by IRCCS AOU San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Largo R. Benzi 10, 16132 Genova, Italy. Phone: 0039-010-555-8372; Fax: caspase-1 (17). IL-18 is released from cells as both pro- and 0039-010-555-8374; E-mail: [email protected]; and Marina Fabbi, mat-IL-18 forms, but only mat-IL-18 can bind to IL-18R. E-mail: [email protected] Moreover, in preclinical tumor models, mat-IL-18 exhibited doi: 10.1158/1078-0432.CCR-13-0568 antitumor properties through the induction of an immune Ó2013 American Association for Cancer Research. response, whereas pro-IL-18 had no activity (18, 19). www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on October 2, 2021. © 2013 American Association for Cancer Research. Published OnlineFirst July 19, 2013; DOI: 10.1158/1078-0432.CCR-13-0568 Carbotti et al. 10% FCS, and antibiotics (Lonza). NK-92 cells (ATCC) Translational Relevance were grown in medium containing 600 IU IL-2 (Novartis). Interleukin (IL)-18 is an immune-enhancing cyto- A vial of each cell line master stock was recently genotyped kine, which is being studied in clinical trials of immu- using the Cell ID System (Promega) and GeneMapper notherapy. IL-18BP is a natural antagonist of IL-18 software, version 4.0. and limits IL-18 biologic activity. Here, we show that Cells (50 Â 103/well) were seeded in 24-well plates in IL-18BP is produced by both tumor cells and tumor- culture medium. The following day, culture medium was associated leukocytes. Expression of IL-18BP in ovarian replaced with medium with or without human recombi- cancer cells in vitro is induced by cytokines such as nant IFN-g (PeproTech), human recombinant IL-27 (R&D IFN-g and IL-27, which may play a role in the tumor System) or human recombinant IL-35 (Enzo Life Sciences). environment. The high local levels of IL-18BP at the For IL-27R blocking experiments, an anti-gp130 antibody tumor site may limit the induction of an efficient immune was added [monoclonal antibody (mAb) 228, R&D Sys- response by either endogenous or therapeutic IL-18. tems)]. Treatment was carried out for 48 hours. Condi- tioned media were then collected, centrifuged, and used for IL-18BP detection. EOC cell lines release pro-IL-18, but not mat-IL-18, due to RT-PCR analysis of IL18BP mRNA expression defective caspase-1 expression or activation, whereas nor- Cells were detached by trypsin and washed, and total mal ovarian epithelial cells secrete mat-IL-18 (20). Indeed, RNA was isolated by the NucleoSpin RNA II kit (Macherey- IL-18 present at high levels in EOC ascites is predominantly Nagel) and reverse-transcribed using the SuperScript II the inactive pro-IL-18 (13), although we cannot exclude Reverse Transcriptase (Invitrogen). Quantitative RT-PCR that low levels of mat-IL-18, eventually present, may con- analysis was conducted using the following primers: tribute to the immune response. POLR2A upper primer GACAATGCAGAGAAGCTGG, lower IL-18 binding protein (IL-18BP) is an inhibitor of IL-18 primer GCAGGAAGACATCATCATCC; GAPDH upper prim- activity, as it binds the mature form of this cytokine and er GAAGGTGAAGGTCGGAGT, lower primer CATGGGTG- blocks its interaction with IL-18R (21) and its isoform "a" is GAATCATATTGGAA; IL18BP upper primer GTGTCCAGC- the mostly expressed form (22). IL-18BP is produced by ATTGGAAGTGACC, and lower primer GGAGGTGCTCAA- monocytes and macrophages (23) and by prostatic (24) TGAAGGAACC. Amplification was carried out by the Mas- and colorectal tumor cells (25) in response to IFN-g stim- tercycler ep realplex instrument (Eppendorf International) ulation. IFN-g is the physiologic inducer of IL-18BP, which using the iQÔ SYBR Green Supermix system (Bio-Rad in turn inhibits IL-18 biologic activity in a negative feed- Laboratories). Relative quantification of mRNAs was calcu- back loop. IL-18BP accumulates in the serum in chro- lated by the DDCt method. For semiquantitative RT-PCR, nic renal failure, in which it may contribute to the defective 2 mL of cDNA was separately amplified with 0.25 U of immune response (26). Taq DNA Polymerase (Roche) in the presence of 1 mmol/L To further address the biologic role of endogenous of the following primers: IL18BP upper primer ACCATG- IL-18 in human EOC, we conducted an integrated ana- AGACACAACTGGACACCAG, lower primer TTAACCCTG- lysis of IL-18 and IL-18BP in patients with EOC. The CTGCTGTGGACTGCTG; housekeeping gene ACTB upper study of IL-18BP also seemed relevant, as IL-18–based primer GGCATCGTGATGGACTCCG, lower primer GCTG- immunotherapy is being evaluated in patients with EOC GAAGGTGGACAGCGA in an Eppendorf Mastercycler ep (refs. 27, 28; NCT00659178) and high levels of IL-18BP Gradient S. PCR products were analyzed on 1% agarose gel may interfere with this treatment. We found that, indeed, stained with ethidium bromide. IL-18BP levels are elevated in the serum and particularly in the ascites of patients with EOC and that IL-18BP Patients is expressed by EOC cells and by reactive leukocytes. Our Clinical samples were obtained upon written informed data also suggest that IL-18BP production may be the consent and previous approval by the Institutional outcome of cross-talk between tumor cells and the micro- Review Board from patients and tumor-free, age-matched environment, involving IFN-g and IL-27, a member of (median ¼ 60 years; range ¼ 43–75) women. All 55 patients the IL-12 cytokine family (29, 30). Together, these data showed evidence of disease and untreated or off treatment support an immune-regulatory role for IL-18BP in EOC, for at least 2 months (Table 1).
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