title: Chemotherapy alters monocyte differentiation to favor generation of cancer-supporting M2 macrophages in the tumor microenvironment.
abstract: Current therapy of gynecologic malignancies consists of platinum-containing chemotherapy. Resistance to therapy is associated with increased levels of interleukin (IL)-6 and prostaglandin E2 (PGE(2)), 2 inflammatory mediators known to skew differentiation of monocytes to tumor-promoting M2 macrophages. We investigated the impact of cisplatin and carboplatin on 10 different cervical and ovarian cancer cell lines as well as on the ability of the tumor cells to affect the differentiation and function of cocultured monocytes in vitro. Treatment with cisplatin or carboplatin increased the potency of tumor cell lines to induce IL-10-producing M2 macrophages, which displayed increased levels of activated STAT3 due to tumor-produced IL-6 as well as decreased levels of activated STAT1 and STAT6 related to the PGE(2) production of tumor cells. Blockade of canonical NF-κB signaling showed that the effect of the chemotherapy was abrogated, preventing the subsequent increased production of PGE(2) and/or IL-6 by the tumor cell lines. Treatment with the COX-inhibitor indomethacin and/or the clinical monoclonal antibody against interleukin-6 receptor (IL-6R), tocilizumab, prevented M2-differentiation. Importantly, no correlation existed between the production of PGE(2) or IL-6 by cancer cells and their resistance to chemotherapy-induced cell death, indicating that other mechanisms underlie the reported chemoresistance of tumors producing these factors. Our data suggest that a chemotherapy-mediated increase in tumor-promoting M2 macrophages may form an indirect mechanism for chemoresistance. Hence, concomitant therapy with COX inhibitors and/or IL-6R antibodies might increase the clinical effect of platinum-based chemotherapy in otherwise resistant tumors.
authors: Department of Clinical Oncology, Leiden University Medical Center, Albinusdreef, Leiden, The Netherlands.
authors: Eveline M
authors: EM
authors: Dijkgraaf
authors: Moniek
authors: M
authors: Heusinkveld
authors: Bart
authors: B
authors: Tummers
authors: Lisa T C
authors: LT
authors: Vogelpoel
authors: Renske
authors: R
authors: Goedemans
authors: Veena
authors: V
authors: Jha
authors: Johan W R
authors: JW
authors: Nortier
authors: Marij J P
authors: MJ
authors: Welters
authors: Judith R
authors: JR
authors: Kroep
authors: Sjoerd H
authors: SH
authors: van der Burg
mesh_terms: D000938:Antigen-Presenting Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016190:Carboplatin / Q000494:pharmacology / Q000627:therapeutic use; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004249:DNA Damage; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D015232:Dinoprostone / Q000096:biosynthesis; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*; D016328:NF-kappa B / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D059016:Tumor Microenvironment / Q000276:immunology*; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D017077:Culture Media, Conditioned; D015850:Interleukin-6; D016328:NF-kappa B; D019947:Receptors, Interleukin-6; D050791:STAT Transcription Factors; D016190:Carboplatin; D015232:Dinoprostone; D002945:Cisplatin