Chemotherapy Alters Monocyte Differentiation to Favor Generation of Cancer-Supporting M2 Macrophages in the Tumor Microenvironment

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 macrophag...

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Bibliographic Details
Published in:	Cancer research (Chicago, Ill.) Vol. 73; no. 8; pp. 2480 - 2492
Main Authors:	DIJKGRAAF, Eveline M, HEUSINKVELD, Moniek, TUMMERS, Bart, VOGELPOEL, LisaT. C, GOEDEMANS, Renske, JHA, Veena, NORTIER, Johan W. R, WELTERS, Marij J. P, KROEP, Judith R, VAN DER BURG, Sjoerd H
Format:	Journal Article
Language:	English
Published:	Philadelphia, PA American Association for Cancer Research 15-04-2013
Subjects:	Antigen-Presenting Cells - cytology Antigen-Presenting Cells - drug effects Antigen-Presenting Cells - immunology Antineoplastic agents Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Biological and medical sciences Carboplatin - pharmacology Carboplatin - therapeutic use Cell Differentiation - drug effects Cell Line, Tumor Cell Survival - drug effects Cisplatin - pharmacology Cisplatin - therapeutic use Culture Media, Conditioned - pharmacology Dendritic Cells - cytology Dendritic Cells - drug effects Dendritic Cells - immunology Dinoprostone - biosynthesis DNA Damage Female Humans Interleukin-6 - biosynthesis Macrophages - cytology Macrophages - drug effects Macrophages - immunology Medical sciences Monocytes - cytology Monocytes - drug effects Monocytes - immunology Multiple tumors. Solid tumors. Tumors in childhood (general aspects) Neoplasms - drug therapy Neoplasms - immunology NF-kappa B - metabolism Ovarian Neoplasms - drug therapy Ovarian Neoplasms - immunology Ovarian Neoplasms - metabolism Pharmacology. Drug treatments Receptors, Interleukin-6 - antagonists & inhibitors Receptors, Interleukin-6 - metabolism Signal Transduction - drug effects STAT Transcription Factors - metabolism Tumor Microenvironment - immunology Tumors Uterine Cervical Neoplasms - drug therapy Uterine Cervical Neoplasms - immunology Uterine Cervical Neoplasms - metabolism Chemotherapy M2 macrophage Treatment Monocyte Cell microenvironment Malignant tumor Cell differentiation Differentiation Cancer
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0008-5472 1538-7445
DOI:	10.1158/0008-5472.can-12-3542