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...

Full description

Saved in:
Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2013-04, Vol.73 (8), p.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: Article
Language:English
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
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
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.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-12-3542