title: Tumour-associated macrophage-mediated survival of myeloma cells through STAT3 activation.
abstract: Overcoming drug resistance is one of the greatest challenges in the treatment of multiple myeloma (MM). The interaction of myeloma cells with the bone marrow (BM) microenvironment is a major factor contributing to drug resistance. Tumour-associated macrophages (TAMs) with different polarization states constitute an important component of this microenvironment. Previous studies have revealed a role of TAMs in MM cell survival and drug resistance; however, the impact of macrophage polarization (anti-tumoural 'M1' versus pro-tumoural 'M2'-like phenotype) in this process has not yet been described. Here, the presence of TAMs was confirmed in BM sections from MM patients, both at diagnosis and relapse, with two M2 markers, CD163 and CD206. By following different TAM subpopulations during disease progression in the syngeneic murine 5T33MM model, we demonstrated a decrease in the number of inflammatory monocytes and an increase in the number of M2-oriented TAMs in BM. Co-culture experiments demonstrated that macrophages provide a survival benefit to myeloma cells that is maintained after treatment with several classes of anti-myeloma agent (melphalan and bortezomib); the greatest effect was observed with M2-polarized macrophages. The pro-survival effect was associated with activation of the STAT3 pathway in 5T33MM cells, less cleavage of caspase-3, and thus less apoptosis. AZD1480, an ATP-competitive JAK2 inhibitor, abrogated the observed TAM-mediated MM cell survival, and partially inhibited resistance to bortezomib. Despite having only a small quantitative impact on myeloid cells in vivo, AZD1480 treatment alone and in combination with bortezomib significantly reduced tumour load. In conclusion, M2 TAMs are present in the MM microenvironment, and contribute to MM cell survival and protection from drug-induced apoptosis. As a result of TAM-induced activation of the STAT3 pathway, 5T33MM cells are sensitized to AZD1480 treatment. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors.affiliation: Laboratory of Haematology and Immunology, Myeloma Centre Brussels, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Nathan
authors.initials: N
authors.lastname: De Beule
authors.affiliation: Laboratory of Haematology and Immunology, Myeloma Centre Brussels, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Kim
authors.initials: K
authors.lastname: De Veirman
authors.affiliation: Laboratory of Haematology and Immunology, Myeloma Centre Brussels, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Ken
authors.initials: K
authors.lastname: Maes
authors.affiliation: Laboratory of Haematology and Immunology, Myeloma Centre Brussels, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Elke
authors.initials: E
authors.lastname: De Bruyne
authors.affiliation: Laboratory of Haematology and Immunology, Myeloma Centre Brussels, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Eline
authors.initials: E
authors.lastname: Menu
authors.affiliation: Laboratory of Molecular and Cellular Technology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Karine
authors.initials: K
authors.lastname: Breckpot
authors.affiliation: Department of Pathology, Universitair Ziekenhuis Brussel, Brussels, Belgium.
authors.forename: Hendrik
authors.initials: H
authors.lastname: De Raeve
authors.affiliation: Department of Pathology, Universitair Ziekenhuis Brussel, Brussels, Belgium.
authors.forename: Rian
authors.initials: R
authors.lastname: Van Rampelbergh
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium.|Myeloid Cell Immunology Laboratory, VIB Inflammation Research Centre, Ghent, Belgium.
authors.forename: Jo A
authors.initials: JA
authors.lastname: Van Ginderachter
authors.affiliation: Department of Clinical Haematology, Universitair Ziekenhuis Brussel, Brussels, Belgium.
authors.forename: Rik
authors.initials: R
authors.lastname: Schots
authors.affiliation: Laboratory of Haematology and Immunology, Myeloma Centre Brussels, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Els
authors.initials: E
authors.lastname: Van Valckenborgh
authors.affiliation: Laboratory of Haematology and Immunology, Myeloma Centre Brussels, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Karin
authors.initials: K
authors.lastname: Vanderkerken
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D000069286:Bortezomib / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D022423:Myeloid Cells / Q000187:drug effects / Q000473:pathology; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D059016:Tumor Microenvironment; D055815:Young Adult
chemical_list: C545606:AZD 1480; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D011720:Pyrazoles; D011743:Pyrimidines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D000069286:Bortezomib
keywords: STAT3; drug resistance; multiple myeloma; tumour-associated macrophages