Bone marrow PMN-MDSCs and neutrophils are functionally similar in protection of multiple myeloma from chemotherapy

•Myeloid cells play a critical role in regulation of myeloma growth.•PMN-MDSCs and neutrophils equally protect myeloma cells from chemotherapy.•PMN-MDSCs and neutrophils mediate chemoprotective effect through soluble factors. Multiple myeloma (MM) is an incurable cancer of plasma cells localized pre...

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Published in:	Cancer letters Vol. 371; no. 1; pp. 117 - 124
Main Authors:	Ramachandran, Indu R., Condamine, Thomas, Lin, Cindy, Herlihy, Sarah E., Garfall, Alfred, Vogl, Dan T., Gabrilovich, Dmitry I., Nefedova, Yulia
Format:	Journal Article
Language:	English
Published:	Ireland Elsevier Ireland Ltd 01.02.2016 Elsevier Limited
Subjects:	Animals Antibiotics Antibiotics, Antineoplastic - pharmacology Antigens Antineoplastic Agents, Alkylating - pharmacology Apoptosis - drug effects Bone marrow Cancer Cell Line, Tumor Cell Lineage Chemoresistance Chemotherapy Coculture Techniques Colleges & universities Disease Models, Animal Doxorubicin - pharmacology Drug Resistance, Neoplasm Experiments Genotype & phenotype Growth factors Hematology, Oncology and Palliative Medicine Humans Immunotherapy Melphalan - pharmacology Mice, Inbred C57BL Multiple myeloma Multiple Myeloma - drug therapy Multiple Myeloma - metabolism Multiple Myeloma - pathology Myeloid Cells - drug effects Myeloid Cells - metabolism Myeloid Cells - pathology Myeloid-derived suppressor cells Neutrophils Neutrophils - drug effects Neutrophils - metabolism Neutrophils - pathology Paracrine Communication Phenotype Time Factors Tumor Cells, Cultured Tumor Microenvironment MM cDC MDSC MNC M-MDSC Myeloid-derived suppressor cells Chemoresistance Multiple myeloma Neutrophils BMS BM TME pDC PMN-MDSC MΦ IMC DC immature myeloid cells macrophages dendritic cells monocytic MDSC plasmacytoid DC multiple myeloma conventional DC bone marrow stroma bone marrow myeloid-derived suppressor cells polymorphonuclear MDSC mononuclear cell tumor microenvironment
ISSN:	0304-3835, 1872-7980, 1872-7980
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Summary:	•Myeloid cells play a critical role in regulation of myeloma growth.•PMN-MDSCs and neutrophils equally protect myeloma cells from chemotherapy.•PMN-MDSCs and neutrophils mediate chemoprotective effect through soluble factors. Multiple myeloma (MM) is an incurable cancer of plasma cells localized preferentially in the bone marrow (BM). Resistance to chemotherapy represents one of the main challenges in MM management. BM microenvironment is known to play a critical role in protection of MM cells from chemotherapeutics; however, mechanisms responsible for this effect are largely unknown. Development of MM is associated with accumulation of myeloid-derived suppressor cells (MDSCs) mostly represented by pathologically activated relatively immature polymorphonuclear neutrophils (PMN-MDSCs). Here, we investigated whether PMN-MDSCs are responsible for BM microenvironment-mediated MM chemoresistance. Using in vivo mouse models allowing manipulation of myeloid cell number, we demonstrated a critical role for myeloid cells in MM growth and chemoresistance. PMN-MDSCs isolated from MM-bearing host are immunosuppressive and thus, functionally distinct from their counterpart in tumor-free host neutrophils. We found, however, that both PMN-MDSCs and neutrophils equally promote MM survival from doxorubicin and melphalan and that this effect is mediated by soluble factors rather than direct cell–cell contact. Our data indicate that targeting PMN-MDSCs would enhance chemotherapy efficacy in MM.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 ObjectType-Article-2 ObjectType-Feature-1 content type line 23
ISSN:	0304-3835 1872-7980 1872-7980
DOI:	10.1016/j.canlet.2015.10.040