title: Bone marrow PMN-MDSCs and neutrophils are functionally similar in protection of multiple myeloma from chemotherapy.
abstract: 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.
authors.affiliation: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, USA; Immunology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: Indu R
authors.initials: IR
authors.lastname: Ramachandran
authors.affiliation: Translational Tumor Immunology Program, The Wistar Institute, Philadelphia, PA, USA; Immunology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Condamine
authors.affiliation: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, USA.
authors.forename: Cindy
authors.initials: C
authors.lastname: Lin
authors.affiliation: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Herlihy
authors.affiliation: Division of Hematology/Oncology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Alfred
authors.initials: A
authors.lastname: Garfall
authors.affiliation: Division of Hematology/Oncology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Dan T
authors.initials: DT
authors.lastname: Vogl
authors.affiliation: Translational Tumor Immunology Program, The Wistar Institute, Philadelphia, PA, USA; Immunology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: Dmitry I
authors.initials: DI
authors.lastname: Gabrilovich
authors.affiliation: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, USA; Immunology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. Electronic address: ynefedova@wistar.org.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Nefedova
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D019070:Cell Lineage; D018920:Coculture Techniques; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008558:Melphalan / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D022423:Myeloid Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019899:Paracrine Communication; D010641:Phenotype; D013997:Time Factors; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment
chemical_list: D000903:Antibiotics, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D004317:Doxorubicin; D008558:Melphalan
keywords: Chemoresistance; Multiple myeloma; Myeloid-derived suppressor cells; Neutrophils