title: Cancer Stem Cell-Secreted Macrophage Migration Inhibitory Factor Stimulates Myeloid Derived Suppressor Cell Function and Facilitates Glioblastoma Immune Evasion.
abstract: Shifting the balance away from tumor-mediated immune suppression toward tumor immune rejection is the conceptual foundation for a variety of immunotherapy efforts currently being tested. These efforts largely focus on activating antitumor immune responses but are confounded by multiple immune cell populations, including myeloid-derived suppressor cells (MDSCs), which serve to suppress immune system function. We have identified immune-suppressive MDSCs in the brains of GBM patients and found that they were in close proximity to self-renewing cancer stem cells (CSCs). MDSCs were selectively depleted using 5-flurouracil (5-FU) in a low-dose administration paradigm, which resulted in prolonged survival in a syngeneic mouse model of glioma. In coculture studies, patient-derived CSCs but not nonstem tumor cells selectively drove MDSC-mediated immune suppression. A cytokine screen revealed that CSCs secreted multiple factors that promoted this activity, including macrophage migration inhibitory factor (MIF), which was produced at high levels by CSCs. Addition of MIF increased production of the immune-suppressive enzyme arginase-1 in MDSCs in a CXCR2-dependent manner, whereas blocking MIF reduced arginase-1 production. Similarly to 5-FU, targeting tumor-derived MIF conferred a survival advantage to tumor-bearing animals and increased the cytotoxic T cell response within the tumor. Importantly, tumor cell proliferation, survival, and self-renewal were not impacted by MIF reduction, demonstrating that MIF is primarily an indirect promoter of GBM progression, working to suppress immune rejection by activating and protecting immune suppressive MDSCs within the GBM tumor microenvironment. Stem Cells 2016;34:2026-2039.
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, 44195, USA.|Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, 44195, USA.
authors.forename: Balint
authors.initials: B
authors.lastname: Otvos
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, 44195, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Silver
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, 44195, USA.
authors.forename: Erin E
authors.initials: EE
authors.lastname: Mulkearns-Hubert
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, 44195, USA.|Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine at Case, Western Reserve University, Cleveland, Ohio, 44195, USA.
authors.forename: Alvaro G
authors.initials: AG
authors.lastname: Alvarado
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, 44195, USA.
authors.forename: Soumya M
authors.initials: SM
authors.lastname: Turaga
authors.affiliation: Department of Pathology, Odense University Hospital, Odense, Denmark.|Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.
authors.forename: Mia D
authors.initials: MD
authors.lastname: Sorensen
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, 44195, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Rayman
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, 44195, USA.|Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine at Case, Western Reserve University, Cleveland, Ohio, 44195, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Flavahan
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, 44195, USA.
authors.forename: James S
authors.initials: JS
authors.lastname: Hale
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, 44195, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Stoltz
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, 44195, USA.
authors.forename: Maksim
authors.initials: M
authors.lastname: Sinyuk
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, 44195, USA.
authors.forename: Qiulian
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, 44195, USA.
authors.forename: Awad
authors.initials: A
authors.lastname: Jarrar
authors.affiliation: Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama, 35294, USA.
authors.forename: Sung-Hak
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, 44195, USA.|Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine at Case, Western Reserve University, Cleveland, Ohio, 44195, USA.|Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, 44106, USA.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Fox
authors.affiliation: Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama, 35294, USA.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Nakano
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, 44195, USA.|Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, 44195, USA.|Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine at Case, Western Reserve University, Cleveland, Ohio, 44195, USA.|Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, 44106, USA.
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Rich
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, 44195, USA.|Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine at Case, Western Reserve University, Cleveland, Ohio, 44195, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Ransohoff
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, 44195, USA.|Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine at Case, Western Reserve University, Cleveland, Ohio, 44195, USA.|Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, 44106, USA.
authors.forename: James
authors.initials: J
authors.lastname: Finke
authors.affiliation: Department of Pathology, Odense University Hospital, Odense, Denmark.|Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.
authors.forename: Bjarne W
authors.initials: BW
authors.lastname: Kristensen
authors.affiliation: Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, 44195, USA.|Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine at Case, Western Reserve University, Cleveland, Ohio, 44195, USA.|Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, 44106, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Vogelbaum
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, 44195, USA.|Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, 44195, USA.|Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine at Case, Western Reserve University, Cleveland, Ohio, 44195, USA.|Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, 44106, USA.
authors.forename: Justin D
authors.initials: JD
authors.lastname: Lathia
mesh_terms: D000818:Animals; D001119:Arginase / Q000378:metabolism; D001932:Brain Neoplasms / Q000276:immunology* / Q000473:pathology; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005260:Female; D005909:Glioblastoma / Q000276:immunology* / Q000473:pathology; D006801:Humans; D057131:Immune Evasion / Q000187:drug effects; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D000072737:Myeloid-Derived Suppressor Cells / Q000187:drug effects / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D017077:Culture Media, Conditioned; D008263:Macrophage Migration-Inhibitory Factors; C574619:ARG1 protein, human; D001119:Arginase
keywords: Cancer stem cells; Glioblastoma; Immunotherapy; MIF; Macrophage migration inhibitory factor; Myeloid-derived suppressor cells; Tumor immune suppression; Tumor microenvironment