title: MIF Is Necessary for Late-Stage Melanoma Patient MDSC Immune Suppression and Differentiation.
abstract: Highly aggressive cancers "entrain" innate and adaptive immune cells to suppress antitumor lymphocyte responses. Circulating myeloid-derived suppressor cells (MDSC) constitute the bulk of monocytic immunosuppressive activity in late-stage melanoma patients. Previous studies revealed that monocyte-derived macrophage migration inhibitory factor (MIF) is necessary for the immunosuppressive function of tumor-associated macrophages and MDSCs in mouse models of melanoma. In the current study, we sought to determine whether MIF contributes to human melanoma MDSC induction and T-cell immunosuppression using melanoma patient-derived MDSCs and an ex vivo coculture model of human melanoma-induced MDSC. We now report that circulating MDSCs isolated from late-stage melanoma patients are reliant upon MIF for suppression of antigen-independent T-cell activation and that MIF is necessary for maximal reactive oxygen species generation in these cells. Moreover, inhibition of MIF results in a functional reversion from immunosuppressive MDSC to an immunostimulatory dendritic cell (DC)-like phenotype that is at least partly due to reductions in MDSC prostaglandin E(2) (PGE(2)). These findings indicate that monocyte-derived MIF is centrally involved in human monocytic MDSC induction/immunosuppressive function and that therapeutic targeting of MIF may provide a novel means of inducing antitumor DC responses in late-stage melanoma patients.
authors.affiliation: Molecular Targets Program, JG Brown Cancer Center, University of Louisville, Louisville, Kentucky. Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky. Department of Medicine, University of Louisville, Louisville, Kentucky. robert.mitchell@louisville.edu kavitha.yaddanapudi@louisville.edu.
authors.forename: Kavitha
authors.initials: K
authors.lastname: Yaddanapudi
authors.affiliation: Molecular Targets Program, JG Brown Cancer Center, University of Louisville, Louisville, Kentucky.
authors.forename: Beatriz E
authors.initials: BE
authors.lastname: Rendon
authors.affiliation: Molecular Targets Program, JG Brown Cancer Center, University of Louisville, Louisville, Kentucky.
authors.forename: Gwyneth
authors.initials: G
authors.lastname: Lamont
authors.affiliation: Molecular Targets Program, JG Brown Cancer Center, University of Louisville, Louisville, Kentucky.
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Kim
authors.affiliation: Molecular Targets Program, JG Brown Cancer Center, University of Louisville, Louisville, Kentucky.
authors.forename: Numan
authors.initials: N
authors.lastname: Al Rayyan
authors.affiliation: Molecular Targets Program, JG Brown Cancer Center, University of Louisville, Louisville, Kentucky.
authors.forename: Jamaal
authors.initials: J
authors.lastname: Richie
authors.affiliation: Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky.
authors.forename: Sabrin
authors.initials: S
authors.lastname: Albeituni
authors.affiliation: Molecular Targets Program, JG Brown Cancer Center, University of Louisville, Louisville, Kentucky.
authors.forename: Sabine
authors.initials: S
authors.lastname: Waigel
authors.affiliation: Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky.
authors.forename: Ashley
authors.initials: A
authors.lastname: Wise
authors.affiliation: Molecular Targets Program, JG Brown Cancer Center, University of Louisville, Louisville, Kentucky. Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky. Department of Medicine, University of Louisville, Louisville, Kentucky. robert.mitchell@louisville.edu kavitha.yaddanapudi@louisville.edu.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Mitchell
mesh_terms: D000818:Animals; D015415:Biomarkers; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D006801:Humans; D016130:Immunophenotyping; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism*; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D015415:Biomarkers; D008263:Macrophage Migration-Inhibitory Factors; D017382:Reactive Oxygen Species