title: Macrophage migration inhibitory factor (MIF) is induced by cytotoxic drugs and is involved in immune escape and migration in childhood rhabdomyosarcoma.
abstract: Macrophage migration inhibitory factor (MIF) is known to be involved in oncogenic transformation, tumour progression, and immunosuppression and is overexpressed in many solid tumours, including paediatric rhabdomyosarcoma (RMS). We investigated the function of MIF in RMS during treatment with cytotoxic drugs. RMS cell lines were analysed by flow cytometry, immunofluorescence staining, and ELISA. We demonstrated the overexpression of MIF in RMS cells and the enhanced expression and secretion after treatment with cytotoxic agents. Migration assays of RMS cells revealed that inhibitors of MIF (ISO-1, Ant.III 4-IPP, Ant.V, sulforaphane (SF)) and blocking antibodies caused reduced migration, indicating a role for MIF in metastatic invasion. Additionally, we investigated the function of MIF in immune escape. The development of a population containing immunosuppressive myeloid-derived suppressor cells was promoted by incubation in conditioned medium of RMS cells comprising MIF and was reversed by MIF inhibitors but not by antibodies. Although most inhibitors may restore immune activity, Ant.III and 10 µM SF disturbed T cell proliferation in a CFSE assay, whereas T cell proliferation was not reduced by 3 µM SF, ISO-1 or antibodies. However, the inhibition of MIF by blocking antibodies did not increase the killing activity of allogenic PBMCs co-cultured with RMS cells. Our results reveal that MIF may be involved in an immune escape mechanism and demonstrate the involvement of MIF in immunogenic cell death during treatment with cytotoxic drugs. Targeting MIF may contribute to the restoration of immune sensitivity and the control of migration and metastatic invasion.
authors.affiliation: Department of Pediatric Surgery and Urology, University Children's Hospital Tübingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany.
authors.forename: Sarah Maria
authors.initials: SM
authors.lastname: Johler
authors.affiliation: Department of Pediatric Surgery and Urology, University Children's Hospital Tübingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Fuchs
authors.affiliation: Department of Pediatric Surgery and Urology, University Children's Hospital Tübingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Seitz
authors.affiliation: Department of Pediatric Surgery and Urology, University Children's Hospital Tübingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany. armeanu@uni-tuebingen.de.
authors.forename: Sorin
authors.initials: S
authors.lastname: Armeanu-Ebinger
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008263:Macrophage Migration-Inhibitory Factors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D012208:Rhabdomyosarcoma / Q000628:therapy*
chemical_list: D000970:Antineoplastic Agents; D008263:Macrophage Migration-Inhibitory Factors
keywords: Immune escape and surveillance; Immunotherapy; MDSCs; MIF inhibitors; Macrophage migration inhibitory factor (MIF); Rhabdomyosarcoma