title: Glioblastoma-induced inhibition of Langerhans cell differentiation from CD34(+) precursors is mediated by IL-6 but unaffected by JAK2/STAT3 inhibition.
abstract: OBJECTIVE
  Langerhans cell (LC) infiltration has been observed in glioblastoma, but the glioblastoma microenvironment may be conditioned to resist antitumor immune responses. As little is known about how glioblastoma may affect dendritic cell differentiation, here we set out to delineate the effects of glioblastoma-derived soluble factors on LC differentiation.
  
  
  METHODS
  CD34(+) precursor cells of the human myeloid cell line MUTZ-3 were differentiated into LC in the presence of conditioned media of the human glioblastoma cell lines U251 or U373 and phenotypically and functionally characterized.
  
  
  RESULTS
  Glioblastoma-conditioned media inhibited LC differentiation, resulting in functional impairment, as determined by allogeneic mixed leukocyte reactivity, and induction of STAT3 activation. IL-6 blockade completely abrogated these glioblastoma-induced immunosuppressive effects and reduced STAT3 phosphorylation. However, neither addition of JSI-124 (cucurbitacin-I; a JAK2/STAT3 inhibitor), nor of GW5074 (a Raf-1 inhibitor), both of which interfere with signaling pathways reported to act downstream of the IL-6 receptor, prevented the observed inhibitory effects on LC differentiation.
  
  
  CONCLUSIONS
  Glioblastoma-derived IL-6 is responsible for the observed suppression of LC differentiation from CD34(+) precursors but appears to exert this effect in a STAT3 and Raf-1 independent fashion.
authors.affiliation: Division of Medical Oncology, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands.
authors.forename: Hester
authors.initials: H
authors.lastname: van Cruijsen
authors.forename: Dinja
authors.initials: D
authors.lastname: Oosterhoff
authors.forename: Jelle J
authors.initials: JJ
authors.lastname: Lindenberg
authors.forename: Sinéad M
authors.initials: SM
authors.lastname: Lougheed
authors.forename: Cynthia
authors.initials: C
authors.lastname: Fehres
authors.forename: Karin
authors.initials: K
authors.lastname: Weijers
authors.forename: Robert
authors.initials: R
authors.lastname: van Boerdonk
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giaccone
authors.forename: Rik J
authors.initials: RJ
authors.lastname: Scheper
authors.forename: Klaas
authors.initials: K
authors.lastname: Hoekman
authors.forename: Tanja D
authors.initials: TD
authors.lastname: de Gruijl
mesh_terms: D018952:Antigens, CD34 / Q000032:analysis*; D001932:Brain Neoplasms / Q000473:pathology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D005909:Glioblastoma / Q000473:pathology*; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology*; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000502:physiology*; D007801:Langerhans Cells / Q000166:cytology*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology
chemical_list: D018952:Antigens, CD34; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D016212:Transforming Growth Factor beta; C507924:JAK2 protein, human; D053614:Janus Kinase 2