title: Glioma-derived extracellular vesicles selectively suppress immune responses.
abstract: BACKGROUND
  Glioma-related immunosuppression is well documented; however, the mechanisms of suppression are not fully understood. Here we explore a role for glioma extracellular vesicles (EVs) as a means of immune modulation.
  
  
  METHODS
  Healthy donor peripheral blood mononuclear cells (PBMCs) were incubated with mitogenic stimuli and various concentrations of glioma-derived EVs. Intracellular signaling and cytokine output were determined by protein microarrays, and phenotypic changes were assessed by flow cytometry. Recall antigen testing, mixed lymphocyte reactions, and migration assays analyzed PBMC functional capacity.
  
  
  RESULTS
  Protein microarray data revealed induction of an immunosuppressive phenotype and cytokine output at high tumor-vesicle concentrations but an activated phenotype at low concentrations. T cell activation antigen expression confirmed differential activation profiles. Functional analyses revealed decreased migratory capacity of PBMCs after incubation with EVs; however, recall antigen and mixed lymphocyte tests indicated that activation capacity is still retained in EV-treated cells.
  
  
  CONCLUSIONS
  The differential effects of high and low EV concentrations dictate modulatory effects on PBMCs. These data provide a role for EVs at high concentrations for inducing selective tolerance of an immune response in a tumor setting. This suggests that lymphocytes in patients' circulation are not irreparably impaired, as previously thought, but can be rescued to augment antitumor responses.
authors.affiliation: Dept of Neurosurgery, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado (J.E.H, T.A.H, D.G., M.W.G); Skaggs School of Pharmacy, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado (J.S.R, T.J.A).
authors.forename: Justin E
authors.initials: JE
authors.lastname: Hellwinkel
authors.affiliation: Dept of Neurosurgery, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado (J.E.H, T.A.H, D.G., M.W.G); Skaggs School of Pharmacy, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado (J.S.R, T.J.A).
authors.forename: Jasmina S
authors.initials: JS
authors.lastname: Redzic
authors.affiliation: Dept of Neurosurgery, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado (J.E.H, T.A.H, D.G., M.W.G); Skaggs School of Pharmacy, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado (J.S.R, T.J.A).
authors.forename: Tessa A
authors.initials: TA
authors.lastname: Harland
authors.affiliation: Dept of Neurosurgery, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado (J.E.H, T.A.H, D.G., M.W.G); Skaggs School of Pharmacy, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado (J.S.R, T.J.A).
authors.forename: Dicle
authors.initials: D
authors.lastname: Gunaydin
authors.affiliation: Dept of Neurosurgery, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado (J.E.H, T.A.H, D.G., M.W.G); Skaggs School of Pharmacy, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado (J.S.R, T.J.A).
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Anchordoquy
authors.affiliation: Dept of Neurosurgery, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado (J.E.H, T.A.H, D.G., M.W.G); Skaggs School of Pharmacy, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado (J.S.R, T.J.A).
authors.forename: Michael W
authors.initials: MW
authors.lastname: Graner
mesh_terms: D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D055354:Exosomes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D000067128:Extracellular Vesicles / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005910:Glioma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D040081:Protein Array Analysis; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
chemical_list: D016207:Cytokines
keywords: T cells; exosomes/extracellular vesicles; glioma; immune suppression; immunology