title: Serum exosomes and cytokines promote a T-helper cell type 2 environment in the peripheral blood of glioblastoma patients.
abstract: BACKGROUND
  Glioblastoma (GBM) is an aggressive infiltrative brain tumor with a particularly poor prognosis that is characterized by microvascular proliferation, necrotic tissue, and significant infiltration of M2-like monocytes. Compromised barrier function in tumor vasculature might be expected to permit communication between the tumor microenvironment and peripheral blood.
  
  
  METHODS
  To ascertain whether tumor-derived vesicles and/or factors might reach the bloodstream and what effects these molecules have on the peripheral compartment, we analyzed blood samples collected from primary GBM patients.
  
  
  RESULTS
  Notably, a significant number of patient sera samples contained tumor exosome-reactive immunoglobulin (Ig)G2 and IgG4 antibody isotypes, which are consistent with Th2 immunity. M2-like monocytes expressing CD14+ and CD163+, another indicator of Th2 bias, are elevated in GBM patient blood and associated with high serum concentrations of colony-stimulating factor 2 and 3, as well as interleukin-2, -4, and -13, the latter 2 cytokines being hallmarks of Th2 immunity. GBM patient sera samples induce high levels of CD163 expression when added to normal monocytes, providing mechanistic evidence of a basis for Th2 bias. Fractionation of GBM patient sera into samples enriched for exosomes or soluble factors proved that both fractions are capable of inducing CD163 expression in normal monocytes.
  
  
  CONCLUSIONS
  The results of the current study indicate a Th2 bias in the periphery of GBM patients, likely as a result of products elaborated by the tumor. Consequentially, through immune modulation these brain tumors exert systemic effects beyond the confines of the CNS.
authors.affiliation: Department of Neurological Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania (L.A.H., B.J.N., D.W.A., D.C.H.); Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania (D.C.H.); Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania (L.C.K.).
authors.forename: Larry A
authors.initials: LA
authors.lastname: Harshyne
authors.affiliation: Department of Neurological Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania (L.A.H., B.J.N., D.W.A., D.C.H.); Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania (D.C.H.); Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania (L.C.K.).
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Nasca
authors.affiliation: Department of Neurological Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania (L.A.H., B.J.N., D.W.A., D.C.H.); Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania (D.C.H.); Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania (L.C.K.).
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Kenyon
authors.affiliation: Department of Neurological Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania (L.A.H., B.J.N., D.W.A., D.C.H.); Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania (D.C.H.); Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania (L.C.K.).
authors.forename: David W
authors.initials: DW
authors.lastname: Andrews
authors.affiliation: Department of Neurological Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania (L.A.H., B.J.N., D.W.A., D.C.H.); Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania (D.C.H.); Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania (L.C.K.).
authors.forename: D Craig
authors.initials: DC
authors.lastname: Hooper
mesh_terms: D001932:Brain Neoplasms / Q000097:blood* / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000097:blood*; D055354:Exosomes / Q000276:immunology*; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000097:blood* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007132:Immunoglobulin Isotypes; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000276:immunology*
chemical_list: D016207:Cytokines; D007132:Immunoglobulin Isotypes
keywords: M2 monocytes; Th2 immunity; exosomes; glioblastoma immunity; peripheral blood mononuclear cells