title: CD4+ T effector memory cell dysfunction is associated with the accumulation of granulocytic myeloid-derived suppressor cells in glioblastoma patients.
abstract: Myeloid-derived suppressor cells (MDSCs) comprise a heterogeneous population of myeloid cells that are significantly expanded in cancer patients and are associated with tumor progression.
  
  
  
  Multicolor flow cytometry was used to study the frequency, phenotype, and function of MDSCs in peripheral blood and freshly resected tumors of 52 participants with primary glioblastoma (GBM).
  
  
  
  The frequency of CD14(high)CD15(pos) monocytic and CD14(low)CD15(pos) granulocytic MDSCs was significantly higher in peripheral blood of GBM participants compared with healthy donors. The majority of granulocytic MDSCs consisted of CD14(low)CD15(high) neutrophilic MDSCs with high T-cell suppressive capacities. At the tumor side, we found an increase in CD14(high)CD15(pos) monocytic MDSCs and high frequencies of CD14(low)CD15(pos) granulocytic MDSCs that displayed an activated phenotype with downregulation of CD16 and upregulation of HLA-DR molecules, which did not inhibit T-cell proliferative responses in vitro. However, a strong association between granulocytic MDSCs and CD4(+) effector memory T-cells (TEM) within the tumors was detected. Tumor-derived CD4(+) TEM expressed high levels of PD-1 when compared with their blood-derived counterparts and were functionally exhausted. The respective ligand, PD-L1, was significantly upregulated on tumor-derived MDSCs, and T-cell co-culture experiments confirmed that glioma-infiltrating MDSCs can induce PD-1 expression on CD4(+) TEM.
  
  
  
  Our findings provide a detailed characterization of different MDSC subsets in GBM patients and indicate that both granulocytic MDSCs in peripheral blood and at the tumor site play a major role in GBM-induced T-cell suppression.
authors.affiliation: Department of Neurology, University Hospital of Regensburg, Regensburg, Germany (D.D., U.B.); Department of Neurosurgery, University Hospital of Muenster, Muenster, Germany (J.W., W.S.); Institute of Neuropathology, University Hospital of Muenster, Muenster, Germany (M.H.); Department of Neurology, University Hospital of Muenster, Muenster, Germany (T.S.-H., H.W., O.M.G.).
authors.forename: Daniel
authors.initials: D
authors.lastname: Dubinski
authors.affiliation: Department of Neurology, University Hospital of Regensburg, Regensburg, Germany (D.D., U.B.); Department of Neurosurgery, University Hospital of Muenster, Muenster, Germany (J.W., W.S.); Institute of Neuropathology, University Hospital of Muenster, Muenster, Germany (M.H.); Department of Neurology, University Hospital of Muenster, Muenster, Germany (T.S.-H., H.W., O.M.G.).
authors.forename: Johannes
authors.initials: J
authors.lastname: Wölfer
authors.affiliation: Department of Neurology, University Hospital of Regensburg, Regensburg, Germany (D.D., U.B.); Department of Neurosurgery, University Hospital of Muenster, Muenster, Germany (J.W., W.S.); Institute of Neuropathology, University Hospital of Muenster, Muenster, Germany (M.H.); Department of Neurology, University Hospital of Muenster, Muenster, Germany (T.S.-H., H.W., O.M.G.).
authors.forename: Martin
authors.initials: M
authors.lastname: Hasselblatt
authors.affiliation: Department of Neurology, University Hospital of Regensburg, Regensburg, Germany (D.D., U.B.); Department of Neurosurgery, University Hospital of Muenster, Muenster, Germany (J.W., W.S.); Institute of Neuropathology, University Hospital of Muenster, Muenster, Germany (M.H.); Department of Neurology, University Hospital of Muenster, Muenster, Germany (T.S.-H., H.W., O.M.G.).
authors.forename: Tilman
authors.initials: T
authors.lastname: Schneider-Hohendorf
authors.affiliation: Department of Neurology, University Hospital of Regensburg, Regensburg, Germany (D.D., U.B.); Department of Neurosurgery, University Hospital of Muenster, Muenster, Germany (J.W., W.S.); Institute of Neuropathology, University Hospital of Muenster, Muenster, Germany (M.H.); Department of Neurology, University Hospital of Muenster, Muenster, Germany (T.S.-H., H.W., O.M.G.).
authors.forename: Ulrich
authors.initials: U
authors.lastname: Bogdahn
authors.affiliation: Department of Neurology, University Hospital of Regensburg, Regensburg, Germany (D.D., U.B.); Department of Neurosurgery, University Hospital of Muenster, Muenster, Germany (J.W., W.S.); Institute of Neuropathology, University Hospital of Muenster, Muenster, Germany (M.H.); Department of Neurology, University Hospital of Muenster, Muenster, Germany (T.S.-H., H.W., O.M.G.).
authors.forename: Walter
authors.initials: W
authors.lastname: Stummer
authors.affiliation: Department of Neurology, University Hospital of Regensburg, Regensburg, Germany (D.D., U.B.); Department of Neurosurgery, University Hospital of Muenster, Muenster, Germany (J.W., W.S.); Institute of Neuropathology, University Hospital of Muenster, Muenster, Germany (M.H.); Department of Neurology, University Hospital of Muenster, Muenster, Germany (T.S.-H., H.W., O.M.G.).
authors.forename: Heinz
authors.initials: H
authors.lastname: Wiendl
authors.affiliation: Department of Neurology, University Hospital of Regensburg, Regensburg, Germany (D.D., U.B.); Department of Neurosurgery, University Hospital of Muenster, Muenster, Germany (J.W., W.S.); Institute of Neuropathology, University Hospital of Muenster, Muenster, Germany (M.H.); Department of Neurology, University Hospital of Muenster, Muenster, Germany (T.S.-H., H.W., O.M.G.).
authors.forename: Oliver M
authors.initials: OM
authors.lastname: Grauer
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D049109:Cell Proliferation / Q000502:physiology; D018920:Coculture Techniques; D005434:Flow Cytometry / Q000379:methods; D005909:Glioblastoma / Q000276:immunology / Q000473:pathology*; D006801:Humans; D007156:Immunologic Memory; D008213:Lymphocyte Activation / Q000276:immunology; D009000:Monocytes / Q000276:immunology; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism*; D000072737:Myeloid-Derived Suppressor Cells / Q000166:cytology* / Q000276:immunology
keywords: PD-1; PD-L1; T effector memory cell; glioblastoma; myeloid-derived suppressor cell