title: Elevated levels of polymorphonuclear myeloid-derived suppressor cells in patients with glioblastoma highly express S100A8/9 and arginase and suppress T cell function.
abstract: Gliomas are primary brain tumors that are associated with a poor prognosis. The introduction of new treatment modalities (including immunotherapy) for these neoplasms in the last 3 decades has resulted in only limited improvement in survival. Gliomas are known to create an immunosuppressive microenvironment that hampers the efficacy of (immuno)therapy. One component of this immunosuppressive environment is the myeloid-derived suppressor cell (MDSC).
  
  
  
  We set out to analyze the presence and activation state of MDSCs in blood (n = 41) and tumor (n = 20) of glioma patients by measuring S100A8/9 and arginase using flow cytometry and qPCR. Inhibition of T cell proliferation and cytokine production after stimulation with anti-CD3/anti-CD28 coated beads was used to measure in vitro MDSC suppression capacity.
  
  
  
  We report a trend toward a tumor grade-dependent increase of both monocytic (M-) and polymorphonuclear (PMN-) MDSC subpopulations in the blood of patients with glioma. M-MDSCs of glioma patients have increased levels of intracellular S100A8/9 compared with M-MDSCs in healthy controls (HCs). Glioma patients also have increased S100A8/9 serum levels, which correlates with increased arginase activity in serum. PMN-MDSCs in both blood and tumor tissue demonstrated high expression of arginase. Furthermore, we assessed blood-derived PMN-MDSC function and showed that these cells have potent T cell suppressive function in vitro.
  
  
  
  These data indicate a tumor grade-dependent increase of MDSCs in the blood of patients with a glioma. These MDSCs exhibit an increased activation state compared with MDSCs in HCs, independent of tumor grade.
authors.affiliation: Tumor Immunology Laboratory, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands (P.R.G., B.M.S., E.D.K.-R., G.J.A.); Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands (K.V., P.W.); Department of Neurosurgery, Radboud University Medical Center, Nijmegen, the Netherlands (S.A.J.H.B., M.L.); Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands (P.W.).
authors.forename: Paul R
authors.initials: PR
authors.lastname: Gielen
authors.affiliation: Tumor Immunology Laboratory, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands (P.R.G., B.M.S., E.D.K.-R., G.J.A.); Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands (K.V., P.W.); Department of Neurosurgery, Radboud University Medical Center, Nijmegen, the Netherlands (S.A.J.H.B., M.L.); Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands (P.W.).
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Schulte
authors.affiliation: Tumor Immunology Laboratory, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands (P.R.G., B.M.S., E.D.K.-R., G.J.A.); Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands (K.V., P.W.); Department of Neurosurgery, Radboud University Medical Center, Nijmegen, the Netherlands (S.A.J.H.B., M.L.); Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands (P.W.).
authors.forename: Esther D
authors.initials: ED
authors.lastname: Kers-Rebel
authors.affiliation: Tumor Immunology Laboratory, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands (P.R.G., B.M.S., E.D.K.-R., G.J.A.); Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands (K.V., P.W.); Department of Neurosurgery, Radboud University Medical Center, Nijmegen, the Netherlands (S.A.J.H.B., M.L.); Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands (P.W.).
authors.forename: Kiek
authors.initials: K
authors.lastname: Verrijp
authors.affiliation: Tumor Immunology Laboratory, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands (P.R.G., B.M.S., E.D.K.-R., G.J.A.); Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands (K.V., P.W.); Department of Neurosurgery, Radboud University Medical Center, Nijmegen, the Netherlands (S.A.J.H.B., M.L.); Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands (P.W.).
authors.forename: Sandra A J F H
authors.initials: SA
authors.lastname: Bossman
authors.affiliation: Tumor Immunology Laboratory, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands (P.R.G., B.M.S., E.D.K.-R., G.J.A.); Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands (K.V., P.W.); Department of Neurosurgery, Radboud University Medical Center, Nijmegen, the Netherlands (S.A.J.H.B., M.L.); Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands (P.W.).
authors.forename: Mark
authors.initials: M
authors.lastname: Ter Laan
authors.affiliation: Tumor Immunology Laboratory, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands (P.R.G., B.M.S., E.D.K.-R., G.J.A.); Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands (K.V., P.W.); Department of Neurosurgery, Radboud University Medical Center, Nijmegen, the Netherlands (S.A.J.H.B., M.L.); Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands (P.W.).
authors.forename: Pieter
authors.initials: P
authors.lastname: Wesseling
authors.affiliation: Tumor Immunology Laboratory, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands (P.R.G., B.M.S., E.D.K.-R., G.J.A.); Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands (K.V., P.W.); Department of Neurosurgery, Radboud University Medical Center, Nijmegen, the Netherlands (S.A.J.H.B., M.L.); Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands (P.W.) gosse.adema@radboudumc.nl.
authors.forename: Gosse J
authors.initials: GJ
authors.lastname: Adema
mesh_terms: D001119:Arginase / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism; D001932:Brain Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D040501:Calgranulin A / Q000378:metabolism*; D040502:Calgranulin B / Q000378:metabolism*; D005909:Glioblastoma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008213:Lymphocyte Activation; D000072737:Myeloid-Derived Suppressor Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D040501:Calgranulin A; D040502:Calgranulin B; D001119:Arginase
keywords: MDSCs; S100A8/9; arginase; glioma