title: Increasing glioma-associated monocytes leads to increased intratumoral and systemic myeloid-derived suppressor cells in a murine model.
abstract: BACKGROUND
  Patients with glioblastoma multiforme (GBM) exhibit marked intratumoral and systemic immunosuppression. GBM is heavily infiltrated with monocytic cells. Monocytes contacting GBM cells develop features of immunosuppressive myeloid-derived suppressor cells (MDSCs), which are elevated in GBM patients. Therefore, we hypothesized that circulating MDSC levels could be raised in vivo by increasing glioma-associated macrophages.
  
  
  METHODS
  GL261-luciferase glioma was implanted intracranially in C57BL/6 mice with or without additional normal syngeneic CD11b+ monocytes. Tumor growth and intratumoral and systemic MDSC (CD11b+/Gr-1+) levels were determined. Green fluorescent protein (GFP)-transgenic monocytes were coinjected intracranially with GL261-luciferase cells. GFP+ cell frequency among splenic and bone marrow MDSCs was determined. Impact of increased MDSC's on spontaneous immune responses to tumor cells expressing a model antigen (ovalbumin [OVA]) was determined.
  
  
  RESULTS
  Tumors grew faster and MDSC's were increased in tumor, spleen, and bone marrow in mice receiving GL261-Luc plus monocytes. Many (30%-50%) systemic MDSC's were GFP+ in mice receiving intracranial tumor plus GFP-transgenic monocytes, suggesting that they originated from glioma-associated monocytes. Tumor-infiltrating OVA-specific CD8+ T cells were markedly reduced in mice receiving GL261-OVA and monocytes compared with mice receiving GL261-OVA alone.
  
  
  CONCLUSIONS
  Increasing glioma-associated macrophages in intracranial GL261 glioma decreases survival and markedly increases intratumoral and systemic MDSC's, many of which originate directly from glioma-associated macrophages. This is associated with decreased spontaneous immune responses to a model antigen. To our knowledge, this is the first evidence in cancer that systemic MDSC's can arise directly from normal monocytes that have undergone intratumoral immunosuppressive education.
authors.affiliation: Department of Neurological Surgery (M.C., T.E.P., A.B., S.C., L.Z., I.F.P.) and Department of Immunology, Mayo Clinic, Rochester, Minnesota (D.N.R., A.J.J.).
authors.forename: Michael
authors.initials: M
authors.lastname: Chae
authors.affiliation: Department of Neurological Surgery (M.C., T.E.P., A.B., S.C., L.Z., I.F.P.) and Department of Immunology, Mayo Clinic, Rochester, Minnesota (D.N.R., A.J.J.).
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Peterson
authors.affiliation: Department of Neurological Surgery (M.C., T.E.P., A.B., S.C., L.Z., I.F.P.) and Department of Immunology, Mayo Clinic, Rochester, Minnesota (D.N.R., A.J.J.).
authors.forename: Alexis
authors.initials: A
authors.lastname: Balgeman
authors.affiliation: Department of Neurological Surgery (M.C., T.E.P., A.B., S.C., L.Z., I.F.P.) and Department of Immunology, Mayo Clinic, Rochester, Minnesota (D.N.R., A.J.J.).
authors.forename: Selby
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Neurological Surgery (M.C., T.E.P., A.B., S.C., L.Z., I.F.P.) and Department of Immunology, Mayo Clinic, Rochester, Minnesota (D.N.R., A.J.J.).
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Neurological Surgery (M.C., T.E.P., A.B., S.C., L.Z., I.F.P.) and Department of Immunology, Mayo Clinic, Rochester, Minnesota (D.N.R., A.J.J.).
authors.forename: Danielle N
authors.initials: DN
authors.lastname: Renner
authors.affiliation: Department of Neurological Surgery (M.C., T.E.P., A.B., S.C., L.Z., I.F.P.) and Department of Immunology, Mayo Clinic, Rochester, Minnesota (D.N.R., A.J.J.).
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Johnson
authors.affiliation: Department of Neurological Surgery (M.C., T.E.P., A.B., S.C., L.Z., I.F.P.) and Department of Immunology, Mayo Clinic, Rochester, Minnesota (D.N.R., A.J.J.).
authors.forename: Ian F
authors.initials: IF
authors.lastname: Parney
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000502:physiology; D001932:Brain Neoplasms / Q000276:immunology / Q000503:physiopathology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005910:Glioma / Q000276:immunology / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000276:immunology / Q000502:physiology*; D013154:Spleen / Q000503:physiopathology
keywords: GL261; glioma; immunosuppression; myeloid-derived suppressor cell; tumor-associated macrophage