title: Dynamics of central and peripheral immunomodulation in a murine glioma model.
abstract: BACKGROUND
  Immunosuppression by gliomas contributes to tumor progression and treatment resistance. It is not known when immunosuppression occurs during tumor development but it likely involves cross-talk among tumor cells, tumor-associated macrophages and microglia (TAMs), and peripheral as well as tumor-infiltrating lymphocytes (TILs).
  
  
  RESULTS
  We have performed a kinetic study of this immunomodulation, assessing the dynamics of immune infiltration and function, within the central nervous system (CNS) and peripherally. PDGF-driven murine glioma cells were injected into the white matter of 13 mice. Four mice were sacrificed 13 days post-injection (dpi), four mice at 26 dpi, and five mice at 40 dpi. Using multiparameter flow cytometry, splenic T cells were assessed for FoxP3 expression to identify regulatory T cells (Tregs) and production of IFN-gamma and IL-10 after stimulation with PMA/ionomycin; within the CNS, CD4+ TILs were quantified, and TAMs were quantified and assessed for TNF-alpha and IL-10 production after stimulation with LPS. Peripheral changes associated with tumor development were noted prior to effects within the CNS. The percentage of FoxP3+ regulatory T cells (Tregs) increased by day 26, with elevated frequencies throughout the duration of the study. This early increase in Tregs was paralleled by an increase in IL-10 production from Tregs. At the final time points examined (tumor morbidity or 40 dpi), there was an increase in the frequency of TAMs with decreased capacity to secrete TNF-alpha. An increase in TIL frequency was also observed at these final time points.
  
  
  CONCLUSIONS
  These data provide insight into the kinetics of the immunosuppressive state associated with tumor growth in a murine model of human gliomas. Functional impairment of TAMs occurs relatively late in the course of GBM tumor growth, potentially providing a window of opportunity for therapeutic strategies directed towards preventing their functional impairment.
authors.affiliation: Department of Neurosurgery, Gabriele Bartoli Brain Tumor Research Laboratory Columbia University, New York, NY, USA. bck2104@columbia.edu
authors.forename: Benjamin C
authors.initials: BC
authors.lastname: Kennedy
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Maier
authors.forename: Randy
authors.initials: R
authors.lastname: D'Amico
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Mandigo
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Fontana
authors.forename: Allen
authors.initials: A
authors.lastname: Waziri
authors.forename: Marcela C
authors.initials: MC
authors.lastname: Assanah
authors.forename: Peter
authors.initials: P
authors.lastname: Canoll
authors.forename: Richard C E
authors.initials: RC
authors.lastname: Anderson
authors.forename: David E
authors.initials: DE
authors.lastname: Anderson
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Bruce
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D015704:CD4 Antigens; D002465:Cell Movement / Q000276:immunology; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005910:Glioma / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D007165:Immunosuppression Therapy; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D017628:Microglia / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D010982:Platelet-Derived Growth Factor / Q000008:administration & dosage / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D015704:CD4 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D010982:Platelet-Derived Growth Factor; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma