title: Glioblastomas induce T-lymphocyte death by two distinct pathways involving gangliosides and CD70.
abstract: Here we report that glioblastoma multiforme (GBM) mediates immunosuppression by promoting T-cell death via tumor-associated CD70 and gangliosides that act through receptor-dependent and receptor-independent pathways, respectively. GBM lines cocultured with T cells induced lymphocyte death. The GBM lines were characterized for their expression of CD70, Fas ligand (FasL), and tumor necrosis factor-alpha (TNF-alpha), and the possible participation of those molecules in T-cell killing was assessed by doing GBM/T cell cocultures in the presence of anti-CD70 antibodies, Fas fusion proteins, or anti-TNF-alpha antibodies. CD70 but not TNF-alpha or FasL is responsible for initiating T-cell death via the receptor-dependent pathway. Of the four GBM cell lines that induced T-cell death, three highly expressed CD70. Two nonapoptogenic GBM lines (CCF3 and U138), on the other hand, had only minimally detectable CD70 expression. Blocking experiments with the anti-CD70 antibody confirmed that elevated CD70 levels were involved in the apoptogenicity of the three GBM lines expressing that molecule. Gangliosides were found to participate in the induction of T-cell apoptosis, because the glucosylceramide synthase inhibitor (PPPP) significantly reduced the abilities of all four apoptogenic lines to kill the lymphocytes. High-performance liquid chromatography (HPLC) and mass spectroscopy revealed that GM2, GM2-like gangliosides, and GD1a were synthesized in abundance by all four apoptogenic GBM lines but not by the two GBMs lacking activity. Furthermore, gangliosides isolated from GBM lines as well as HPLC fractions containing GM2 and GD1a were directly apoptogenic for T cells. Our results indicate that CD70 and gangliosides are both products synthesized by GBMs that may be key mediators of T-cell apoptosis and likely contribute to the T-cell dysfunction observed within the tumor microenvironment.
authors.affiliation: Department of Neurosurgery, Brain Tumor Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Chahlavi
authors.forename: Patricia
authors.initials: P
authors.lastname: Rayman
authors.forename: Amy L
authors.initials: AL
authors.lastname: Richmond
authors.forename: Kaushik
authors.initials: K
authors.lastname: Biswas
authors.forename: Renliang
authors.initials: R
authors.lastname: Zhang
authors.forename: Michael
authors.initials: M
authors.lastname: Vogelbaum
authors.forename: Charles
authors.initials: C
authors.lastname: Tannenbaum
authors.forename: Gene
authors.initials: G
authors.lastname: Barnett
authors.forename: James H
authors.initials: JH
authors.lastname: Finke
mesh_terms: D015703:Antigens, CD / Q000096:biosynthesis / Q000276:immunology*; D017209:Apoptosis / Q000276:immunology; D001932:Brain Neoplasms / Q000276:immunology* / Q000473:pathology; D053282:CD27 Ligand; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D053222:Fas Ligand Protein; D005732:Gangliosides / Q000276:immunology*; D005909:Glioblastoma / Q000276:immunology* / Q000473:pathology; D006801:Humans; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000276:immunology; D008565:Membrane Proteins / Q000096:biosynthesis / Q000276:immunology*; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology
chemical_list: D015703:Antigens, CD; D053282:CD27 Ligand; C505771:CD70 protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D005732:Gangliosides; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha