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Glioblastomas Induce T-Lymphocyte Death by Two Distinct Pathways Involving Gangliosides and CD70

¹ Department of Neurosurgery, Brain Tumor Institute, ² Department of Immunology, Lerner Research Institute, and ³ Department of Cell Biology, Cleveland Clinic Foundation, Cleveland, Ohio

Requests for reprints: James H. Finke, Department of Immunology, NB30, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195. Phone: 216-444-5186; Fax: 216-444-9329; E-mail: finkej{at}ccf.org.

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- (TNF-), 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- antibodies. CD70 but not TNF- 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.

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