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Identification of CD70-mediated Apoptosis of Immune Effector Cells as a Novel Immune Escape Pathway of Human Glioblastoma¹

Laboratories of Molecular Neuro-Oncology [J. W., J. P. S., A. R., M. W.] and Neurodegeneration [C. B., J. B. S.], Department of Neurology, and Department of Immunology [G. J., H-G. R.], Institute for Cell Biology, University of Tübingen, 72076 Tübingen, Germany; Institute of Neuropathology, University of Zürich, 8091 Zürich, Switzerland [I. R., A. A.]; and International Agency for Research on Cancer, 69372 Lyon, France [H. H., H. O.]

Interactions of CD70, a tumor necrosis factor-related cell surface ligandand its receptor, CD27, are thought to play an important role for T-, B-, and natural killer-cell activation. However, ligation of CD27 can also induce apoptosis. Human glioblastoma is paradigmatic for cancer-associated immunosuppression. We identified CD70 as a radioinducible gene in U87 MG glioma cells. A screening of a panel of human glioma cell lines revealed that 11 of 12 cell lines expressed CD70 mRNA and protein. Two human neuroblastoma cell lines did not express CD70. CD70 mRNA expression was enhanced by irradiation in 8 of 12 glioma cell lines in a p53-independent manner. No alteration in CD70 expression was observed after glioma cell exposure to cytotoxic drugs such as lomustine. CD70 protein was also detected by immunocytochemistry in 5 of 12 glioblastomas and 3 of 4 anaplastic astrocytomas in vivo. CD27 expression was not detected in any glioma cell line, and there was no evidence for autocrine or backward signaling of the CD70 system in human glioma cells. Unexpectedly, CD70 expressed on glioma cells did not increase the immunogenicity of glioma cells in vitro. In contrast, CD70-positive glioma cells induced apoptosis in peripheral blood mononuclear cells (PBMCs) in a CD70-dependent manner. Neutralization of CD70 expressed on glioma cells prevented apoptosis and enhanced the release of tumor necrosis factor- in cocultures of glioma cells and PBMCs. The effects of CD70-expressing glioma cells on PBMCs were mimicked by agonistic CD27 antibodies. Conversely, the shedding of CD27 by PBMCs was identified as a possible escape mechanism from glioma cell-induced CD70-dependent apoptosis. Thus, induction of B-cell and T-cell apoptosis via interactions of CD70 expressed on glioma cells and CD27 expressed on B and T cells may be a novel way for the immune escape of malignant gliomas.

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