Identification of CD70-mediated apoptosis of immune effector cells as a novel immune escape pathway of human glioblastoma.
Interactions of CD70, a tumor necrosis factor-related cell surface ligand and 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-alpha 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.
Wischhusen
Jörg
J
Laboratories of Molecular Neuro-Oncology, Institute for Cell Biology, University of Tübingen, 72076 Tübingen, Germany.
Jung
Gundram
G
Radovanovic
Ivan
I
Beier
Christoph
C
Steinbach
Joachim P
JP
Rimner
Andreas
A
Huang
Huatao
H
Schulz
Jörg B
JB
Ohgaki
Hiroko
H
Aguzzi
Adriano
A
Rammensee
Hans-Georg
HG
Weller
Michael
M
D015703:Antigens, CD; D017209:Apoptosis / Q000276:immunology*; D053282:CD27 Ligand; D005909:Glioblastoma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D014407:Tumor Cells, Cultured; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000276:immunology / Q000502:physiology
D015703:Antigens, CD; D053282:CD27 Ligand; C505771:CD70 protein, human; D008565:Membrane Proteins; D012333:RNA, Messenger; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7