Tomas Hrbac1, Alena Kopkova2, Frantisek Siegl2, Marek Vecera2, Michaela Ruckova2, Tomas Kazda3, Radim Jancalek4, Michal Hendrych5, Marketa Hermanova5, Vaclav Vybihal6, Pavel Fadrus6, Martin Smrcka6, Filip Sokol7, Vaclav Kubes7, Radim Lipina1, Ondrej Slaby2,8,9, Leos Kren10, Jiri Sana11,9. 1. Department of Neurosurgery, University Hospital Ostrava, Ostrava, Czech Republic. 2. Central European Institute of Technology, Masaryk University, Brno, Czech Republic. 3. Department of Radiation Oncology, Masaryk Memorial Cancer Institute and Faculty of Medicine of Masaryk University, Brno, Czech Republic. 4. Department of Neurosurgery, St. Anne's University Hospital and Faculty of Medicine of Masaryk University, Brno, Czech Republic. 5. First Department of Pathology, St. Anne's University Hospital and Faculty of Medicine of Masaryk University, Brno, Czech Republic. 6. Department of Neurosurgery, University Hospital Brno, Brno, Czech Republic. 7. Department of Pathology, University Hospital Brno, Brno, Czech Republic. 8. Department of Biology, Faculty of Medicine of Masaryk University, Brno, Czech Republic. 9. Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, Brno, Czech Republic. 10. Department of Pathology, University Hospital Brno, Brno, Czech Republic; Kren.Leos@fnbrno.cz. 11. Central European Institute of Technology, Masaryk University, Brno, Czech Republic; sana.jiri@gmail.com.
Abstract
BACKGROUND/AIM: Glioblastoma (GBM) is one of the deadliest human cancers responding very poorly to therapy. Although the central nervous system has been traditionally considered an immunologically privileged site with an enhanced immune response, GBM appears to benefit from this immunosuppressive milieu. Immunomodulatory molecules play an important role in immune tumor-host interactions. Non-classical human leukocyte antigens (HLA) class Ib molecules HLA-E, HLA-F, and HLA-G have been previously described to be involved in protecting semi-allogeneic fetal allografts from the maternal immune response and in transplant tolerance as well as tumoral immune escape. Unfortunately, their role in GBM remains poorly understood. Our study, therefore, aimed to characterize the relationship between the expression of these molecules in GBM on the transcriptional level and clinicopathological and molecular features of GBM as well as the effect of ionizing radiation. MATERIALS AND METHODS: We performed the analysis of HLA-E, HLA-F, and HLA-G mRNA expression in 69 GBM tissue samples and 21 non-tumor brain tissue samples (controls) by reverse transcription polymerase chain reaction. Furthermore, two primary GBM cell cultures had been irradiated to identify the effect of ionizing radiation on the expression of non-classical HLA molecules. RESULTS: Analyses revealed that both HLA-E and HLA-F are significantly up-regulated in GBM samples. Subsequent survival analysis showed a significant association between low expression of HLA-E and shorter survival of GBM patients. The dysregulated expression of both molecules was also observed between patients with methylated and unmethylated O-6-methylguanine-DNA methyltransferase (MGMT) promoter. Finally, we showed that ionizing radiation increased HLA-E expression level in GBM cells in vitro. CONCLUSION: HLA-E and HLA-F play an important role in GBM biology and could be used as diagnostic biomarkers, and in the case of HLA-E also as a prognostic biomarker.
BACKGROUND/AIM: Glioblastoma (GBM) is one of the deadliest human cancers responding very poorly to therapy. Although the central nervous system has been traditionally considered an immunologically privileged site with an enhanced immune response, GBM appears to benefit from this immunosuppressive milieu. Immunomodulatory molecules play an important role in immune tumor-host interactions. Non-classical human leukocyte antigens (HLA) class Ib molecules HLA-E, HLA-F, and HLA-G have been previously described to be involved in protecting semi-allogeneic fetal allografts from the maternal immune response and in transplant tolerance as well as tumoral immune escape. Unfortunately, their role in GBM remains poorly understood. Our study, therefore, aimed to characterize the relationship between the expression of these molecules in GBM on the transcriptional level and clinicopathological and molecular features of GBM as well as the effect of ionizing radiation. MATERIALS AND METHODS: We performed the analysis of HLA-E, HLA-F, and HLA-G mRNA expression in 69 GBM tissue samples and 21 non-tumor brain tissue samples (controls) by reverse transcription polymerase chain reaction. Furthermore, two primary GBM cell cultures had been irradiated to identify the effect of ionizing radiation on the expression of non-classical HLA molecules. RESULTS: Analyses revealed that both HLA-E and HLA-F are significantly up-regulated in GBM samples. Subsequent survival analysis showed a significant association between low expression of HLA-E and shorter survival of GBM patients. The dysregulated expression of both molecules was also observed between patients with methylated and unmethylated O-6-methylguanine-DNA methyltransferase (MGMT) promoter. Finally, we showed that ionizing radiation increased HLA-E expression level in GBM cells in vitro. CONCLUSION: HLA-E and HLA-F play an important role in GBM biology and could be used as diagnostic biomarkers, and in the case of HLA-E also as a prognostic biomarker.
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