Immune checkpoint molecule herpes virus entry mediator is overexpressed and associated with poor prognosis in human glioblastomaResearch in context
Ming-Zhi Han,
Shuai Wang,
Wen-Bo Zhao,
Shi-Lei Ni,
Ning Yang,
Yang Kong,
Bin Huang,
An-Jing Chen,
Xin-Gang Li,
Jian Wang,
Dong-Hai Wang
Affiliations
Ming-Zhi Han
Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Shandong University, Key Laboratory of Brain Functional Remodeling, Shandong, 107# Wenhua Xi Road, Jinan 250012, China; K.G. Jebsen Brain Tumour Research Center, Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway
Shuai Wang
Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Shandong University, Key Laboratory of Brain Functional Remodeling, Shandong, 107# Wenhua Xi Road, Jinan 250012, China
Wen-Bo Zhao
Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Shandong University, Key Laboratory of Brain Functional Remodeling, Shandong, 107# Wenhua Xi Road, Jinan 250012, China
Shi-Lei Ni
Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Shandong University, Key Laboratory of Brain Functional Remodeling, Shandong, 107# Wenhua Xi Road, Jinan 250012, China
Ning Yang
Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Shandong University, Key Laboratory of Brain Functional Remodeling, Shandong, 107# Wenhua Xi Road, Jinan 250012, China
Yang Kong
Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Shandong University, Key Laboratory of Brain Functional Remodeling, Shandong, 107# Wenhua Xi Road, Jinan 250012, China
Bin Huang
Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Shandong University, Key Laboratory of Brain Functional Remodeling, Shandong, 107# Wenhua Xi Road, Jinan 250012, China
An-Jing Chen
Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Shandong University, Key Laboratory of Brain Functional Remodeling, Shandong, 107# Wenhua Xi Road, Jinan 250012, China
Xin-Gang Li
Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Shandong University, Key Laboratory of Brain Functional Remodeling, Shandong, 107# Wenhua Xi Road, Jinan 250012, China
Jian Wang
Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Shandong University, Key Laboratory of Brain Functional Remodeling, Shandong, 107# Wenhua Xi Road, Jinan 250012, China; K.G. Jebsen Brain Tumour Research Center, Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway
Dong-Hai Wang
Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Shandong University, Key Laboratory of Brain Functional Remodeling, Shandong, 107# Wenhua Xi Road, Jinan 250012, China; Corresponding author.
Background: Dysregulation of immune checkpoint molecules leads to immune evasion in human tumours but has become a viable target for tumour therapy. Here, we examined expression of Herpes virus entry mediator (HVEM), an immune checkpoint molecule, in human glioblastoma (GBM) to assess its potential as a molecular target for treatment. Methods: Molecular and clinical data from publicly available genomic databases containing WHO grade II-IV human glioma cases (n = 1866) were analyzed. Immunohistochemistry was applied to assess HVEM protein levels in primary tumour sections. Statistical analysis was performed using Matlab and R language. Findings: HVEM was found to be elevated in aggressive gliomas, particularly in the mesenchymal and isocitrate dehydrogenase (IDH) wild-type molecular subtypes of GBM. HVEMhigh tumours tended to be associated with amplification of EGFR and loss of PTEN, while HVEMlow tumours harbored mutations in IDH1 (93%). HVEM exhibited potential as a prognostic marker based on Cox regression and nomogram models. HVEM displayed intra-tumour heterogeneity and was more highly expressed in peri-necrotic and microvascular regions. Gene ontology and pathway analysis revealed enrichment of HVEM in multiple immune regulatory processes, such as suppression of T cell mediated immunity in GBM. Finally, in cell lineage analysis, HVEM was found to be tightly associated with several infiltrating immune and stromal cell types which localized to the tumour microenvironment. Interpretation: Our data highlights the importance of HVEM in the development of GBM and as a potential molecular target in combination with current immune checkpoint blockades for treatment of GBM. Keywords: Glioma, HVEM, Immune response, Prognosis, Tumour microenvironment
