Immune Checkpoint Molecule Herpes Virus Entry Mediator Is Overexpressed and Associated With Poor Prognosis in Human Glioblastoma

EBioMedicine. 2019 May;43:159-170. doi: 10.1016/j.ebiom.2019.04.002. Epub 2019 Apr 12.


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.

MeSH terms

  • Biomarkers, Tumor*
  • Disease Progression
  • Gene Expression Regulation, Neoplastic*
  • Genetic Heterogeneity
  • Genetic Variation
  • Genomics / methods
  • Glioblastoma / genetics*
  • Glioblastoma / immunology
  • Glioblastoma / mortality*
  • Glioblastoma / pathology
  • Humans
  • Immunohistochemistry
  • Immunomodulation / genetics
  • Kaplan-Meier Estimate
  • Neoplasm Grading
  • Prognosis
  • Receptors, Tumor Necrosis Factor, Member 14 / genetics*
  • Stromal Cells / metabolism
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • Tumor Microenvironment / genetics
  • Tumor Microenvironment / immunology


  • Biomarkers, Tumor
  • Receptors, Tumor Necrosis Factor, Member 14
  • TNFRSF14 protein, human