IDH mutant gliomas escape natural killer cell immune surveillance by downregulation of NKG2D ligand expression

Neuro Oncol. 2016 Oct;18(10):1402-12. doi: 10.1093/neuonc/now061. Epub 2016 Apr 25.


Background: Diffuse gliomas are poorly immunogenic, fatal brain tumors. The basis for insufficient antitumor immunity in diffuse gliomas is unknown. Gain-of-function mutations in isocitrate dehydrogenases (IDH1 and IDH2) promote diffuse glioma formation through epigenetic reprogramming of a number of genes, including immune-related genes. Here, we identify epigenetic dysregulation of natural killer (NK) cell ligand genes as significant contributors to immune escape in glioma.

Methods: We analyzed the database of The Cancer Genome Atlas for immune gene expression patterns in IDH mutant or wild-type gliomas and identified differentially expressed immune genes. NKG2D ligand expression levels and NK cell-mediated lysis were measured in IDH mutant and wild-type patient-derived glioma stem cells and genetically engineered astrocytes. Finally, we assessed the impact of hypomethylating agent 5-aza-2'deoxycytodine (decitabine) as a potential NK cell sensitizing agent in IDH mutant cells.

Results: IDH mutant glioma stemlike cell lines exhibited significantly lower expression of NKG2D ligands compared with IDH wild-type cells. Consistent with these findings, IDH mutant glioma cells and astrocytes are resistant to NK cell-mediated lysis. Decitabine increases NKG2D ligand expression and restores NK-mediated lysis of IDH mutant cells in an NKG2D-dependent manner.

Conclusions: IDH mutant glioma cells acquire resistance to NK cells through epigenetic silencing of NKG2D ligands ULBP1 and ULBP3. Decitabine-mediated hypomethylation restores ULBP1 and ULBP3 expression in IDH mutant glioma cells and may provide a clinically useful method to sensitize IDH mutant gliomas to NK cell-mediated immune surveillance in patients with IDH mutated diffuse gliomas.

Keywords: IDH mutation; NKG2D ligands; Natural Killer cells; glioma; immune escape; immunotherapy.

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Azacitidine / analogs & derivatives
  • Azacitidine / pharmacology
  • Brain Neoplasms / genetics
  • Brain Neoplasms / immunology
  • Brain Neoplasms / pathology*
  • DNA Methylation
  • Decitabine
  • Down-Regulation
  • GPI-Linked Proteins / biosynthesis
  • Gene Expression Regulation, Neoplastic / genetics*
  • Glioma / genetics
  • Glioma / immunology
  • Glioma / pathology*
  • Humans
  • Immunologic Surveillance
  • Intercellular Signaling Peptides and Proteins / biosynthesis*
  • Isocitrate Dehydrogenase / genetics*
  • Killer Cells, Natural / immunology
  • Mutation
  • Real-Time Polymerase Chain Reaction
  • Transcriptome
  • Tumor Escape / drug effects
  • Tumor Escape / genetics*


  • Antineoplastic Agents
  • GPI-Linked Proteins
  • Intercellular Signaling Peptides and Proteins
  • ULBP2 protein, human
  • Decitabine
  • Isocitrate Dehydrogenase
  • Azacitidine