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

Xiaoran Zhang, Aparana Rao, Paola Sette, Christopher Deibert, Alexander Pomerantz, Wi Jin Kim, Gary Kohanbash, Yigang Chang, Yongseok Park, Johnathan Engh, Jaehyuk Choi, Timothy Chan, Hideho Okada, Michael Lotze, Paola Grandi, Nduka Amankulor*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

119 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1402-1412
Number of pages11
Issue number10
StatePublished - Oct 1 2016


  • IDH mutation
  • NKG2D ligands
  • Natural Killer cells
  • glioma
  • immune escape
  • immunotherapy

ASJC Scopus subject areas

  • Clinical Neurology
  • Oncology
  • Cancer Research


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