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 journalArticle

37 Citations (Scopus)

Abstract

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
JournalNeuro-Oncology
Volume18
Issue number10
DOIs
StatePublished - Oct 1 2016

Fingerprint

Glioma
Natural Killer Cells
Down-Regulation
Ligands
decitabine
Epigenomics
Astrocytes
Genes
Isocitrate Dehydrogenase
Atlases
Brain Neoplasms
Immunity
Stem Cells
Genome
Databases
Gene Expression
Cell Line
Mutation

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

Cite this

Zhang, X., Rao, A., Sette, P., Deibert, C., Pomerantz, A., Kim, W. J., ... Amankulor, N. (2016). IDH mutant gliomas escape natural killer cell immune surveillance by downregulation of NKG2D ligand expression. Neuro-Oncology, 18(10), 1402-1412. https://doi.org/10.1093/neuonc/now061
Zhang, Xiaoran ; Rao, Aparana ; Sette, Paola ; Deibert, Christopher ; Pomerantz, Alexander ; Kim, Wi Jin ; Kohanbash, Gary ; Chang, Yigang ; Park, Yongseok ; Engh, Johnathan ; Choi, Jaehyuk ; Chan, Timothy ; Okada, Hideho ; Lotze, Michael ; Grandi, Paola ; Amankulor, Nduka. / IDH mutant gliomas escape natural killer cell immune surveillance by downregulation of NKG2D ligand expression. In: Neuro-Oncology. 2016 ; Vol. 18, No. 10. pp. 1402-1412.
@article{6ee57d070564440ea9641d82352eb6c3,
title = "IDH mutant gliomas escape natural killer cell immune surveillance by downregulation of NKG2D ligand expression",
abstract = "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",
author = "Xiaoran Zhang and Aparana Rao and Paola Sette and Christopher Deibert and Alexander Pomerantz and Kim, {Wi Jin} and Gary Kohanbash and Yigang Chang and Yongseok Park and Johnathan Engh and Jaehyuk Choi and Timothy Chan and Hideho Okada and Michael Lotze and Paola Grandi and Nduka Amankulor",
year = "2016",
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language = "English (US)",
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Zhang, X, Rao, A, Sette, P, Deibert, C, Pomerantz, A, Kim, WJ, Kohanbash, G, Chang, Y, Park, Y, Engh, J, Choi, J, Chan, T, Okada, H, Lotze, M, Grandi, P & Amankulor, N 2016, 'IDH mutant gliomas escape natural killer cell immune surveillance by downregulation of NKG2D ligand expression', Neuro-Oncology, vol. 18, no. 10, pp. 1402-1412. https://doi.org/10.1093/neuonc/now061

IDH mutant gliomas escape natural killer cell immune surveillance by downregulation of NKG2D ligand expression. / Zhang, Xiaoran; Rao, Aparana; Sette, Paola; Deibert, Christopher; Pomerantz, Alexander; Kim, Wi Jin; Kohanbash, Gary; Chang, Yigang; Park, Yongseok; Engh, Johnathan; Choi, Jaehyuk; Chan, Timothy; Okada, Hideho; Lotze, Michael; Grandi, Paola; Amankulor, Nduka.

In: Neuro-Oncology, Vol. 18, No. 10, 01.10.2016, p. 1402-1412.

Research output: Contribution to journalArticle

TY - JOUR

T1 - IDH mutant gliomas escape natural killer cell immune surveillance by downregulation of NKG2D ligand expression

AU - Zhang, Xiaoran

AU - Rao, Aparana

AU - Sette, Paola

AU - Deibert, Christopher

AU - Pomerantz, Alexander

AU - Kim, Wi Jin

AU - Kohanbash, Gary

AU - Chang, Yigang

AU - Park, Yongseok

AU - Engh, Johnathan

AU - Choi, Jaehyuk

AU - Chan, Timothy

AU - Okada, Hideho

AU - Lotze, Michael

AU - Grandi, Paola

AU - Amankulor, Nduka

PY - 2016/10/1

Y1 - 2016/10/1

N2 - 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.

AB - 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.

KW - IDH mutation

KW - NKG2D ligands

KW - Natural Killer cells

KW - glioma

KW - immune escape

KW - immunotherapy

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U2 - 10.1093/neuonc/now061

DO - 10.1093/neuonc/now061

M3 - Article

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AN - SCOPUS:84991392300

VL - 18

SP - 1402

EP - 1412

JO - Neuro-Oncology

JF - Neuro-Oncology

SN - 1522-8517

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