Format

Send to

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

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

Author information

1
University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (X.Z., W.J.K.); Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania (A.P., A.R., C.D., P.S., Y.C., J.E., P.G., N.A.); Department of Neurological Surgery, University of California San Francisco, San Francisco, California (G.K., H.O.); Department of Biostatistics, University of Pittsburgh, Pittsburgh, Pennsylvania (Y.P.); Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois (J.C); Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York (T.C); Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania (M.L.); Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, Pennsylvania (A.P.).
2
University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (X.Z., W.J.K.); Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania (A.P., A.R., C.D., P.S., Y.C., J.E., P.G., N.A.); Department of Neurological Surgery, University of California San Francisco, San Francisco, California (G.K., H.O.); Department of Biostatistics, University of Pittsburgh, Pittsburgh, Pennsylvania (Y.P.); Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois (J.C); Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York (T.C); Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania (M.L.); Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, Pennsylvania (A.P.) amankulornm@upmc.edu.

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

PMID:
27116977
PMCID:
PMC5035522
DOI:
10.1093/neuonc/now061
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Silverchair Information Systems Icon for PubMed Central
Loading ...
Support Center