异柠檬酸脱氢酶（IDH）突变型胶质瘤通过下调自然杀伤细胞2D型受体（NKG2D）配体的表达来逃避自然杀伤细胞的免疫监视。
IDH mutant gliomas escape natural killer cell immune surveillance by downregulation of NKG2D ligand expression.
作者信息
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
机构信息
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.).
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.)
出版信息
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.
背景
弥漫性胶质瘤是免疫原性差的致命性脑肿瘤。弥漫性胶质瘤抗肿瘤免疫不足的原因尚不清楚。异柠檬酸脱氢酶（IDH1和IDH2）的功能获得性突变通过对包括免疫相关基因在内的许多基因进行表观遗传重编程来促进弥漫性胶质瘤的形成。在此，我们确定自然杀伤（NK）细胞配体基因的表观遗传失调是胶质瘤免疫逃逸的重要因素。
方法
我们分析了癌症基因组图谱数据库中IDH突变型或野生型胶质瘤的免疫基因表达模式，并鉴定出差异表达的免疫基因。在IDH突变型和野生型患者来源的胶质瘤干细胞和基因工程星形胶质细胞中测量NKG2D配体表达水平和NK细胞介导的细胞裂解。最后，我们评估了低甲基化剂5-氮杂-2'-脱氧胞苷（地西他滨）作为IDH突变细胞中潜在NK细胞致敏剂的影响。
结果
与IDH野生型细胞相比，IDH突变型胶质瘤干细胞样细胞系中NKG2D配体的表达明显降低。与这些发现一致，IDH突变型胶质瘤细胞和星形胶质细胞对NK细胞介导的细胞裂解具有抗性。地西他滨以NKG2D依赖的方式增加NKG2D配体表达并恢复NK介导的IDH突变细胞的裂解。
结论
IDH突变型胶质瘤细胞通过NKG2D配体ULBP1和ULBP3的表观遗传沉默获得对NK细胞的抗性。地西他滨介导的低甲基化恢复了IDH突变型胶质瘤细胞中ULBP1和ULBP3的表达，并可能提供一种临床上有用的方法，使IDH突变的弥漫性胶质瘤患者的IDH突变型胶质瘤对NK细胞介导的免疫监视敏感。
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