Pharmacologic inhibition of lysine-specific demethylase 1 as a therapeutic and immune-sensitization strategy in pediatric high-grade glioma
Pharmacologic inhibition of lysine-specific demethylase 1 as a therapeutic and immune-sensitization strategy in pediatric high-grade glioma
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DOI：
10.1093/neuonc/noaa058
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发表时间：
2020-09-01
期刊：
影响因子：
15.9
通讯作者：
Chandra, Joya
中科院分区：
文献类型：
--
作者：
Bailey, Cavan P.;Figueroa, Mary;Chandra, Joya
背景。弥漫性中线胶质瘤（DMG），包括脑干弥漫性内在脑桥胶质瘤（DIPG），是无法治愈的小儿高级胶质瘤（pHGG）。H3组蛋白尾部（H3.1/3.3-K27M）的突变是DIPG的一个特征，使它们对染色质修饰剂的小分子抑制具有治疗敏感性。赖氨酸特异性去甲基酶1 （LSD1）的药理抑制与临床相关，但尚未在pHGG或dipg中仔细研究。采用患者源性DIPG细胞系、原位小鼠模型和pHGG数据集来评估LSD1抑制剂对细胞毒性和免疫基因表达的影响。用LSD1抑制剂预处理DIPG细胞，评估免疫细胞的细胞毒性，并利用信息学平台检测phgg的免疫浸润。使用临床相关的LSD1抑制剂在DIPG细胞系中建立了选择性细胞毒性和免疫原性基因标记。儿童HGG患者的测序数据表明，这种lsd1依赖性基因标记有利于生存。用这些抑制剂预处理DIPG增加了自然杀伤细胞（NK细胞）的裂解。催化LSD1抑制剂在体内诱导肿瘤消退，增强NK细胞输注，减轻肿瘤负担。患者数据的CIBERSORT分析证实NK浸润有利于患者生存，而CD8 T细胞对患者预后不利。催化LSD1抑制剂对NK细胞无干扰，而支架LSD1抑制剂对NK细胞有毒性，并且不会诱导DIPG细胞的基因标记。使用催化抑制剂抑制LSD1具有选择性细胞毒性，并促进免疫基因标记，增加NK细胞在体外和体内的杀伤，这代表了pHGG的治疗机会。
Background. Diffuse midline gliomas (DMG), including brainstem diffuse intrinsic pontine glioma (DIPG), are incurable pediatric high-grade gliomas (pHGG). Mutations in the H3 histone tail (H3.1/3.3-K27M) are a feature of DIPG, rendering them therapeutically sensitive to small-molecule inhibition of chromatin modifiers. Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) is clinically relevant but has not been carefully investigated in pHGG or DIPG.Methods. Patient-derived DIPG cell lines, orthotopic mouse models, and pHGG datasets were used to evaluate effects of LSD1 inhibitors on cytotoxicity and immune gene expression. Immune cell cytotoxicity was assessed in DIPG cells pretreated with LSD1 inhibitors, and informatics platforms were used to determine immune infiltration of pHGG.Results. Selective cytotoxicity and an immunogenic gene signature were established in DIPG cell lines using clinically relevant LSD1 inhibitors. Pediatric HGG patient sequencing data demonstrated survival benefit of this LSD1-dependent gene signature. Pretreatment of DIPG with these inhibitors increased lysis by natural killer (NK) cells. Catalytic LSD1 inhibitors induced tumor regression and augmented NK cell infusion in vivo to reduce tumor burden. CIBERSORT analysis of patient data confirmed NK infiltration is beneficial to patient survival, while CD8 T cells are negatively prognostic. Catalytic LSD1 inhibitors are nonperturbing to NK cells, while scaffolding LSD1 inhibitors are toxic to NK cells and do not induce the gene signature in DIPG cells.Conclusions. LSD1 inhibition using catalytic inhibitors is selectively cytotoxic and promotes an immune gene signature that increases NK cell killing in vitro and in vivo, representing a therapeutic opportunity for pHGG.