Department of Pediatrics , Research, The MD Anderson Cancer Center, Houston, Texas.
Department of Epigenetics and Molecular Carcinogenesis, The MD Anderson Cancer Center, Houston, Texas.
Neuro Oncol. 2020 Sep 29;22(9):1302-1314. doi: 10.1093/neuonc/noaa058.
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.
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.
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.
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.
1. LSD1 inhibition using several clinically relevant compounds is selectively cytotoxic in DIPG and shows in vivo efficacy as a single agent.2. An LSD1-controlled gene signature predicts survival in pHGG patients and is seen in neural tissue from LSD1 inhibitor-treated mice.3. LSD1 inhibition enhances NK cell cytotoxicity against DIPG in vivo and in vitro with correlative genetic biomarkers.
弥漫性中线脑胶质瘤（DMG），包括脑桥弥漫性内在脑桥胶质瘤（DIPG），是无法治愈的小儿高级别脑胶质瘤（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物的小分子抑制具有治疗敏感性。组蛋白赖氨酸特异性去甲基酶 1（LSD1）的药理学抑制在临床上是相关的，但在 pHGG 或 DIPG 中尚未得到仔细研究。
使用患者来源的 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。在 LSD1 抑制剂预处理的 DIPG 细胞中评估免疫细胞的细胞毒性，并使用信息学平台确定 pHGG 的免疫浸润。
使用临床上相关的 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特征。儿科 HGG 患者测序数据表明，这种 LSD1 依赖性基因特征具有生存获益。用这些抑制剂预处理 DIPG 可增加自然杀伤（NK）细胞的溶解。催化 LSD1 抑制剂诱导肿瘤消退，并增强 NK 细胞输注体内以减少肿瘤负担。对患者数据的 CIBERSORT 分析证实 NK 浸润有利于患者生存，而 CD8 T 细胞则具有负预后。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，并且不会诱导 DIPG 细胞中的基因特征。
使用催化抑制剂抑制 LSD1 在体外和体内选择性细胞毒性，并促进免疫基因特征，增加 NK 细胞的杀伤作用，为 pHGG 提供了治疗机会。
