PO.IM02.06 · 免疫学
三突变型星形细胞瘤中依赖 BRD 和 EHMT 的免疫抑制性转录组
BRD- and EHMT-dependent immunosuppressive transcriptome in triple-mutant Astrocytoma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
星形细胞瘤（WHO II 级和 III 级）主要发生于成年早中期，尽管采用最佳标准治疗，仍常进展为侵袭性更强的继发性 GBM。开发更有效的治疗策略需要更全面地理解星形细胞瘤细胞逃避抗肿瘤免疫所采用的机制。大多数（约 80%）II 级和 III 级星形细胞瘤携带异柠檬酸脱氢酶突变（例如 IDH1 R132H），通常与 p53 突变和 ATRX 失活同时出现（即 IDH1 R132H/p53 mut/ATRX loss，为简便起见称为三突变），表明这一三突变背景在肿瘤生长和肿瘤微环境重编程（可能包括免疫逃逸机制）中具有重要作用。我们近期的研究结果表明，三突变诱导多条具有抗肿瘤免疫调节潜力的通路，包括检查点配体、IFN-gamma 信号不敏感、MHC-I 和 -II 抗原呈递通路（MHC APP）下调，以及调节星形细胞瘤免疫微环境的失调细胞因子/趋化因子谱。此外，我们发现与三突变星形细胞瘤相关的免疫调节转录组成分被标准治疗放疗（IR）和替莫唑胺（TMZ）所增强。表观遗传机制协调肿瘤细胞和免疫抑制性微环境。BET 蛋白作为表观遗传阅读器，通过结合乙酰化赖氨酸残基和/或蛋白伴侣来调节基因表达，而 EHMT1/2 作为组蛋白赖氨酸-N-甲基转移酶与基因的表观遗传沉默相关。我们发现依赖 BRD 和 EHMT 的组蛋白修饰在三突变星形细胞瘤细胞中升高，二者共同产生免疫调节转录组。泛 BET 溴结构域抑制剂（例如 JQ1）显著抑制与三突变星形细胞瘤相关以及由 IR/TMZ 诱导的免疫抑制性转录组，而泛 EHMT 抑制剂 UNC0642 显著上调 MHC APP 基因和 IFN 信号相关基因。意义：我们的发现鉴定出可靶向的表观遗传决定因素，它们诱导与三突变星形细胞瘤免疫抑制性微环境相关的免疫抑制性转录组。
查看英文原文 English abstract
Astrocytomas (WHO grade II and III) primarily occur in early-middle adult life and frequently progress to more aggressive secondary GBM despite best standard-of-care therapy. Developing more effective therapeutic strategies requires a more complete understanding of the mechanisms employed by astrocytoma cells to escape anti-tumor immunity. The majority (~80%) of grade II & III astrocytoma carry mutations in isocitrate dehydrogenase (e.g., IDH1 R132H ), which typically occurs in combination with p53 mutation and ATRX inactivation (i.e., IDH1 R132H /p53 mut /ATRX loss, triple-mut for simplicity), indicating that this triple mutation background has an important role in tumor growth and tumor microenvironment reprogramming potentially including immune evasion mechanisms. Our recent findings show that triple-mut induces multiple pathways with anti-tumor immune modulating potential including checkpoint ligands, IFN-gamma signaling insensitivity, down-regulation of MHC-I and -II antigen presentation pathways (MHC APP), and dysregulated cytokine/chemokine profiles that modulate the astrocytoma immune microenvironment. Furthermore, we found that the components of the immune-modulating transcriptome associated with triple-mut astrocytom are augmented by standard-of-care radiation (IR) and temozolomide (TMZ). Epigenetic mechanisms orchestrate the tumor cell and the immunosuppressive microenvironment. BET proteins as epigenetic readers regulate gene expression by binding to acetylated lysine residues and/or protein partners, while EHMT1/2 as histone-lysine-N-methyltransferases associated with epigenetic silencing of genes. We show that BRD- and EHMT-dependent histone modifications are elevated in triple-mut astrocytoma cells and together generate the immune-modulating transcriptome. Pan-BET bromodomain inhibitors (e.g., JQ1) significantly inhibited the immunosuppressive transcriptome associated with triple-mut astrocytoma and induced by IR/TMZ, and the pan -EHMT inhibitor UNC0642 significantly up-regulated MHC APP genes and IFN signaling-related genes. SIGNIFICANCE: our findings identify targetable epigenetic determinants that induce an immunosuppressive transcriptome associated with the immunosuppressive microenvironment in triple-mut astrocytoma.
利益披露 Disclosure
Y. Li, None.