LBPO.IM01 · 免疫学 · Late-Breaking
靶向SUV39H1表观遗传沉默以诱导病毒模拟并抑制胶质母细胞瘤生长
Targeting suv39h1 epigenetic silencing to induce viral mimicry and suppress glioblastoma growth
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
胶质母细胞瘤（GBM）仍是最具侵袭性和治疗抵抗性的脑肿瘤之一。SUV39H1等组蛋白甲基转移酶对转座元件（TEs）的表观遗传沉默通过阻止病毒模拟而抑制先天免疫激活。在本研究中，我们探讨了对SUV39H1进行药理或基因抑制是否能够重新激活被沉默的逆转录元件并在GBM中刺激抗肿瘤免疫。我们证明，在鼠源胶质瘤模型（CT2A和005-GSC）中抑制SUV39H1可导致胞质双链RNA（dsRNA）的强烈积累、包括LINE-1在内的内源性逆转录元件的上调，以及干扰素刺激基因（ISGs）的激活，这些都是病毒模拟诱导的特征。这些分子变化伴随复制应激标志物的升高，包括胞质dsDNA、gammaH2AX和phospho-RPA32 T21的增加，提示一种双重的抗肿瘤活性机制。在体内，使用小分子抑制剂F5446进行SUV39H1治疗可显著减少肿瘤生长并延长原位GBM模型的生存期。对治疗后GBM肿瘤的免疫荧光分析显示LINE-1 ORF2蛋白表达增加，且肿瘤驻留小胶质细胞向促炎表型转变，表现为CD86⁺小胶质细胞增加和ARG1⁺小胶质细胞减少，提示由表观遗传重编程驱动的肿瘤微环境重塑。总之，我们的研究结果将SUV39H1定位为一个抑制胶质母细胞瘤中免疫刺激信号的核心表观遗传屏障。抑制它可刺激病毒模拟并诱导复制应激，为使GBM对免疫治疗敏感提供了一种有前景的策略。本研究为未来将表观遗传药物与免疫检查点抑制剂相结合以克服胶质母细胞瘤免疫逃逸的联合治疗铺平了道路。
查看英文原文 English abstract
Glioblastoma (GBM) remains one of the most aggressive and treatment-resistant brain tumors. Epigenetic silencing of transposable elements (TEs) by histone methyltransferases such as SUV39H1 suppresses innate immune activation by preventing viral mimicry. In this study, we investigated whether pharmacological or genetic inhibition of SUV39H1 could reactivate silenced retroelements and stimulate anti-tumor immunity in GBM. We demonstrate that SUV39H1 inhibition in murine glioma models (CT2A and 005-GSC) leads to a robust accumulation of cytosolic double-stranded RNA (dsRNA), upregulation of endogenous retroelements including LINE-1, and activation of interferon-stimulated genes (ISGs), all hallmarks of viral mimicry induction. These molecular changes were accompanied by elevated replication stress markers, including increased cytosolic dsDNA, gammaH2AX, and phospho-RPA32 T21 , indicating a dual mechanism of anti-tumor activity. In vivo, SUV39H1 treatment with the small-molecule inhibitor F5446 significantly reduced tumor growth and extended survival in orthotopic GBM models. Immunofluorescence analysis of treated GBM tumors revealed increased LINE-1 ORF2 protein expression and a shift in tumor-resident microglia toward a pro-inflammatory phenotype, characterized by increased CD86⁺ microglia and reduced ARG1⁺ microglia, suggesting tumor microenvironment remodeling driven by epigenetic reprogramming. Together, our findings position SUV39H1 as a central epigenetic barrier that represses immune-stimulatory signals in glioblastoma. Its inhibition stimulates viral mimicry and induces replication stress, presenting a promising strategy for sensitizing GBM to immunotherapy. This study paves the way for future combination therapies integrating epigenetic drugs with immune checkpoint inhibitors to overcome immune evasion in glioblastoma.
利益披露 Disclosure
Y. Kim, None..
C. Spruck, None.