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髓细胞特异性KDM6B抑制使胶质母细胞瘤对PD1阻断敏感

原文发布日期：2023-08-31

英文摘要：

摘要翻译：

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文章：

髓细胞特异性KDM6B抑制使胶质母细胞瘤对PD1阻断敏感

Myeloid-specific KDM6B inhibition sensitizes glioblastoma to PD1 blockade

原文发布日期：2023-08-31

英文摘要：

Glioblastoma (GBM) tumors are enriched in immune-suppressive myeloid cells and are refractory to immune checkpoint therapy (ICT). Targeting epigenetic pathways to reprogram the functional phenotype of immune-suppressive myeloid cells to overcome resistance to ICT remains unexplored. Single-cell and spatial transcriptomic analyses of human GBM tumors demonstrated high expression of an epigenetic enzyme—histone 3 lysine 27 demethylase (KDM6B)—in intratumoral immune-suppressive myeloid cell subsets. Importantly, myeloid cell-specific Kdm6b deletion enhanced proinflammatory pathways and improved survival in GBM tumor-bearing mice. Mechanistic studies showed that the absence of Kdm6b enhances antigen presentation, interferon response and phagocytosis in myeloid cells by inhibition of mediators of immune suppression including Mafb, Socs3 and Sirpa. Further, pharmacological inhibition of KDM6B mirrored the functional phenotype of Kdm6b-deleted myeloid cells and enhanced anti-PD1 efficacy. This study thus identified KDM6B as an epigenetic regulator of the functional phenotype of myeloid cell subsets and a potential therapeutic target for enhanced response to ICT.

摘要翻译：

胶质母细胞瘤（Glioblastoma, GBM）肿瘤富含免疫抑制性髓系细胞，并对免疫检查点治疗（Immune Checkpoint Therapy, ICT）不敏感。靶向表观遗传路径以重新编程免疫抑制性髓系细胞的功能表型，从而克服对ICT的耐药性仍未被探索。通过单细胞和空间转录组分析发现，人类GBM肿瘤中存在高度表达一种表观遗传酶——历史素-3去甲基酶（Histone 3 lysine 27 demethylase, KDM6B）的髓系细胞亚群。 importantly, 髓系细胞特定性地删除Kdm6b显著增强促炎通路并改善了带有GBM肿瘤的小鼠存活率。机制研究显示，Kdm6b缺失增强了髓系细胞的抗原呈递、干扰素响应和吞噬作用，这些功能是通过抑制免疫抑制因子（包括Mafb, Socs3 和 Sirpa）来实现的。此外，药物抑制KDM6B的行为镜像了Kdm6b去除了髓系细胞特定性功能表型并增强了对PD-1治疗的疗效。本研究因此将KDM6B识别为一种调控髓系细胞亚群功能表型的表观遗传调节因子，并可能成为增强对ICT反应的潜在治疗靶点。