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Meningeal lymphatic vessels regulate brain tumor drainage and immunity.
Cell Research ( IF 28.1 ) Pub Date : 2020-02-24 , DOI: 10.1038/s41422-020-0287-8 Xueting Hu 1 , Qiuping Deng 1 , Lu Ma 1 , Qingqing Li 2 , Yidong Chen 2 , Yuhan Liao 2 , Fan Zhou 3 , Chen Zhang 4 , Linlin Shao 5 , Jun Feng 5 , Tubao He 1 , Weihai Ning 6 , Yan Kong 7 , Yingqing Huo 1 , Aibin He 1, 8 , Bing Liu 3 , Jingjing Zhang 9 , Ralf Adams 10 , Yulong He 11 , Fuchou Tang 2, 8 , Xiuwu Bian 12 , Jincai Luo 1
Cell Research ( IF 28.1 ) Pub Date : 2020-02-24 , DOI: 10.1038/s41422-020-0287-8 Xueting Hu 1 , Qiuping Deng 1 , Lu Ma 1 , Qingqing Li 2 , Yidong Chen 2 , Yuhan Liao 2 , Fan Zhou 3 , Chen Zhang 4 , Linlin Shao 5 , Jun Feng 5 , Tubao He 1 , Weihai Ning 6 , Yan Kong 7 , Yingqing Huo 1 , Aibin He 1, 8 , Bing Liu 3 , Jingjing Zhang 9 , Ralf Adams 10 , Yulong He 11 , Fuchou Tang 2, 8 , Xiuwu Bian 12 , Jincai Luo 1
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Recent studies have shown that meningeal lymphatic vessels (MLVs), which are located both dorsally and basally beneath the skull, provide a route for draining macromolecules and trafficking immune cells from the central nervous system (CNS) into cervical lymph nodes (CLNs), and thus represent a potential therapeutic target for treating neurodegenerative and neuroinflammatory diseases. However, the roles of MLVs in brain tumor drainage and immunity remain unexplored. Here we show that dorsal MLVs undergo extensive remodeling in mice with intracranial gliomas or metastatic melanomas. RNA-seq analysis of MLV endothelial cells revealed changes in the gene sets involved in lymphatic remodeling, fluid drainage, as well as inflammatory and immunological responses. Disruption of dorsal MLVs alone impaired intratumor fluid drainage and the dissemination of brain tumor cells to deep CLNs (dCLNs). Notably, the dendritic cell (DC) trafficking from intracranial tumor tissues to dCLNs decreased in mice with defective dorsal MLVs, and increased in mice with enhanced dorsal meningeal lymphangiogenesis. Strikingly, disruption of dorsal MLVs alone, without affecting basal MLVs or nasal LVs, significantly reduced the efficacy of combined anti-PD-1/CTLA-4 checkpoint therapy in striatal tumor models. Furthermore, mice bearing tumors overexpressing VEGF-C displayed a better response to anti-PD-1/CTLA-4 combination therapy, and this was abolished by CCL21/CCR7 blockade, suggesting that VEGF-C potentiates checkpoint therapy via the CCL21/CCR7 pathway. Together, the results of our study not only demonstrate the functional aspects of MLVs as classic lymphatic vasculature, but also highlight that they are essential in generating an efficient immune response against brain tumors.
中文翻译：
脑膜淋巴管调节脑肿瘤引流和免疫。
最近的研究表明，位于颅骨下方背侧和基底的脑膜淋巴管（MLV）提供了从中枢神经系统（CNS）排出大分子并将免疫细胞运输到颈部淋巴结（CLN）的途径，并且因此代表了治疗神经退行性疾病和神经炎症疾病的潜在治疗靶点。然而，MLV 在脑肿瘤引流和免疫中的作用仍有待探索。在这里，我们发现，患有颅内神经胶质瘤或转移性黑色素瘤的小鼠的背侧 MLV 经历了广泛的重塑。 MLV 内皮细胞的 RNA-seq 分析揭示了参与淋巴重塑、液体引流以及炎症和免疫反应的基因组的变化。单独破坏背侧 MLV 会损害肿瘤内液体引流以及脑肿瘤细胞向深部 CLN (dCLN) 的扩散。值得注意的是，在背侧 MLV 有缺陷的小鼠中，从颅内肿瘤组织到 dCLN 的树突状细胞 (DC) 运输减少，而在背侧脑膜淋巴管生成增强的小鼠中增加。引人注目的是，仅破坏背侧 MLV，而不影响基础 MLV 或鼻 LV，会显着降低纹状体肿瘤模型中抗 PD-1/CTLA-4 检查点联合疗法的疗效。此外，携带过度表达 VEGF-C 的肿瘤的小鼠对抗 PD-1/CTLA-4 联合治疗表现出更好的反应，并且这种反应被 CCL21/CCR7 阻断所消除，表明 VEGF-C 通过 CCL21/CCR7 途径增强检查点治疗。总之，我们的研究结果不仅证明了 MLV 作为经典淋巴管系统的功能，而且还强调它们对于产生针对脑肿瘤的有效免疫反应至关重要。
更新日期：2020-02-24
中文翻译：
脑膜淋巴管调节脑肿瘤引流和免疫。
最近的研究表明，位于颅骨下方背侧和基底的脑膜淋巴管（MLV）提供了从中枢神经系统（CNS）排出大分子并将免疫细胞运输到颈部淋巴结（CLN）的途径，并且因此代表了治疗神经退行性疾病和神经炎症疾病的潜在治疗靶点。然而，MLV 在脑肿瘤引流和免疫中的作用仍有待探索。在这里，我们发现，患有颅内神经胶质瘤或转移性黑色素瘤的小鼠的背侧 MLV 经历了广泛的重塑。 MLV 内皮细胞的 RNA-seq 分析揭示了参与淋巴重塑、液体引流以及炎症和免疫反应的基因组的变化。单独破坏背侧 MLV 会损害肿瘤内液体引流以及脑肿瘤细胞向深部 CLN (dCLN) 的扩散。值得注意的是，在背侧 MLV 有缺陷的小鼠中，从颅内肿瘤组织到 dCLN 的树突状细胞 (DC) 运输减少，而在背侧脑膜淋巴管生成增强的小鼠中增加。引人注目的是，仅破坏背侧 MLV，而不影响基础 MLV 或鼻 LV，会显着降低纹状体肿瘤模型中抗 PD-1/CTLA-4 检查点联合疗法的疗效。此外，携带过度表达 VEGF-C 的肿瘤的小鼠对抗 PD-1/CTLA-4 联合治疗表现出更好的反应，并且这种反应被 CCL21/CCR7 阻断所消除，表明 VEGF-C 通过 CCL21/CCR7 途径增强检查点治疗。总之，我们的研究结果不仅证明了 MLV 作为经典淋巴管系统的功能，而且还强调它们对于产生针对脑肿瘤的有效免疫反应至关重要。
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