Meningeal lymphatic vessels regulate brain tumor drainage and immunity
Meningeal lymphatic vessels regulate brain tumor drainage and immunity
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脑膜淋巴管调节脑肿瘤引流和免疫
DOI：
10.1038/s41422-020-0287-8
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发表时间：
2020-02-24
期刊：
影响因子：
44.1
通讯作者：
Luo, Jincai
中科院分区：
文献类型：
--
作者：
Hu, Xueting;Deng, Qiuping;Luo, Jincai
最近的研究表明，脑膜淋巴管（MLV），这是位于背侧和底部的颅骨下，提供了一个通道，从中枢神经系统（CNS）到颈部淋巴结（CLN）引流大分子和运输免疫细胞，因此代表了一个潜在的治疗目标，用于治疗神经退行性疾病和神经炎症性疾病。然而，MLV在脑肿瘤引流和免疫中的作用仍未被探索。在这里，我们表明，背MLV进行广泛的重建与颅内胶质瘤或转移性黑色素瘤的小鼠。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会损害瘤内液体引流和脑肿瘤细胞向深部CLN（dCLN）的播散。值得注意的是，在背侧MLV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，这种运输增加。引人注目的是，在不影响基底MLV或鼻LV的情况下，单独破坏背侧MLV显著降低了纹状体肿瘤模型中组合抗PD-1/CTLA-4检查点疗法的功效。此外，携带过表达VEGF-C的肿瘤的小鼠对抗PD-1/CTLA-4联合治疗显示出更好的应答，并且这被CCL 21/CCR 7阻断消除，表明VEGF-C通过CCL 21/CCR 7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方面，而且还强调了它们在产生针对脑肿瘤的有效免疫应答中至关重要。
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.