Volume 30, No 3, Mar 2020

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 30 Issue 3, March 2020: 229-243   |  Open Access

ORIGINAL ARTICLES

Meningeal lymphatic vessels regulate brain tumor drainage and immunity

Xueting Hu¹ , Qiuping Deng¹ , Lu Ma¹ , Qingqing Li² , Yidong Chen² , Yuhan Liao² , Fan Zhou³ , Chen Zhang⁴ , Linlin Shao⁵ , Jun Feng⁵ , Tubao He¹ , Weihai Ning⁶ , Yan Kong⁷ , Yingqing Huo¹ , Aibin He^1,8 , Bing Liu³ , Jingjing Zhang⁹ , Ralf Adams¹⁰ , Yulong He¹¹ , Fuchou Tang^2,8 , Xiuwu Bian¹² , Jincai Luo^1,*

¹Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, 100871 Beijing, China
²Biodynamic Optical Imaging Center, College of Life Sciences, Peking University, 100871 Beijing, China
³State Key Laboratory of Proteomics, Translational Medicine Center of Stem Cells, 307-Ivy Translational Medicine Center, Laboratory of Oncology, Affiliated Hospital, Academy of Military Medical Sciences, 100071 Beijing, China
⁴Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, 100069 Beijing, China
⁵Eye Hospital of China Academy of Chinese Medical Sciences, 100040 Beijing, China
⁶Sanbo Brain Hospital, Capital Medical University, 100093 Beijing, China
⁷Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cell Biology, Peking University Cancer Hospital and Institute, 100142 Beijing, China
⁸Peking-Tsinghua Center for Life Sciences, 100871 Beijing, China
⁹Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001 Guangdong, China
¹⁰Max-Planck-Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, and University of Münster, Faculty of Medicine, Münster D48149, Germany
¹¹Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215123 Jiangsu, China
¹²Institute of Pathology and Southwest Cancer Center, Key Laboratory of the Ministry of Education, Southwest Hospital, Army Medical University (Third Military Medical University), 400038 Chongqing, China
These authors contributed equally: Xueting Hu, Qiuping Deng, Lu Ma Correspondence: Jincai Luo(jincailuo@pku.edu.cn)

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.

https://doi.org/10.1038/s41422-020-0287-8

FULL TEXT | PDF

Browse 880