2. Academic Validation
  3. Meningeal lymphatic vessels regulate brain tumor drainage and immunity

Meningeal lymphatic vessels regulate brain tumor drainage and immunity

  • Cell Res. 2020 Mar;30(3):229-243. 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 13
Affiliations

Affiliations

  • 1 Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, 100871, Beijing, China.
  • 2 Biodynamic Optical Imaging Center, College of Life Sciences, Peking University, 100871, Beijing, China.
  • 3 State 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.
  • 4 Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, 100069, Beijing, China.
  • 5 Eye Hospital of China Academy of Chinese Medical Sciences, 100040, Beijing, China.
  • 6 Sanbo Brain Hospital, Capital Medical University, 100093, Beijing, China.
  • 7 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cell Biology, Peking University Cancer Hospital and Institute, 100142, Beijing, China.
  • 8 Peking-Tsinghua Center for Life Sciences, 100871, Beijing, China.
  • 9 Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, Guangdong, China.
  • 10 Max-Planck-Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, and University of Münster, Faculty of Medicine, Münster, D-48149, Germany.
  • 11 Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, 215123, Jiangsu, China.
  • 12 Institute 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.
  • 13 Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, 100871, Beijing, China. [email protected].
  • # Contributed equally.
PMID: 32094452 DOI: 10.1038/s41422-020-0287-8
Abstract

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.

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