Meningeal lymphatic vessels regulate brain tumor drainage and immunity

Xueqiang Hu ,Yidong Chen,Chen Zhang,Qingqing Li,Linlin Shao ,Fuchou Tang,Yingqing Huo,Tubao He,Xiu‐Wu Bian ,Yulong He,Qiuping Deng,Jie Feng ,Ralf H Adams ,Fan Zhou,Lu Ma,Jingjing Zhang,Bing Liu,Weihai Ning,Aibin He,Ke Yan ,Yuhan Liao,Jincai Luo

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.

Highlights

The concept of immune privilege in the central nervous system (CNS) has been substantially reconsidered in the past decade.[1]This concept was proposed more than half a century ago based on the experimental findings that foreign tissue grafts including tumors in the brain parenchyma were not rejected by the immune system of the host.[2,3] the CNS has unique anatomical features such as the blood–brain barrier and a lack of classic lymphatic vessels (LVs) in the parenchyma
We investigated the changes of meningeal lymphatic vessels (MLVs) in mice bearing GL261 or B16 tumors using LYVE-1 immunostaining and found significant lymphatic remodeling, especially in the dorsal meninges 1 week after tumor cell injection (Fig. 1a)
We found that CD11c+MHCII+fluorescein isothiocyanate (FITC)+ cells in the deep CLNs (dCLNs) were dramatically reduced in dorsal MLV-defective mice (Supplementary information, Fig. S7a; Fig. 3d), suggesting that dorsal MLVs are critical for the trafficking of dendritic cell (DC) to dCLNs

Summary

Introduction

The concept of immune privilege in the central nervous system (CNS) has been substantially reconsidered in the past decade.[1] This concept was proposed more than half a century ago based on the experimental findings that foreign tissue grafts including tumors in the brain parenchyma were not rejected by the immune system of the host.[2,3] the CNS has unique anatomical features such as the blood–brain barrier and a lack of classic lymphatic vessels (LVs) in the parenchyma. These studies indicate that the immune system functions in some sub-regions of the CNS to in the periphery

Methods

Results

Conclusion