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    Home > Active Ingredient News > Immunology News > Experts commented on the key role and mechanismof the meninges' lymphatic tubes in anti-brain tumor immunity.

    Experts commented on the key role and mechanismof the meninges' lymphatic tubes in anti-brain tumor immunity.

    • Last Update: 2020-07-22
    • Source: Internet
    • Author: User
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    Li Huabing, a researcher (Shanghai Jiaotong University School of Medicine Shanghai Institute of Immunology) and Yu Pengchun researcher (Oklahoma Medical Research Foundation), belong to one of the most feared tumors, which cause up to about 200000 deaths worldwide every year (1). In China, brain tumors are also the top ten in cancer incidence rate and death rate.unfortunately, the current treatment for brain tumors is very limited, and the prognosis is not good.in recent years, tumor immunotherapy dominated by PD-1 antibody has brought revolutionary progress to the treatment of many kinds of tumors, but its curative effect on brain tumors is not good. One of the important reasons is that the immune response induced by brain tumors is very limited.understanding how the immune system recognizes brain tumor antigen and finds effective methods to enhance immune response have become the key to the success of anti brain tumor immunotherapy.the lymphatic system plays an important role in maintaining body fluid balance and immune surveillance, but the traditional view is that the central nervous system lacks classical lymphatic system.on the other hand, the blood-brain barrier effectively protects the central nervous system from external pathogens, but it also hinders the immune system from effectively monitoring brain cell carcinogenesis.however, a recent study has found lymphatic vessels in the dura of mice and humans along the venous sinus [2]. The concept that the brain is an immune immune immune organ has been challenged.further experiments found that this meningeal lymphatic vessel can promote T cells migration from cerebrospinal fluid (CSF) to cervical lymph nodes, and affect the generation and development of nervous system inflammation [3].however, there are few studies on the relationship between meningeal lymphatic vessels and the immunity of brain tumors.on February 25, 2020, Professor Luo Jincai of the Institute of molecular medicine of Peking University and his collaborators published a research paper entitled "meningeal lymphatic vessels regular brain tumor drainage and immunity" in cell research.this study creatively proved that meningeal lymphatic vessels can enhance the immune response against brain tumors by promoting the migration of immune cells, and enhance the therapeutic effect of immunotherapy for brain tumors, thus revealing a new function of meningeal lymphatic vessels.in this study, using a mouse brain tumor model, the researchers first found that brain tumor cells could induce the remodeling and regeneration of meningeal lymphatic vessels (Fig. 1) [4].Figure 1: intracranial transplantation significantly induces meningeal lymphangiogenesis and remodeling.subsequently, the authors elucidated the key role and mechanism of meningeal lymphangiopathy in the anti-tumor effect of PD-1 and CTLA-4 double antibodies through the injury model of meningeal lymphatic vessels, magnetic resonance imaging, and a series of histological and cellular biological methods.importantly, the team also found that the expression of vascular endothelial growth factor C (VEGF-C) induces meningeal lymphatic remodeling, which can promote the delivery of dendritic cells to cervical lymph nodes, increase the number of CD8 + T cells in brain tumors and lymph nodes, and thus significantly enhance the anti-tumor effect of PD-1 and CTLA-4 antibodies (Fig. 2).Figure 2: The anti-tumor effect of PD-1 and CTLA-4 double antibodies is dependent on the integrity of meningeal lymphatic vessels (left side) and enhanced by overexpression of VEGF-C (right side). It is reported that the project is sponsored by Professor Luo Jincai, Institute of molecular medicine, Peking University, Professor Tang Fuhui, biomedical frontier innovation center, Peking University, academician Bian Xiuwu, Southwest Hospital of the Third Military Medical University, and the fifth medical center of PLA General Hospital Liu Bing, Professor He Yulong, Tang Zhongying hematology research center of Soochow University.the doctoral students of Peking University Hu Xueting, Deng Qiuping and Ma Lu are the co authors, and Professor Luo Jincai is the corresponding author. interestingly, on January 15, nature published a research paper entitled "vegf-c-driven lymphatic drainage capabilities immunity of brain tumours [5], which also reported similar conclusions. this research work from Professor Akiko Iwasaki, Professor Jean Leon Thomas and their collaborators from Yale University in the United States also found that overexpression of VEGF-C in mouse brain tissue can effectively increase the number of tumor-specific T cells in lymph nodes and brain tissue, and make the anti-tumor effect of PD-1 antibody significantly enhanced. expert comments Li Huabing (Professor, Institute of immunology, Shanghai Jiaotong University) is from Professor Luo Jincai of the Institute of molecular medicine of Peking University and Akiko of Yale University The latest independent research of Iwasaki team studied the occurrence and development of brain tumors in mouse models from the perspective of vascular biology and immunobiology respectively. Through a large number of solid data, the same conclusion was reached: immune cells communicate with the central immune system through meningeal lymphatic vessels, thus playing an important role in the control of the occurrence and development of glioblastoma. because brain tumors are different from those in other parts of the body, overexpression of vascular endothelial growth factor C (VEGF-C) does not accelerate the growth of brain tumors, but the increase of meningeal lymphatic vessel density can enhance the monitoring of brain tumors by immune system. in terms of immunological mechanism, the two articles complement each other: the results of the former showed that the increase of meningeal lymphatic vessels caused by VEGF-C overexpression could promote the transport of dendritic cells, while the latter showed that the increase of meningeal lymphatic vessels caused by VEGF-C overexpression could promote the activation and infiltration of tumor specific T cells. immunocheckpoint inhibitor antibodies have limited therapeutic effect on brain tumors, but the combination of adenovirus vector mediated VEGF-C overexpression and immune checkpoint inhibitor PD-1 / PD-L1 antibody can significantly enhance T cell attack on brain tumor and prolong the survival time of brain tumor mice. this study is expected to bring light to the clinical treatment of patients with brain tumors. the interaction between nervous system and immune system is a frontier research hotspot in recent years, but most of them focus on peripheral organs. the types and functions of immune cells in the brain have their own organ specificity. The interaction between immune cells and nerve cells in the brain is still a relatively blank field. The in-depth study of these problems will provide more and better solutions for various clinical central nervous system related diseases. at the same time, these two independent parallel studies also reflect the importance of interdisciplinary. Full communication and cooperation between immunologists and experts in various disease-related research will provide us with more ideas to solve the problems of clinical patients and provide a good transformation export for basic immunology research. expert comments: Professor Luo Jincai laboratory, Institute of molecular medicine, Peking University, and Akiko, Yale University, USA These two independent research results published by Professor Iwasaki's research group, through complementary technical means, jointly prove that promoting the reconstruction of meningeal lymphatic vessels can effectively improve the therapeutic effect of immunotherapy for brain tumors. among them, Akiko Iwasaki laboratory overexpressed VEGF-C in mouse brain tissue through AAV and mRNA vector, and found that VEGF-C could significantly enhance the anti-tumor effect of PD-1 antibody. however, Luo Jincai's research not only used the overexpression of VEGF-C (gain of function) to prove the "Sufficiency" of meningeal lymphatic vessels in promoting anti-tumor immune effect, but also further proved the "necessity" of meningeal lymphatic vessels for the anti-tumor effect of PD-1 / CTLA-4 antibody combination. in addition, both studies have explored the immunological mechanism of lymphatic vessels in promoting anti-tumor immunity in brain tissue. there are different meningeal lymphatic systems in the dorsal and basal parts of the brain. in 2015, meningeal lymphatic vessels located on the dorsal side of mouse brain were found (louveau a et al., nature, 2015), which is considered as the main route of cerebrospinal fluid drainage. however, a paper published in 2019 (AHN j et al., nature, 2019) put forward a different view that the meningeal lymphatic vessels at the bottom of the brain base are the main pathways for macromolecular absorption and cerebrospinal fluid drainage. it is worth noting that both Luo Jincai and Akiko Iwasaki laboratory have emphasized the function of dorsal meningeal lymphatic system in anti-tumor immunity. in addition, the data from luojincai laboratory also show that the lymphatic system in the basal part of the brain does not seem to play a significant role in anti-tumor immunity compared with the dorsal meningeal lymphatic vessels. more studies are needed to further reveal the similarities and differences in the role of lymphatic system in different physiological and pathological processes, as well as the molecular and cellular mechanisms. to sum up, the two frontier studies published by Luo Jincai and Akiko Iwasaki laboratory, through convincing evidence, jointly reveal the key role of meningeal lymphatic vessels in the immune response of brain tumors, which is one of the remarkable breakthroughs in lymphatic research field in recent years. more importantly, these two research results provide new strategies for enhancing the immune response of brain tumors, lay a solid theoretical foundation for optimizing immunotherapy for brain tumors, and point out the promising development direction. original link: references 1. DeAngelis LM. Global sequences of malignant CNS tubes: a call to action. Lancet Neurology, 18:324-325, February 2019. Louveau a et al., structural and functional features of central nervous system lymphatic vessels. Nature, 523: 337-341, 2015.3. Louveau a et al., structural and functional features of central nervous system lymphatic vessels. CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature.  Nature Neuroscience, 21: 1380-1391, 2018.4. Hu X et al., Meningeal lymphatic vessels regulate brain tumor drainage and immunity. Cell Research, XXX, 2020.5. Song E et al., VEGF-C-driven lymphatic drainage enables immunosurveillance of brain tumours. Nature, 577: 689-694, 2020.
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