VEGF-C-driven lymphatic drainage enables immunosurveillance of brain tumours
Eric Song,Tianyang Mao,Huiping Dong,Ligia Simoes Braga Boisserand,Salli Antila,Marcus Bosenberg,Kari Alitalo,Jean-Leon Thomas,Jean-Leon Thomas,Akiko Iwasaki,Akiko Iwasaki,Akiko Iwasaki +11 more
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TLDR
In a mouse model of glioblastoma, treatment with VEGF-C increases lymphatic drainage in the central nervous system and improves the immune response, suggesting that modulating meningeal lymphatics could enhance checkpoint inhibitor therapy.Abstract:
Immune surveillance against pathogens and tumours in the central nervous system is thought to be limited owing to the lack of lymphatic drainage. However, the characterization of the meningeal lymphatic network has shed light on previously unappreciated ways that an immune response can be elicited to antigens that are expressed in the brain1-3. Despite progress in our understanding of the development and structure of the meningeal lymphatic system, the contribution of this network in evoking a protective antigen-specific immune response in the brain remains unclear. Here, using a mouse model of glioblastoma, we show that the meningeal lymphatic vasculature can be manipulated to mount better immune responses against brain tumours. The immunity that is mediated by CD8 T cells to the glioblastoma antigen is very limited when the tumour is confined to the central nervous system, resulting in uncontrolled tumour growth. However, ectopic expression of vascular endothelial growth factor C (VEGF-C) promotes enhanced priming of CD8 T cells in the draining deep cervical lymph nodes, migration of CD8 T cells into the tumour, rapid clearance of the glioblastoma and a long-lasting antitumour memory response. Furthermore, transfection of an mRNA construct that expresses VEGF-C works synergistically with checkpoint blockade therapy to eradicate existing glioblastoma. These results reveal the capacity of VEGF-C to promote immune surveillance of tumours, and suggest a new therapeutic approach to treat brain tumours.read more
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Therapeutic Targeting of the Tumor Microenvironment
TL;DR: A comprehensive analysis of the current therapies targeting the tumor microenvironment (TME) is provided in this paper, combining a discussion of the underlying basic biology with clinical evaluation of different therapeutic approaches, and highlighting the challenges and future perspectives.
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The Lymphatic Vasculature in the 21st Century: Novel Functional Roles in Homeostasis and Disease
TL;DR: It is proposed that subtle asymptomatic alterations in lymphatic vascular function could underlie the variability seen in the body's response to a wide range of human diseases.
Journal ArticleDOI
Functional characterization of the dural sinuses as a neuroimmune interface.
Justin Rustenhoven,Antoine Drieu,Tornike Mamuladze,Kalil Alves de Lima,Taitea Dykstra,Morgan Wall,Zachary Papadopoulos,Mitsuhiro Kanamori,Andrea Francesca Salvador,Wendy Baker,Mackenzie Lemieux,Sandro Da Mesquita,Sandro Da Mesquita,Andrea Cugurra,Andrea Cugurra,James A. J. Fitzpatrick,Sanja Sviben,Ross G. Kossina,Peter O. Bayguinov,R. Reid Townsend,Qiang Zhang,Petra Erdmann-Gilmore,Igor Smirnov,Maria Beatriz Lopes,Jasmin Herz,Jonathan Kipnis +25 more
TL;DR: In this article, the authors demonstrate that CSF-derived antigens in the cerebrospinal fluid accumulate around the dural sinuses, are captured by local antigen-presenting cells, and are presented to patrolling T-cells.
Journal ArticleDOI
Meningeal lymphatic dysfunction exacerbates traumatic brain injury pathogenesis.
Ashley C. Bolte,Arun B. Dutta,Mariah E. Hurt,Igor Smirnov,Michael A. Kovacs,Celia A. McKee,Hannah E. Ennerfelt,Daniel Shapiro,Bao H. Nguyen,Elizabeth L. Frost,Catherine R. Lammert,Jonathan Kipnis,John R. Lukens +12 more
TL;DR: It is demonstrated in an experimental mouse model of TBI that mild forms of brain trauma cause severe deficits in meningeal lymphatic drainage that begin within hours and last out to at least one month post-injury.
Journal ArticleDOI
Cerebrospinal fluid outflow: a review of the historical and contemporary evidence for arachnoid villi, perineural routes, and dural lymphatics.
TL;DR: The question of how cerebrospinal fluid (CSF) drains from the subarachnoid space has long puzzled scientists and clinicians as mentioned in this paper, with one side favoring direct efflux to the dural lymphatic vessels within the skull and spinal column and another side advocating for pathways along exiting cranial and spinal nerves.
References
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A Randomized Trial of Bevacizumab for Newly Diagnosed Glioblastoma
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Journal ArticleDOI
Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis
Mihaela Skobe,Thomas Hawighorst,David A. Jackson,Remko Prevo,Lauren Janes,Paula Velasco,Lucia Riccardi,Kari Alitalo,Kevin P. Claffey,Michael Detmar +9 more
TL;DR: The occurrence and biological significance of intratumoral lymphangiogenesis within human breast cancers after orthotopic transplantation onto nude mice are established and VEGF-C is identified as a molecular link between tumor lymphang iogenesis and metastasis.
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A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules
Aleksanteri Aspelund,Salli Antila,Steven T. Proulx,Tine V. Karlsen,Sinem Karaman,Michael Detmar,Helge Wiig,Kari Alitalo +7 more
TL;DR: The presence of a lymphatic vessel network in the dura mater of the mouse brain is discovered and it is shown that these dural lymphatic vessels are important for the clearance of macromolecules from the brain.
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