Immune surveillance against pathogens and tumors in the central nervous system (CNS) is thought to be limited due to the lack of lymphatic drainage. However, recent characterization of the meningeal lymphatic network sheds new light on previously unappreciated ways of eliciting immune response to antigens expressed in the brain 1-3. Despite the remarkable progress made in our understanding of the development and structure of meningeal lymphatics, its contribution in evoking a protective antigen-specific immune response in the brain still remains unclear. Here we examine whether meningeal lymphatic vasculature can be manipulated to mount better immune responses against brain tumors. Using a mouse model of glioblastoma multiforme (GBM), we show that very limited CD8 T cell immunity to GBM antigen is elicited when the tumor is confined to the CNS, resulting in uncontrolled tumor growth. However, ectopic VEGF-C expression promotes enhanced CD8 T cell priming in the draining deep cervical lymph nodes, migration of CD8 T cells into the tumor and rapid clearance of the GBM, resulting in long-lasting antitumor memory response. Further, VEGF-C mRNA works synergistically with checkpoint Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Cranial lymphatic vessels (LVs) are involved in the transport of fluids, macromolecules and central nervous system (CNS) immune responses. Little information about spinal LVs is available, because these delicate structures are embedded within vertebral tissues and difficult to visualize using traditional histology. Here we show an extended vertebral column LV network using three-dimensional imaging of decalcified iDISCO+-clarified spine segments. Vertebral LVs connect to peripheral sensory and sympathetic ganglia and form metameric vertebral circuits connecting to lymph nodes and the thoracic duct. They drain the epidural space and the dura mater around the spinal cord and associate with leukocytes. Vertebral LVs remodel extensively after spinal cord injury and VEGF-C-induced vertebral lymphangiogenesis exacerbates the inflammatory responses, T cell infiltration and demyelination following focal spinal cord lesion. Therefore, vertebral LVs add to skull meningeal LVs as gatekeepers of CNS immunity and may be potential targets to improve the maintenance and repair of spinal tissues.

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In this study, we evaluated an MRI fingerprinting approach (MRvF) designed to provide high-resolution parametric maps of the microvascular architecture (i.e., blood volume fraction, vessel diameter) and function (blood oxygenation) simultaneously. The method was tested in rats (n = 115), divided in 3 models: brain tumors (9 L, C6, F98), permanent stroke, and a control group of healthy animals. We showed that fingerprinting can robustly distinguish between healthy and pathological brain tissues with different behaviors in tumor and stroke models. In particular, fingerprinting revealed that C6 and F98 glioma models have similar signatures while 9 L present a distinct evolution. We also showed that it is possible to improve the results of MRvF and obtain supplemental information by changing the numerical representation of the vascular network. Finally, good agreement was found between MRvF and conventional MR approaches in healthy tissues and in the C6, F98, and permanent stroke models. For the 9 L glioma model, fingerprinting showed blood oxygenation measurements that contradict results obtained with a quantitative BOLD approach. In conclusion, MR vascular fingerprinting seems to be an efficient technique to study microvascular properties in vivo. Multiple technical improvements are feasible and might improve diagnosis and management of brain diseases.