Role of the Tumor Microenvironment in Aggressive Meningiomas

Meningioma

meningioma, meningeal lymphatic vessels, NF2, meningeal micro-environment, immune cells, neurosurgery

Meningiomas are the most common primary tumors of the central nervous system in adults. High-grade forms have a high frequency of neurofibromatosis 2 (NF2) mutations and represent 25% of meningiomas, with multiple recurrences associated with morbidity and reduced survival without medical options, including immunotherapy. The meninges play a key role in neuro-immune communication through the diversity of their immune cells and the presence of meningeal lymphatic vessels (MLV). Recent data, including from our team, shows frequent infiltration of lymphocytes and myeloid cells specific to benign meningiomas. Our hypothesis is that the immune microenvironment composed of meningeal immune cells and MLVs regulates the malignant histological progression of NF2-mutated meningiomas and their immune surveillance evasion behavior This study aims to characterize the different cellular populations of the meningioma microenvironment. We will describe the exact participation of immune and vascular cell populations in the initiation and progression of meningioma, using MRI imaging and surgical biopsies of the dura mater and meningioma in patients undergoing neurosurgery for meningioma resection.

The objective of this study is to characterize the different cellular populations of the microenvironment of meningioma, particularly the immune and vascular cell populations, in order to better understand their role in the initiation and progression of this tumor. For this purpose, we will use MRI imaging and surgical biopsies of the dura mater and meningioma to characterize cellular phenotypes and their interactions in the tissue microenvironment. The research will be conducted on a cohort of patients treated for meningioma in neurosurgery services. Samples required for the study will be obtained from surgical waste of patients who underwent meningioma resection. Data necessary for the study will be collected from the patient's medical records, MRI examinations, and data specific to the characteristics of the surgical waste. Prospective patients will be informed of the study through an information note. Patients who do not object to their participation will undergo neurosurgery intervention in accordance with the usual service protocol. During the intervention, surgical waste will be produced, including the meningioma and adjacent dura mater, which will be collected under the responsibility of the neuro-pathologist who will also take fragments for routine diagnostic histological analysis. We will then perform a targeted mutational analysis associated with neuropathological evaluation of the tumor grade in order to select 10 cases of grade I meningioma and 10 cases of grade II and III meningioma carrying the NF2 mutation. An in-depth analysis will then be carried out on these samples using 10x Genomic's single-cell RNA sequencing (scRNA-seq) technology. This analysis will help to understand the tumor's heterogeneity and establish the phenotype and differentiation trajectory of tumor cells, dura mater cells, and associated immune cells. In addition to RNA analysis, the expression of genetic signatures will be validated by RNAscope tests, while Hyperion imaging will allow visualization of the interrelationships between different types of cells and their spatial distribution. The iDISCO+ immunolabeling combined with three-dimensional fluorescence microscopy imaging will enable visualization of specific protein expression profiles of meningioma and dura mater cell types in 3D. Once the analyses are complete, meningioma and dura mater samples will be destroyed. Preoperative MRI images will also be retrieved and analyzed.

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