The clinical, genetic, and immune landscape of meningioma in patients with NF2-schwannomatosis

Abstract

NF2-schwannomatosis is the most common genetic predisposition syndrome associated with meningioma. Meningioma in NF2-schwannomatosis is a major source of morbidity and mortality. This is due to accumulative tumor burden in patients with synchronous schwannomas and ependymomas, sometimes including complex collision tumors. Balancing the impact of multiple interventions against the natural history of various index tumors, and the ongoing risk of de novo tumors over an individual's lifetime makes decision-making complex. The management of any given individual meningioma is often different from a comparable sporadic tumor. There is typically a greater emphasis on conservative management and tolerating growth until a risk boundary is reached, whereby symptomatic deterioration or higher risk from anticipated future treatment is threatened. Management by high-volume multidisciplinary teams improves quality of life and life expectancy. Surgery remains the mainstay treatment for symptomatic and rapidly enlarging meningioma. Radiotherapy has an important role but carries a higher risk compared to its use in sporadic disease. Whilst bevacizumab is effective in NF2-associated schwannoma and cystic ependymoma, it has no value in the management of meningioma. In this review, we describe the natural history of the disease, underlying genetic, molecular, and immune microenvironment changes, current management paradigms, and potential therapeutic targets.

Keywords: NF2; NF2-schwannomatosis; clinical management; meningioma; tumor microenvironment.

Figure 1.

The NF2 gene product merlin is a key tumor suppressor protein. The NF2 gene product merlin acts as a scaffolding protein that links the actin cytoskeleton to the extracellular matrix (ECM) via transmembrane proteins such as integrin and CD44 to maintain contact inhibition. Furthermore, merlin interacts with receptor tyrosine kinases (RTK) and acts at cell-cell tight and adherens junctions linking cadherins to intracellular actin filaments. Active merlin discourages aberrant cell division by negatively regulating cellular proliferation and survival signaling pathways: mammalian target of rapamycin (mTOR) through tuberous sclerosis complex 1/2 (TSC1/2) and Ras homolog enriched in brain (RHEB), phosphoinositide 3-kinase/protein kinase B/c-Jun N-terminal kinase (PI3K/Akt/JNK), Ras/Raf/mitogen-activated protein kinase/extracellular signal-regulated kinase (Ras/Raf/MEK/ERK), and Src/focal adhesion kinase/Rac/p21-activated kinase (Src/FAK/Rac/PAK). Proteins that are downregulated by active merlin are presented with a bold, red outline. However, merlin upregulates the Hippo pathway via the activation of large tumor suppressor kinase 1 and 2 (LATS1/2) to initiate yes-associated protein 1/transcriptional coactivator with PDZ-binding motif (YAP/TAZ) degradation. Furthermore, the stimulator of interferon genes (STING) pathway is positively regulated by merlin via interferon regulatory factor 3 (IRF3) interaction thus allowing RNA and DNA sensing to occur within the healthy cell. Created with BioRender.com.

Figure 2.

Natural history of NF2-associated meningioma. Each row depicts T1 weighted, contrast-enhanced coronal MRI scans of the brain from patients with NF2-schwannomatosis. Each scan undertaken one year apart, with the most recent scan on the right. (A) Quiescent: Right convexity meningioma demonstrating no significant change in volume during follow-up. (B) Saltatory: Left tentorial meningioma demonstrating an initial volume increase between the first and second scans, with subsequent stabilization. (C) Linear: Slowly progressive increase in volume of multiple convexity and parasagittal meningioma during follow-up. (D) Exponential: A right parasagittal meningioma demonstrating a small increase in tumor volume between the first and second scans, with a subsequent dramatic increase in volume one year later, leading to the development of neurological deficits and necessitating surgical resection.

Figure 3.

The tumor microenvironment of NF2-associated meningioma. TME of NF2-associated meningioma, the extracellular matrix (ECM) of secreted proteins, proteoglycans and enzymes is interspersed with meningioma tumor cells derived from arachnoid and dural border cells expressing major histocompatibility complex I (MHC I). Vascularization occurs upon vascular endothelial growth factor (VEGF) secretion from arachnoid and dural border cells, as well as macrophages which stimulate increased angiogenesis and vascular permeabilization. Meningioma reside outside the blood brain barrier which permits the extravasation of peripheral myeloid-derived immune cells into the tumor tissue, such as monocytes that polarize into either M1/M2 TAM. M2 TAMs overexpress CSF1R to bind growth factor CSF1, and express PD-L1 and MHC II. Lymphoid immune cells such as T cells that display T cell receptors (TCR) and PD-1, as well as B cells and natural killer (NK) cells become suppressed in the tumor microenvironment (TME), therefore, reducing antitumor immunity. Created with BioRender.com.