A faulty immune response inside rare nerve tumours is deafening and killing patients, and this project aims to fix it. People with NF2-related schwannomatosis (NF2-SWN) develop benign tumours on the nerves connecting the inner ear to the brain. These growths cause profound deafness, balance problems, speech difficulties, and can compress the brainstem, leading to hydrocephalus and death. Current treatments—surgery, radiation, and a blood-vessel-blocking drug—carry severe side effects and often fail long-term. The researchers have discovered that tumour-killing CD8+ T cells enter these tumours but become dysfunctional, losing their ability to destroy abnormal cells. The project has two goals: first, to map how tumour materials drain through newly identified lymphatic vessels in the brain’s border regions to activate immune responses; second, to dissect exactly why the CD8+ T cells fail and test whether re-energising them can shrink tumours. If successful, this work could reveal new immune-based treatments for NF2-SWN. Because many drugs that reinvigorate T cells are already approved for other cancers, the findings might enable compassionate off-label use and clinical trials for these patients, offering an alternative to today’s toxic, limited options.
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NF2-related schwannomatosis (NF2-SWN) is a rare tumour predisposition syndrome characterised by multiple benign neoplasms within the central and peripheral nervous system and brain meninges. Bilateral vestibular schwannomas (VS), which form from abnormal Schwann cells lining the vestibulocochlear (sensory) nerves that transmit signals from the inner ear to the brain, are the hallmark of the syndrome. VS tumours in individuals with NF2-SWN are life-limiting, causing profound deafness, imbalance, difficulties in speech, mental health problems, and can lead to brain stem compression, hydrocephalus and death. Surgery, radiation and off-label use of Bevacizumab (a drug that blocks blood vessel development) are the only current treatments for NF2-SWN, all of which have significant side effects and have limited long-term effectiveness in many patients. Consequently, new treatments for NF2-SWN patients and VS tumours are urgently needed. The overall aim of this project is to provide a step-change in our understanding of the immune response to VS tumours, underpinning the development of new therapeutic approaches for NF2-SWN. VS tumours grow in a specific location within the cranium (outside of the brain tissue). Due to their location, how they are recognised by the immune system and how tumour materials are able to drain from them into specialised immune tissues (lymph nodes), to activate tumour-specific immune responses, is unknown. Specifically, how VS tumours and tumour materials interact with recently identified vessels within the border regions of the brain (meningeal lymphatic vessels) to support development of anti-tumour immune responses has not been investigated. Moreover, whether these routes can be targeted to enhance immunity to VS tumours and suppress tumour growth and symptoms, is untested. In Objective 1 of this project, we aim to fully define how VS tumours interface with cranial lymphatic vessel networks and cervical lymph nodes to coordinate anti-tumour immunity. There is growing evidence that VS tumours are comprised of various populations of tumour cells, immune cells and tissue (stromal) cells. In particular, we have discovered that although CD8+ T cells (immune cells that are meant to kill infected and neoplastic cells) are observed in human VS tumours, they exhibit a particular signature (phenotype), suggesting that they are dysfunctional and have lost protective tumour-killing ability. This indicates that approaches to reinvigorate CD8+ T cells, to enhance their neoplastic cell-killing capacity, may be effective at treating NF2-SWN VS tumours. Whilst such T cell targeted therapies have been highly effective in other tumours, they have not been explored in the context of NF2-SWN. In Objective 2 of this project we will dissect the compartmentalisation, identity and function of CD8+ T cells in VS tumours, and we will examine how targeting T cell activation and function can improve tumour control. Collectively, the work in this project will transform our understanding of NF2-SWN VS biology and will reveal new immune-based approaches to potentially treat VS tumours in patients with the NF2-SWN syndrome. Our results will be of significant interest to NF2-SWN patient groups and charities, such as NF2 Biosolutions, who we are partnered with and which supports extensive PPIE for our research. Our results will also have substantial impact for clinicians and pharmaceutical companies and may pave the way for compassionate (off-label) use and clinical trials of approved immune-targeted drugs for individuals with NF2-SWN.
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