Defining the role of the meninges in brain tumours

Brain tumours are highly immunosuppressed, which has meant that they are uniquely resistant to immunotherapies. Importantly, T cell infiltration into tumours, which predicts immunotherapy responses, is low in glioblastoma, the most common form of brain tumour. Immune responses in the brain are unique, and brain tumours are no exception. The brain is remarkably tolerant of foreign antigens, shielded by a property known as immune privilege. For decades the immune system and the brain were thought to be isolated from one another, but my postdoctoral work showed that they are in constant communication. This neuroimmune communication occurs in the meninges, which have emerged as an immunological organ that services the brain. To understand the uniquely immunosuppressive environment of primary brain tumours and their poor responses to immunotherapy, we must first understand the unique ways in which the meninges handle immune responses to brain tumours. We have exciting preliminary data showing the formation of tertiary lymphoid structures (TLS) within the meninges of tumour bearing mice. This indicates that immune responses are being mounted to the tumour. What is the significance of meningeal immune responses to tumours and why does immunotherapy not lead to tumour killing by immune cells? In collaboration with the Brain Cancer Research Lab at the Walter and Eliza Hall Institute, we will study meningeal immunity in their translationally-relevant Nes-Cre::Nf1fl/fl/p53fl/fl::Ptenfl/fl::Luciferase (NPPL) model of glioblastoma. Importantly, this model spontaneously develops tumours between 6 and 9 months of age. Unlike most brain tumour models this is integrated into the surrounding brain tissue, is slow growing, and has an intact immune system, making this model well-suited to study the immune response to brain tumours. We will use this model to study (1) meningeal immune responses to brain tumours, (2) how these are altered by immunotherapy, and (3) their significance to tumour progression.