Charting CNS Adaptive Immune Responses in Development and Disease

The central nervous system (CNS) is actively surveilled by the immune system through networks of meningeal lymphatic vessels (MLVs), skull bone marrow, and the dura. Childhood brain tumours (cBTs) exploit these developmental immune programs to establish local immunotolerance. Preliminary data in cBT mouse models show that tumour-derived cytokines remodel the dura and skull bone marrow, promoting immunosuppressive myeloid and Treg populations, while inducing dense lymphoid aggregates with dysfunctional germinal centre-like B cell populations. MLV impairment restricts antigen drainage, amplifying tolerance and blunting anti-tumour immunity. This project has three objectives: (1) Investigating MLV dysfunction in cBTs: define how tumour growth impairs lymphatic drainage, alters antigen clearance, and remodels dural immune niches. (2) Model and characterise antigen-specific T and B cell responses in the developing and malignant CNS: employ engineered model antigen tumour and neural stem cell mouse models with single-cell immune profiling to track adaptive responses. (3) Spatiotemporal characterisation of germinal centre reactions within the dura: map GC architecture, clonal dynamics, and memory B cell origins in patients and mice. This integrated programme will reveal how cBTs hijack CNS immune privilege, identify cellular and molecular drivers of immune evasion, and provide a roadmap for targeted immunotherapeutic strategies in paediatric brain tumours.