Integrative CSF profiling identifies disease-specific immune responses in leptomeningeal disease

Assessing anti-tumor immune responses and immune microenvironment alterations in central nervous system (CNS) neoplasms like brain tumors and leptomeningeal disease (LMD) provides prognostic insights and predictive biomarkers. Cerebrospinal fluid (CSF) liquid biopsy (LB) is a promising minimally-invasive approach, but its ability to reflect these processes remains unclear. We used single-cell RNA and T cell receptor (TCR) sequencing of CSF cells and spatial transcriptomics of CNS lesions in LMD patients with CNS lymphoma (CNSL), glioblastoma (GB), and brain metastases (BrM), compared to neuroinflammatory CNS disorders to unveil the immune complexity during the disease course. We identified disease-specific CSF environments reflecting parenchymal tumor microenvironment features. CNSL showed robust T cell responses, while BrM and GB were dominated by myeloid cells. Unique mechanisms of disease progression and resistance linked to CSF cell dynamics highlight the potential of scRNAseq-based CSF LB for uncovering disease biology, predicting biomarkers, and developing personalized therapies for CNS neoplasms.