Decoding the immune response in leptomeningeal disease through single-cell sequencing of cerebrospinal fluid

Abstract

AbstractAssessing anti-tumor immune responses and immune microenvironments in central nervous system (CNS) neoplasms, such as brain tumors and leptomeningeal disease (LMD), provides prognostic insights and predictive biomarkers. Liquid biopsy of the cerebrospinal fluid (CSF) represents a promising minimally-invasive approach, but its ability to reflect immune responses against tumors remains unclear. Here, we used single-cell sequencing of CSF cells and spatial transcriptomics of CNS lesions to compare and contrast LMD patients with CNS lymphoma (CNSL), glioblastoma (GB) and brain metastases (BrM), to neuroinflammatory CNS disorders. We identified disease-specific CSF environments, reflecting parenchymal tumor microenvironment features. CNSL showed robust T cell responses, while BrM and GB were dominated by both blood-derived and tissue-resident myeloid cells. Longitudinal CSF sampling unveiled mechanisms of disease progression and therapy resistance, highlighting the potential of CSF liquid biopsies for uncovering disease biology, discovering cellular biomarkers and developing personalized therapies for CNS neoplasms.