Spatial immune profiling defines a subset of human gliomas with functional tertiary lymphoid structures

Adult-type diffuse gliomas, the most common primary brain tumors, respond poorly to immune-based therapies and are considered immunologically "cold" tumors. Here, we examined the features and clinical relevance of glioma intratumoral tertiary lymphoid structures (TLSs) using spatial transcriptome and proteome profiling. In a cohort of 642 gliomas, TLSs were present in 15% of tumors and associated with a remodeled perivascular space and spatial redistribution of extracellular matrix components. Three distinct TLS subtypes could be defined based on differing cellular composition and immune activity. While all subtypes lacked classical germinal center architecture, certain TLSs exhibited features of dynamic immune functions, including clonal T and B cell expansion, generation of IgA⁺ and IgG⁺ plasma cells, and dendritic cell-T cell interactions. The presence of TLSs with active immune response features correlated with improved overall survival. Thus, a functional adaptive immune response is detectable in some gliomas, with implications for stratification and treatment.