Single cell RNA-Seq of meninges immune landscape in GBM

ABSTRACT: The meninges play a critical role in the immunosurveillance of the central nervous system, but the contribution of the dura to the immune response to glioblastoma (GBM) remains elusive. Using single cell sequencing and T-cell receptor tracking to analyze a unique cohort of GBM clinical samples and mouse-preclinical models in combination with genetic perturbations, photoactivable mice, in vivo mRNA delivery and engineered human CAR T cells, we identified MHC class II-dependent immune cell hubs in the dura that promote T-cell responses to GBM. Dura-primed CD8+ T cells migrate to the tumor microenvironment (TME) and display enhanced effector functions against GBM. In mechanistic studies we established that this enhanced effector phenotype of dura-primed CD8+ T cells is driven by the expression of PLAC8, which stabilizes phosphorylated STAT5 via MDM2. Moreover, we identified dural IL-33 as inducer of PLAC8 expression in CD8+ T cells. Local lipid nanoparticle-based in vivo delivery of mRNA encoding an engineered IL-33 improved CD8+ T-cell effector functions and prolonged survival in glioma-bearing mice. In summary, we identified the dura as a site for the induction of GBM-reactive T cells with improved effector function via a novel IL-33-PLAC8-MDM2-pSTAT5 axis. These findings define a novel role for the dura in the control of the T-cell response to GBM, and identify novel targets for therapeutic intervention.

ORGANISM(S): Mus musculus

PROVIDER: GSE304648 | GEO | 2026/08/26

REPOSITORIES: GEO