Astrocyte-driven suppression of tumor-specific T-cell immunity in glioblastoma

Glioblastoma (GBM) is the most common and aggressive brain cancer, showing minimal response to available therapies. A highly immunosuppressive tumor microenvironment (TME) contributes to the limited therapeutic response of GBM. Astrocytes are major components of the central nervous system (CNS), with important immunoregulatory roles. However, little is known about the role of astrocytes and their subsets in the immune response to GBM. Using single-cell and bulk RNA sequencing in GBM clinical samples and mouse pre-clinical models, in combination with multiplexed immunofluorescence microscopy, in vivo CRISPR-based cell-specific genetic perturbations, and in vitro mouse and human experimental systems we identified an astrocyte subset that limits tumor-specific immunity by inducing CD8+ and CD4+ T-cell apoptosis via the death receptor ligand TRAIL. Moreover, we identified IL-11 produced by tumor cells as a driver of STAT3-dependent TRAIL expression in GBM-associated astrocytes. pSTAT3+ TRAIL+ astrocytes were co-localized with apoptotic T cells in human GBM samples and were associated with a shorter time to recurrence and overall decreased survival in GBM patients. Conversely, genetic inactivation of the IL-11 receptor or TRAIL in astrocytes extended survival in GBM mouse models and boosted tumor-specific T cells and tumor-associated macrophage responses. Finally, a GBM-targeting oncolytic HSV-1 virus engineered to express a TRAIL-blocking single-chain antibody in the TME extended survival and boosted tumor-specific immunity in GBM pre-clinical models. In summary, we established that IL-11/STAT3-driven astrocytes suppress GBM-specific protective immunity by inducing TRAIL-dependent T-cell apoptosis, and we developed engineered therapeutic viruses to target this novel mechanism of astrocyte-driven tumor immunoevasion.