Language
English
Publication Date
7-1-2025
Journal
Nature
DOI
10.1038/s41586-025-08997-x
PMID
40399681
PMCID
PMC12765214
PubMedCentral® Posted Date
1-5-2026
PubMedCentral® Full Text Version
Author MSS
Abstract
Glioblastoma is the most common and aggressive primary brain cancer and shows minimal response to therapies. The immunosuppressive tumour microenvironment in glioblastoma contributes to the limited therapeutic response. Astrocytes are abundant in the central nervous system and have important immunoregulatory roles. However, little is known about their role in the immune response to glioblastoma1. Here we used single-cell and bulk RNA sequencing of clinical glioblastoma samples and samples from preclinical models, multiplexed immunofluorescence, in vivo CRISPR-based cell-specific genetic perturbations and in vitro mouse and human experimental systems to address this gap in knowledge. We identified an astrocyte subset that limits tumour immunity by inducing T cell apoptosis through the death receptor ligand TRAIL. Moreover, we identified that IL-11 produced by tumour cells is a driver of STAT3-dependent TRAIL expression in astrocytes. Astrocyte signalling through STAT3 and TRAIL expression were associated with a shorter time to recurrence and overall decreased survival in patients with glioblastoma. Genetic inactivation of the IL-11 receptor or TRAIL in astrocytes extended survival in mouse models of glioblastoma and enhanced T cell and macrophage responses. Finally, treatment with an oncolytic HSV-1 virus engineered to express a TRAIL-blocking single-chain antibody in the tumour microenvironment extended survival and enhanced tumour-specific immunity in preclinical models of glioblastoma. In summary, we establish that IL-11–STAT3-driven astrocytes suppress glioblastoma-specific protective immunity by inducing TRAIL-dependent T cell apoptosis, and engineered therapeutic viruses can be used to target this mechanism of astrocyte-driven tumour immunoevasion.
Keywords
Glioblastoma, Astrocytes, Animals, Mice, Humans, T-Lymphocytes, STAT3 Transcription Factor, TNF-Related Apoptosis-Inducing Ligand, Apoptosis, Female, Tumor Microenvironment, Brain Neoplasms, Male, Herpesvirus 1, Human, Cell Line, Tumor, Oncolytic Viruses, Signal Transduction, Disease Models, Animal, Macrophages, Single-Cell Analysis, Mice, Inbred C57BL, Oncolytic Virotherapy
Published Open-Access
yes
Recommended Citation
Faust Akl, Camilo; Andersen, Brian M; Li, Zhaorong; et al., "Glioblastoma-Instructed Astrocytes Suppress Tumour-Specific T Cell Immunity" (2025). Faculty, Staff and Students Publications. 6277.
https://digitalcommons.library.tmc.edu/baylor_docs/6277