Glioblastoma-instructed astrocytes suppress tumour-specific T cell immunity

Camilo Faust Akl, Brian M. Andersen, Zhaorong Li, Federico Giovannoni, Martin Diebold, Liliana M. Sanmarco, Michael Kilian, Luca Fehrenbacher, Florian Pernin, Joseph M. Rone, Hong-Gyun Lee, Gavin Piester, Jessica E. Kenison, Joon-Hyuk Lee, Tomer Illouz, Carolina M. Polonio, Léna Srun, Jazmin Martinez, Elizabeth N. Chung, Anton Schüle, Agustin Plasencia, Lucinda Li, Kylynne Ferrara, Mercedes Lewandrowski, Craig A. Strathdee, Lorena Lerner, Christophe Quéva, Iain C. Clark, Benjamin Deneen, Judy Lieberman, David H. Sherr, Jack P. Antel, Michael A. Wheeler, Keith L. Ligon, E. Antonio Chiocca, Marco Prinz, David A. Reardon and Francisco J. Quintana ()
Additional contact information
Camilo Faust Akl: Harvard Medical School
Brian M. Andersen: Harvard Medical School
Zhaorong Li: Harvard Medical School
Federico Giovannoni: Harvard Medical School
Martin Diebold: University of Freiburg
Liliana M. Sanmarco: Harvard Medical School
Michael Kilian: Harvard Medical School
Luca Fehrenbacher: University of Freiburg
Florian Pernin: McGill University
Joseph M. Rone: Harvard Medical School
Hong-Gyun Lee: Harvard Medical School
Gavin Piester: Harvard Medical School
Jessica E. Kenison: Harvard Medical School
Joon-Hyuk Lee: Harvard Medical School
Tomer Illouz: Harvard Medical School
Carolina M. Polonio: Harvard Medical School
Léna Srun: Harvard Medical School
Jazmin Martinez: Harvard Medical School
Elizabeth N. Chung: Harvard Medical School
Anton Schüle: Harvard Medical School
Agustin Plasencia: Harvard Medical School
Lucinda Li: Harvard Medical School
Kylynne Ferrara: Harvard Medical School
Mercedes Lewandrowski: Boston Children’s Hospital
Craig A. Strathdee: Oncorus
Lorena Lerner: Oncorus
Christophe Quéva: Oncorus
Iain C. Clark: Harvard Medical School
Benjamin Deneen: Baylor College of Medicine
Judy Lieberman: Boston Children’s Hospital
David H. Sherr: Boston University School of Medicine
Jack P. Antel: McGill University
Michael A. Wheeler: Harvard Medical School
Keith L. Ligon: Brigham and Women’s Hospital
E. Antonio Chiocca: Brigham and Women’s Hospital
Marco Prinz: University of Freiburg
David A. Reardon: Harvard Medical School
Francisco J. Quintana: Harvard Medical School

Nature, 2025, vol. 643, issue 8070, 219-229

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41586-025-08997-x

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