Glioblastoma-instructed astrocytes suppress tumour-specific T cell immunity.

in Nature by 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, Francisco J Quintana

TLDR

  • Glioblastoma shows limited response to therapies due to an immunosuppressive tumour microenvironment, particularly mediated by astrocytes.
  • The study identified an astrocyte subset that suppresses tumour immunity by inducing T cell apoptosis through TRAIL, driven by IL-11 and STAT3.
  • Targeting the IL-11-STAT3-TRAIL axis in astrocytes and engineered therapeutic viruses may improve treatment outcomes for glioblastoma patients.

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 glioblastoma. 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.

Overview

  • The study investigates the role of astrocytes in the immune response to glioblastoma, a common and aggressive primary brain cancer.
  • The research team used single-cell and bulk RNA sequencing, multiplexed immunofluorescence, and in vitro and in vivo experiments to examine the interactions between astrocytes and T cells in glioblastoma.
  • The primary objective of the study is to understand how astrocytes regulate the immune response to glioblastoma and identify potential therapeutic targets for improving treatment outcomes.

Comparative Analysis & Findings

  • The study identified an astrocyte subset that limits tumour immunity by inducing T cell apoptosis through the death receptor ligand TRAIL.
  • IL-11 produced by tumour cells was found to be a driver of STAT3-dependent TRAIL expression in astrocytes.
  • 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.

Implications and Future Directions

  • The findings suggest that targeting the IL-11-STAT3-TRAIL axis in astrocytes may be a promising therapeutic strategy for improving the response to glioblastoma treatment.
  • The study highlights the potential of engineered therapeutic viruses that target the TRAIL mechanism of astrocyte-driven tumour immunoevasion.
  • Future studies should investigate the translation of these findings to human clinical trials and explore the potential for combination therapy with existing treatments.
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