New therapeutic approach stops glioblastoma from hijacking the immune system

A study appearing in Nature investigated the role of astrocytes, an abundant cell type in the brain, in regulating an immune response against glioblastoma (GBM)—a highly aggressive brain cancer. Researchers found a subset of astrocytes that limits the immune response and can be targeted with therapeutics.

GBM is a brain cancer that has remained untreatable for decades. Immunotherapies that have worked in other cancers are ineffective in GBM, potentially due to the local suppression of immune responses in the tumor microenvironment. Astrocytes are abundant cells of the central immune system that regulate inflammation in multiple diseases.

In this study, the researchers examined how their role in the immune response could provide insights into effectively treating GBM.

The team investigated astrocyte subsets through a combination of high-resolution sequencing methods of clinical samples and mouse models. In addition, they used multiplex microscopy, in vivo genetic deletion and in vitro model systems. They used therapeutic oncolytic viruses, which were engineered to express a blocking antibody in situ.

The researchers identified a novel mechanism whereby GBM cells exploit astrocytes to evade immune responses. Specifically, they:

• Found a group of astrocytes specialized in killing T cells—white blood cells essential to the immune response. Deactivating this group of astrocytes boosts T cell activity, remodels the area around the tumor, and enhances the protective immune responses against the tumor while extending survival in mice.
• Demonstrated that the tumor cells release an inflammatory molecule called IL-11 that further activates these T-cell killing astrocytes, leading to shorter survival and faster cancer recurrence.
• Designed a novel therapeutic approach to target this pathway by engineering a virus to produce an antibody that suppress this immunosuppressive mechanism.

This study highlights an astrocyte-driven mechanism used by GBM to escape protective immune responses. The findings could guide novel immunotherapies for GBM.

Since they found that GBM exploits astrocytes by producing IL-11, the next steps are to investigate how IL-11 affects other cell types in the GBM tumor microenvironment and brain metastases, including investigating the broader effects of IL-11 on the successful mounting of immune responses.