Microglia induce an interferon-stimulated gene expression profile in glioblastoma and increase glioblastoma resistance to temozolomide.

in Neuropathology and applied neurobiology by Mia Dahl Sørensen, Rikke Frydendahl Sick Olsen, Mark Burton, Stephanie Kavan, Stine Asferg Petterson, Mads Thomassen, Torben Arvid Kruse, Morten Meyer, Bjarne Winther Kristensen

TLDR

  • The study found that microglia can make glioblastoma cells more resistant to chemotherapy. The study also found that the genes that become more active in the glioblastoma cells when they are exposed to microglia are the same genes that make other types of cancer cells more resistant to chemotherapy. This suggests that targeting these genes in glioblastoma cells could be a new way to treat the disease.

Abstract

Glioblastoma is the most malignant primary brain tumour. Even with standard treatment comprising surgery followed by radiation and concomitant temozolomide (TMZ) chemotherapy, glioblastoma remains incurable. Almost all patients with glioblastoma relapse owing to various intrinsic and extrinsic resistance mechanisms of the tumour cells. Glioblastomas are densely infiltrated with tumour-associated microglia and macrophages (TAMs). These immune cells affect the tumour cells in experimental studies and are associated with poor patient survival in clinical studies. The aim of the study was to investigate the impact of microglia on glioblastoma chemo-resistance. We co-cultured patient-derived glioblastoma spheroids with microglia at different TMZ concentrations and analysed cell death. In addition, we used RNA sequencing to explore differentially expressed genes after co-culture. Immunostaining was used for validation. Co-culture experiments showed that microglia significantly increased TMZ resistance in glioblastoma cells. RNA sequencing revealed upregulation of a clear interferon-stimulated gene (ISG) expression signature in the glioblastoma cells after co-culture with microglia, including genes such as IFI6, IFI27, BST2, MX1 and STAT1. This ISG expression signature is linked to STAT1 signalling, which was confirmed by immunostaining. The ISG expression profile observed in glioblastoma cells with enhanced TMZ resistance corresponded to the interferon-related DNA damage resistance signature (IRDS) described in different solid cancers. Here, we show that the IRDS signature, linked to chemo-resistance in other cancers, can be induced in glioblastoma by microglia. ISG genes and the microglia inducing the ISG expression could be promising novel therapeutic targets in glioblastoma.

Overview

  • The study investigates the impact of microglia on glioblastoma chemo-resistance. The study co-cultured patient-derived glioblastoma spheroids with microglia at different TMZ concentrations and analysed cell death. RNA sequencing was used to explore differentially expressed genes after co-culture. Immunostaining was used for validation. The study aims to achieve the primary objective of identifying novel therapeutic targets in glioblastoma.

Comparative Analysis & Findings

  • Co-culture experiments showed that microglia significantly increased TMZ resistance in glioblastoma cells. RNA sequencing revealed upregulation of a clear interferon-stimulated gene (ISG) expression signature in the glioblastoma cells after co-culture with microglia, including genes such as IFI6, IFI27, BST2, MX1 and STAT1. This ISG expression profile observed in glioblastoma cells with enhanced TMZ resistance corresponded to the interferon-related DNA damage resistance signature (IRDS) described in different solid cancers.

Implications and Future Directions

  • The study's findings suggest that microglia can induce chemo-resistance in glioblastoma by upregulating ISG genes. The study identifies ISG genes and the microglia inducing the ISG expression as promising novel therapeutic targets in glioblastoma. Future research could focus on developing targeted therapies against ISG genes and microglia in glioblastoma.
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