Pathways Regulated by Glucocorticoids in Glioblastoma and Crosstalk with the Microenvironment

Glioblastoma (GBM) is the most aggressive brain tumour in adults, with an average survival of just 18 months. Current treatment includes surgery in combination with radiotherapy and chemotherapy. Oncolytic viruses (OVs) are emerging to supplement standard cancer therapies as they kill tumour cells directly and activate immune surveillance. Most GBM patients are prescribed Dexamethasone (Dex), a synthetic glucocorticoid and potent anti-inflammatory drug that reduces brain inflammation, thereby limiting deleterious symptoms of GBM. While essential as part of standard therapy, it remains unclear how Dex might influence the efficacy of emerging immunotherapies such as OVs in GBM.

In silico analysis of public RNA-seq data predicted potential crosstalk between glucocorticoids and reovirus in IL-6, AP-1 and TNF pathways. In vitro studies showed that Dex impairs direct GBM killing by reovirus. Dex did not influence virus entry or replication within GBM cells, suggesting that Dex alters GBM response to the virus. To elucidate the pathways involved, the effect of Dex on GBM cell infection by reovirus was explored by RNA-seq analysis. Gene ontology analysis demonstrated that Dex reduced pro-inflammatory signals, dysregulated activation of interferon response, and affected anti-apoptotic genes as well as cell cycle and ER stress response. A GBM-immune coculture model was used to investigate the effect of Dex on the ability of reovirus to activate immune cells and target GBM cells for destruction. Dex also impaired killing of GBM cells by immune cells. Dex altered expression of NK cell ligands on the surface of GBM cells which is predicted to reduce recruitment of NK cells. Dex significantly reduced NK cell number and activation in the presence of reovirus to reduce NK cells cytotoxic function. Consistent with this, the inhibitory effect of Dex was lost following NK cell depletion.

This study elucidates the potential pathways of Dex treatment during virus immunotherapy and emphasizes the importance of careful consideration for Dex management during immunotherapy to enhance treatment outcomes for GBM patients.