Investigating IFN-γ, IL-21 and TNF-α as a novel cytokine therapy in glioblastoma

Abstract

Gliomas are the most common primary malignant brain tumours found in humans, in which grade IV glioblastoma accounts for the vast majority of all glioma diagnoses. Current glioblastoma treatments are associated with poor survival and high rates of tumour recurrence, thus alternative therapies urgently need to be developed. Cancer immunotherapies have significant therapeutic potential, as they can alter the immune system to promote anti-tumour immunity. IL-21 is an emerging cytokine that is rapidly gaining popularity as a novel therapeutic agent for various cancer types, though very little is known about the impact of IL-21 in glioblastoma. On the other hand, both IFN-γ and TNF-α have shown significant potential as individual cancer immunotherapies, but very few studies have explored their combined effects in glioblastoma. Although IFN-γ, IL-21 and TNF-α each demonstrated independent anti-tumour effects on two glioblastoma cell lines (U251 and U373), tumour rejection was potently enhanced when the cytokines were administered together. In particular, the combination of IFN-γ, IL-21 and TNF-α significantly induced cell death and inhibited proliferation in both glioblastoma cell lines. Furthermore, results showed that IFN-γ, IL-21 and TNF-α either induced or enhanced the expression of a range of co-stimulatory immunological ligands on U251 and U373 cells. In addition, IFN-γ, IL-21 and TNF-α impaired tumour-mediated immunosuppression by downregulating Foxp3 expression in CD4+ and CD8+ T cells, even when co-cultured with the glioblastoma secretome. Altogether, these results established that IFN-γ, IL-21 and TNF-α could have significant therapeutic value as a novel cytokine therapy in glioblastoma through direct inhibitory anti-tumour effects and modulation of tumourassociated immunosuppression, thus they have the potential to simultaneously promote tumour rejection and restore immune function in glioblastoma patients, but this requires substantial further investigation.