IL-18, a therapeutic target for immunotherapy boosting, promotes temozolomide chemoresistance via the PI3K/AKT pathway in glioma

Abstract

Background: Temozolomide (TMZ) resistance is still the urgent topic in treatments of glioma. Recent studies show inflammation is involved in tumor chemoresistance.Interleukin-18, a proinflammatory cytokine, is highly expressed in glioma and related with worse prognosis. However, its effects on glioma remain unclear. Methods and Results: In this research, we detected that interleukin-18 enhanced growth and inhibited apoptosis in cultured glioma cells via CCK8 and EdU assay. Further, in vivo studies revealed that interleukin-18 promoted glioma growth in mice bearing tumors. Mechanical exploration indicated that interleukin-18 stimulation could activate the PI3K/AKT pathway, and the PI3K inhibition could reduce the interleukin-18-induced proliferation of glioma cells. We found that interleukin-18 upregulated CD274 expression in glioma cells.Furthermore, we established a tumor xenograft model and explored the therapeutic efficacy of anti-interleukin-18 monoclonal antibodies. Targeting interleukin-18 prolonged survival and attenuated CD274 expression in the mice-bearing tumor. Combined application of anti-PD-1 and anti-interleukin-18 monoclonal antibodies showed better efficacy in suppressing tumor growth than either treatment alone in mice bearing tumors. Conclusion: Interleukin-18 promotes temozolomide chemoresistance in glioma via PI3K/Akt activation and establishes an immunosuppressive milieu by modulating CD274. This study highlights the therapeutic value of interleukin-18 in glioma.