STING activation induces cytotoxic and immune responses in meningiomas via inflammatory cell death pathways

Meningiomas are common tumors of the central nervous system that are typically treated with surgery but lack alternative treatment options. Activation of the stimulator of interferon genes pathway with an agonist such as 8803 can trigger anti-tumor immune responses. Using integrated molecular approaches, here we show this pathway is expressed in both neoplastic and immune populations within meningiomas associated with promoter hypomethylation and increased chromatin accessibility. Treatment of diverse patient meningiomas ex vivo with 8803 induces direct tumor cytotoxicity through pyroptosis and the induction of gasdermin D membrane pore formation. Direct tumor cytotoxicity triggered by 8803 activates macrophages and upregulates matrix metalloproteinase production facilitating degradation of tumor stroma collagen. Treatment of preclinical meningiomas with 8803 induces survival benefits, including in an immune competent orthotopic setting, through remodeling of the tumor microenvironment, immune infiltration, and down regulation of tumor-mediated immune suppression thereby nominating 8803 for treatment consideration in meningiomas. Overall design: Ex-vivo, patient derived meningiomas were processed as single cell suspensions post resection. RNA-seq profiling was applied to each patient sample with both a control treatment, and an 8803 STING-agoinst treatment