Targeting SERPINA3 in Gliomas Extends Survival and Reprograms the Immune Landscape 2260933

Abstract

Abstract Introduction Malignant gliomas remain the most lethal cancers, with WHO grade IV having a 5-year survival rate below 7 percent. These tumors are characterized by high proliferation and an immunosuppressive tumor microenvironment (TME) that inhibits anti-tumor immunity. Using the TCGA and CGGA databases, we identified SERPINA3 as a critical, novel tumor vulnerability. Patients with high expression of SERPINA3 have worse survival compared to their low expression counterparts. SERPINA3 inhibits immune-activating proteases, and we hypothesize that it contributes to immune evasion and tumor progression in gliomas. Methods To test this, we screened three murine glioma cell lines for SERPINA3 expression using western blot analysis and found high expression in GL261. We used CRISPR to generate a SERPINA3 knockout (KO) GL261 line and intracranially implanted either wild-type (WT) or KO tumor lines into syngeneic mice. Results Mice bearing KO tumors showed significantly longer survival (MST 68 days) than WT controls (MST 28 days). Ongoing studies are profiling the TME immune landscape to determine how SERPINA3 affects immune cell infiltration and activation using flow cytometry. Conclusion These findings identify SERPINA3 as a novel regulator of glioma progression. Targeting SERPINA3 may enhance anti-tumor response and present a promising immunotherapeutic strategy for malignant gliomas. Funding Source N/A Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)