Abstract 2801: SRY-mediated upregulation of PD-L1 promotes immune evasion in hepatocellular carcinoma and contributes to sex-specific disparities in immunotherapy response

Key Points

• This study investigates how the SRY gene influences immune responses in hepatocellular carcinoma, especially regarding gender disparities in immunotherapy effectiveness.
• Utilized multiple HCC mouse models including chemically induced, hydrodynamic, orthotopic, and subcutaneous.
• Performed castration to eliminate hormonal effects on the immune response.
• Used techniques such as flow cytometry, immunofluorescence, and ELISA to analyze T cell activity in the tumor microenvironment.
• Conducted PCR array, CUT&Tag, qPCR, WB, and luciferase assays to study SRY’s regulation of immune checkpoints.
• Validated findings using clinical samples to correlate SRY with immune markers and PD-L1.
• In castrated male SRY-KO mice, an increase in CD8+ T cells and elevated immune markers like GZMB, TNF-α, and IFN-γ were observed.
• SRY-KI in castrated males resulted in reduced CD8+ T cells and diminished immune marker function.
• Ectopic SRY in castrated females led to impaired T cell infiltration and function.
• SRY-overexpressing HCC cells showed upregulation of PD-L1, confirmed by luciferase assays linking SRY to IRF1 activation.
• PD-L1 knockdown in SRY-overexpressing tumors reversed immune suppression and enhanced tumor growth, highlighting the oncogenic role of SRY.