PD-L1 splice variant-driven soluble PD-L1 secretion promotes immune evasion in gastric cancer

Soluble PD-L1 (sPD-L1) is implicated in tumor immunosuppression, but its cellular origins and clinical significance in gastric cancer (GC) remain unclear. This study aims to investigate the role of PD-L1 splice variants in generating sPD-L1 and evaluates its clinical significance and impact on immune evasion in GC. We measured serum sPD-L1 levels in GC patients and correlated them with clinicopathological features. The results revealed that elevated sPD-L1 was associated with tumor progression and immune infiltration. RNA sequencing identified a novel exon 5-6 skipping variant, designated PD-L1-V1, which lacks the transmembrane domain. PD-L1-V1 expression positively correlated with sPD-L1 levels and GC progression, and negatively with immune infiltration. Further cellular assays confirmed that the PD-L1-V1 protein was primarily secreted extracellularly rather than localized to the cell membrane, representing a major source of sPD-L1 in GC cells. Functionally, PD-L1-V1 suppressed T cell activation, proliferation and cytotoxicity through binding to PD-1. In a tumor-bearing mouse model, PD-L1-V1 promoted tumor growth and impaired T cell function, which was reversed by anti-PD-1 treatment. In conclusion, this study identifies a PD-L1 splice variant that drives sPD-L1-mediated immune evasion in GC, offering insights into disease pathogenesis and suggesting potential biomarkers and therapeutic strategies targeting PD-L1 alternative splicing or anti-PD-1 immunotherapy.