627 Inhibition of PAI-1 blocks PD-L1 endocytosis and improves the response of melanoma cells to immune checkpoint blockade

Immune checkpoint molecules, especially PD-1 and its ligand PD-L1, act as a major mechanism of cancer immune evasion. Although anti–PD-1/PD-L1 monotherapy increases therapeutic efficacy in melanoma treatment, only subset patients exhibits long-term tumor remission, the underlying resistance to PD-1/PD-L1 inhibitors remains unclear. In this study, we demonstrated that cell surface retention PD-L1 is inversely correlated with PAI-1 expression vitro, vivo, clinical specimens. Moreover, extracellular induced internalization surface-expressed by triggering clathrin-mediated endocytosis. The endocytosed was transported lysosomes for degradation endolysosomal systems, resulting reduction PD-L1. Notably, inhibition pharmacological inhibitor tiplaxtinin led elevated on plasma membrane, both vitro vivo. Strikingly, targeting treatment synergizes anti–PD-L1 blockade therapy syngeneic murine model melanoma. Our findings demonstrate role activity modulation promoting lysosomal provides an insight into combination immunotherapy promising regimen treatment.