Inhibition of PAI-1 Blocks PD-L1 Endocytosis and Improves the Response of Melanoma Cells to Immune Checkpoint Blockade

• Published in: Journal of investigative dermatology Vol. 141; no. 11; pp. 2690 - 2698.e6
• Main Authors: Tseng, Yu-Ju, Lee, Chih-Hung, Chen, Wei-Yu, Yang, Jenq-Lin, Tzeng, Hong-Tai
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.11.2021
• Subjects: siPai-1; CAV; CLA; siRNA; TPX
• ISSN: 0022-202X; 1523-1747
• DOI: 10.1016/j.jid.2021.03.030

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