Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
Nanhu Brain-Computer Interface Institute, Hangzhou, 311100, China.
Adv Sci (Weinh). 2024 Nov;11(41):e2400340. doi: 10.1002/advs.202400340. Epub 2024 Sep 4.
The intracellular distribution and transportation process are essential for maintaining PD-L1 (programmed death-ligand 1) expression, and intervening in this cellular process may provide promising therapeutic strategies. Here, through a cell-based high content screening, it is found that the ABCB1 (ATP binding cassette subfamily B member 1) modulator zosuquidar dramatically suppresses PD-L1 expression by triggering its autophagic degradation. Mechanistically, ABCB1 interacts with PD-L1 and impairs COP II-mediated PD-L1 transport from ER (endoplasmic reticulum) to Golgi apparatus. The treatment of zosuquidar enhances ABCB1-PD-L1 interaction and leads the ER retention of PD-L1, which is subsequently degraded in the SQSTM1-dependent selective autophagy pathway. In CT26 mouse model and a humanized xenograft mouse model, zosuquidar significantly suppresses tumor growth and accompanies by increased infiltration of cytotoxic T cells. In summary, this study indicates that ABCB1 serves as a negative regulator of PD-L1, and zosuquidar may act as a potential immunotherapy agent by triggering PD-L1 degradation in the early secretory pathway.
细胞内分布和运输过程对于维持 PD-L1（程序性死亡配体 1）的表达至关重要，干预这一细胞过程可能提供有前途的治疗策略。在这里，通过基于细胞的高内涵筛选，发现 ABCB1（ATP 结合盒亚家族 B 成员 1）调节剂唑吡司特通过触发其自噬降解，显著抑制 PD-L1 的表达。在机制上，ABCB1 与 PD-L1 相互作用，并损害 COP II 介导的 PD-L1 从内质网（ER）到高尔基体的运输。唑吡司特的处理增强了 ABCB1-PD-L1 的相互作用，并导致 PD-L1 在 ER 中的滞留，随后在 SQSTM1 依赖性选择性自噬途径中降解。在 CT26 小鼠模型和人源化异种移植小鼠模型中，唑吡司特显著抑制肿瘤生长，并伴有细胞毒性 T 细胞的浸润增加。总之，这项研究表明，ABCB1 是 PD-L1 的负调节剂，唑吡司特可能通过在早期分泌途径中触发 PD-L1 降解，作为一种潜在的免疫治疗药物发挥作用。
