Targeting VPS18 hampers retromer trafficking of PD-L1 and augments immunotherapy
Ting Dong, Huanmin Niu, Zhaojun Chu, Chengjun Zhou, Yinghui Gao, Mengqi Jia, Bin Sun, Xiaoxue Zheng, Wenru Zhang, Jiaozhen Zhang, Yanhai Luo, Yong Sun, Chan Wang, Qiqi Lu, Changhong Liu, Guangfeng Shao, Hong‐Xiang Lou, Huiqing Yuan
Abstract
Immune checkpoint inhibitors targeting programmed cell death 1 (PD-1) or programmed cell death-ligand 1 (PD-L1) have achieved impressive antitumor clinical outcomes. However, the limited response rates suggest the incomplete understanding of PD-L1 regulation. Here, we demonstrate that vacuole protein sorting 11 and 18 (VPS11/18), two key players in vesicular trafficking, positively regulate PD-L1 and confer resistance to immune checkpoint blockade therapy. VPS11/18 interact with PD-L1 in endosome recycling accompanied by promoting PD-L1 glycosylation and protein stability. VPS18 deficiency enhances antitumor immune response. Pharmacological inhibition by VPS18 inhibitor RDN impaired PD-L1 member trafficking and protein stability. Combination treatment of RDN and anti-cytotoxic T lymphocyte-associated antigen 4 synergistically enhances antitumor efficacy in aggressive and drug-resistant tumors. RDN exerted lung-preferred distribution and good bioavailability, suggesting a favorable drug efficacy. Together, our study links VPS18/11-mediated trans-Golgi network recycling of PD-L1 and points to a promising treatment strategy for the enhancement of antitumor immunity.