Manipulation of PD‐L1 Endosomal Trafficking Promotes Anticancer Immunity. Issue 6 (25th December 2022)

• Record Type: Journal Article
• Authors: Ye, Zuodong; Xiong, Yiding; Peng, Wang; Wei, Wenjie; Huang, Lihong; Yue, Juliana; Zhang, Chunyuan; Lin, Ge; Huang, Feng; Zhang, Liang; Zheng, Songguo; Yue, Jianbo
• Is Part Of: Advanced science. Volume 10:Issue 6(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-12-25
• Subjects: 6J1 -- anticancer immunity -- endocytosis -- endosomal trafficking -- extracellular vesicle -- PD‐L1 -- Rab5 -- Rab27; Science -- Periodicals; 505
• DOI: 10.1002/advs.202206411
• Languages: English
• ISSNs: 2198-3844

Abstract

Abstract: The aberrant regulation of PD‐L1 in tumor cells remains poorly understood. Here, the authors systematically investigate the endosomal trafficking of plasma membrane PD‐L1 in tumor cells. They show that plasma membrane PD‐L1 is continuously internalized, and then trafficked from early endosomes to multivesicular bodies/late endosomes, recycling endosomes, lysosomes, and/or extracellular vesicles (EVs). This constitutive endocytic trafficking of PD‐L1 is Rab5‐ and clathrin‐dependent. Triazine compound 6J1 blocks the endosomal trafficking of PD‐L1 and induces its accumulation in endocytic vesicles by activating Rab5. 6J1 also promotes exosomal PD‐L1 secretion by activating Rab27. Together, these effects result in a decrease in the membrane level of PD‐L1 in 6J1‐treated tumor cells and enables tumor cells to be more susceptible to the tumor‐killing activity of T cells in vitro. 6J1 also increases tumor‐infiltrating cytotoxic T cells and promotes chemokines secretion in the tumor microenvironment. Rab27 knockdown abolishes 6J1‐induced PD‐L1 secretion in EVs and revokes the exhausted tumor‐infiltrating T cells in tumors, thereby improving the anticancer efficacy of 6J1. Furthermore, a combination of 6J1 and an anti‐PD‐1 antibody significantly improves the anticancer immune response. Therefore, manipulating PD‐L1 endosomal trafficking provides a promising means to promote an anticancer immune response in addition to the immune checkpoint‐blocking antibody therapy. Abstract : The plasma membrane PD‐L1 undergoes a constitutive endosomal trafficking process. 6J1 (a triazine compound) blocks PD‐L1's endosomal trafficking and induces its secretion in extracellular vesicles (EVs), decreasing PD‐L1 at the plasma membrane. A combination of 6J1 with the inhibition of PD‐L1 secretion in EVs or with a PD‐1 monoclonal antibody significantly promotes the anticancer immune response.