Manipulation of PD-L1 Endosomal Trafficking Promotes Anticancer Immunity

作者：Ye, Zuodong; Xiong, Yiding; Peng, Wang; Wei, Wenjie; Huang, Lihong; Yue, Juliana; Zhang, Chunyuan; Lin, Ge; Huang, Feng; Zhang, Liang; Zheng, Songguo; Yue, Jianbo^*

来源：Advanced Science, 2023, 10(6).

DOI：10.1002/advs.202206411

• anticancer immunity
• endocytosis
• endosomal trafficking
• extracellular vesicle
• PD-L1
• Rab5
• Rab27

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.

• 单位
  中山大学; 南方科技大学