Manipulation of PD-L1 Endosomal Trafficking Promotes Anticancer Immunity.


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.





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Publication Info

Ye, Zuodong, Yiding Xiong, Wang Peng, Wenjie Wei, Lihong Huang, Juliana Yue, Chunyuan Zhang, Ge Lin, et al. (2023). Manipulation of PD-L1 Endosomal Trafficking Promotes Anticancer Immunity. Advanced science (Weinheim, Baden-Wurttemberg, Germany), 10(6). p. e2206411. 10.1002/advs.202206411 Retrieved from

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Jianbo Yue

Professor of Biology at Duke Kunshan University

Jianbo earned his Ph.D. in Pharmacology from Pennsylvania State University, followed by postdoctoral training at Stanford University. He then started his independent academic career at the University of Hong Kong and City University of Hong Kong, prior to his appointment at DKU. His laboratory focuses on cell signaling and drug discovery, with research interests spanning autophagy, endosomal trafficking, metastasis, anticancer immunity, as well as the roles of calcium ions (Ca2+) and reactive oxygen species (ROS).

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