Manipulation of PD-L1 Endosomal Trafficking Promotes Anticancer Immunity

Ye, Zuodong1,2; Xiong, Yiding3; Peng, Wang1,2; Wei, Wenjie4; Huang, Lihong1,2; Yue, Juliana5,7; Zhang, Chunyuan6; Lin, Ge6; Huang, Feng3; Zhang, Liang1,2; Zheng, Songguo3; Yue, Jianbo1

2022-12-01

10.1002/advs.202206411

ADVANCED SCIENCE   影响因子和分区

2198-3844

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.

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

SCI ; EI

英语

其他

NSFC["21778045","32070702","82161128014"] ; Shenzhen Science and Technology Innovation Committee["SGDX20201103093201010","JSGG20200225150702770","JCYJ20210324134007020"] ; ITF["MRP/064/21","GHP/097/20GD","MHP/072/21"]

Chemistry ; Science & Technology - Other Topics ; Materials Science

Chemistry, Multidisciplinary ; Nanoscience & Nanotechnology ; Materials Science, Multidisciplinary

WOS:000903688200001

WILEY

20230113327901

Antibodies ; Cell membranes ; Chemical activation ; Cytology ; Immune system ; Molecular biology ; T-cells

Biological Materials and Tissue Engineering:461.2 ; Biology:461.9 ; Immunology:461.9.1 ; Chemical Reactions:802.2 ; Chemical Products Generally:804

2-s2.0-85145179004

Web of Science

1.City Univ Hong Kong, Shenzhen Res Inst, Shenzhen 518057, Peoples R China
2.City Univ Hong Kong, Dept Biomed Sci, Hong Kong 999077, Peoples R China
3.Sun Yat Sen Univ, Affiliated Hosp 3, Dept Clin Immunol, Guangzhou 510630, Peoples R China
4.South Univ Sci & Technol China, Res Core Facil, Shenzhen 518052, Peoples R China
5.Brigham Young Univ, Dept Biol, Provo, UT 84602 USA
6.Chinese Univ Hong Kong, Sch Biomed Sci, Hong Kong 999077, Peoples R China
7.Duke Kunshan Univ, Div Nat & Appl Sci, Synear Mol Biol Lab, Kunshan 215316, Peoples R China

Ye, Zuodong,Xiong, Yiding,Peng, Wang,et al. Manipulation of PD-L1 Endosomal Trafficking Promotes Anticancer Immunity[J]. ADVANCED SCIENCE,2022,10(6).

Ye, Zuodong.,Xiong, Yiding.,Peng, Wang.,Wei, Wenjie.,Huang, Lihong.,...&Yue, Jianbo.(2022).Manipulation of PD-L1 Endosomal Trafficking Promotes Anticancer Immunity.ADVANCED SCIENCE,10(6).

Ye, Zuodong,et al."Manipulation of PD-L1 Endosomal Trafficking Promotes Anticancer Immunity".ADVANCED SCIENCE 10.6(2022).