TRAPPC4 regulates the intracellular trafficking of PD-L1 and antitumor immunity

Yimeng Ren, Yun Qian, Luoyan Ai, Yile Xie, Yaqi Gao, Ziyan Zhuang, Jinxian Chen, Ying-Xuan Chen and Jing-Yuan Fang ()
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Yimeng Ren: Renji Hospital, School of Medicine, Shanghai Jiao Tong University
Yun Qian: Renji Hospital, School of Medicine, Shanghai Jiao Tong University
Luoyan Ai: Renji Hospital, School of Medicine, Shanghai Jiao Tong University
Yile Xie: Renji Hospital, School of Medicine, Shanghai Jiao Tong University
Yaqi Gao: Renji Hospital, School of Medicine, Shanghai Jiao Tong University
Ziyan Zhuang: Renji Hospital, School of Medicine, Shanghai Jiao Tong University
Jinxian Chen: Renji Hospital, School of Medicine, Shanghai Jiao Tong University
Ying-Xuan Chen: Renji Hospital, School of Medicine, Shanghai Jiao Tong University
Jing-Yuan Fang: Renji Hospital, School of Medicine, Shanghai Jiao Tong University

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract Tumor cells evade T cell-mediated immunosurveillance via the interaction between programmed death-1 (PD-1) ligand 1 (PD-L1) on tumor cells and PD-1 on T cells. Strategies disrupting PD-1/PD-L1 have shown clinical benefits in various cancers. However, the limited response rate prompts us to investigate the molecular regulation of PD-L1. Here, we identify trafficking protein particle complex subunit 4 (TRAPPC4), a major player in vesicular trafficking, as a crucial PD-L1 regulator. TRAPPC4 interacts with PD-L1 in recycling endosomes, acting as a scaffold between PD-L1 and RAB11, and promoting RAB11-mediated recycling of PD-L1, thus replenishing its distribution on the tumor cell surface. TRAPPC4 depletion leads to a significant reduction of PD-L1 expression in vivo and in vitro. This reduction in PD-L1 facilitates T cell-mediated cytotoxicity. Overexpression of Trappc4 sensitizes tumor cells to checkpoint therapy in murine tumor models, suggesting TRAPPC4 as a therapeutic target to enhance anti-tumor immunity.

Date: 2021
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DOI: 10.1038/s41467-021-25662-9

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