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; Jing-Yuan Fang

doi:10.1038/s41467-021-25662-9

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

Nat Commun. 2021 Sep 13;12(1):5405. doi: 10.1038/s41467-021-25662-9.

Authors

Yimeng Ren^#¹, Yun Qian^#¹, Luoyan Ai^{1

2}, Yile Xie¹, Yaqi Gao¹, Ziyan Zhuang¹, Jinxian Chen³, Ying-Xuan Chen¹, Jing-Yuan Fang⁴

Affiliations

¹ State Key Laboratory for Oncogenes and Related Genes; Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
² Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China.
³ Division of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
⁴ State Key Laboratory for Oncogenes and Related Genes; Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. jingyuanfang@sjtu.edu.cn.

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
B7-H1 Antigen / genetics
B7-H1 Antigen / immunology*
B7-H1 Antigen / metabolism
Cell Line, Tumor
Colorectal Neoplasms / genetics
Colorectal Neoplasms / immunology*
Colorectal Neoplasms / metabolism
Cytotoxicity, Immunologic / genetics
Cytotoxicity, Immunologic / immunology
Endosomes / immunology
Endosomes / metabolism
Gene Expression Regulation, Neoplastic / immunology*
HCT116 Cells
Humans
Intracellular Space / metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Nerve Tissue Proteins / genetics
Nerve Tissue Proteins / immunology*
Nerve Tissue Proteins / metabolism
Programmed Cell Death 1 Receptor / genetics
Programmed Cell Death 1 Receptor / immunology
Programmed Cell Death 1 Receptor / metabolism
Protein Binding
Protein Transport
RNA Interference
T-Lymphocytes / immunology
T-Lymphocytes / metabolism
Vesicular Transport Proteins / genetics
Vesicular Transport Proteins / immunology*
Vesicular Transport Proteins / metabolism

Substances

B7-H1 Antigen
Nerve Tissue Proteins
Programmed Cell Death 1 Receptor
TRAPPC4 protein, human
Vesicular Transport Proteins