Extracellular Vesicles From Gastric Cancer Cells Induce PD-L1 Expression on Neutrophils to Suppress T-Cell Immunity

Yinghong Shi; Jiahui Zhang; Zheying Mao; Han Jiang; Wei Liu; Hui Shi; Runbi Ji; Wenrong Xu; Hui Qian; Xu Zhang

doi:10.3389/fonc.2020.00629

Extracellular Vesicles From Gastric Cancer Cells Induce PD-L1 Expression on Neutrophils to Suppress T-Cell Immunity

Front Oncol. 2020 May 13:10:629. doi: 10.3389/fonc.2020.00629. eCollection 2020.

Authors

Yinghong Shi^{1

2}, Jiahui Zhang^{1

2}, Zheying Mao^{1

2}, Han Jiang^{1

2}, Wei Liu^{1

2}, Hui Shi^{1

2}, Runbi Ji^{2

3}, Wenrong Xu^{1

2}, Hui Qian^{1

2}, Xu Zhang^{1

2}

Affiliations

¹ Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China.
² Zhenjiang Key Laboratory of High Technology for Basic and Translational Research on Exosomes, Zhenjiang, China.
³ Department of Clinical Laboratory, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, China.

Abstract

Neutrophils are prominent components of solid tumors and exhibit distinct phenotypes in different tumor milieu. We have previously shown that tumor extracellular vesicles (EVs) could induce pro-tumor activation of neutrophils; however, the role of tumor EV-elicited neutrophils in tumor immunity remains unclear. Herein, we reported that gastric cancer cell-derived EVs (GC-EVs) induced the expression of programmed death-ligand 1 (PD-L1) on neutrophils. GC-EVs transported high-mobility group box-1 (HMGB1) to activate signal transducer and activator of transcription 3 (STAT3) and upregulate PD-L1 gene expression in neutrophils. Blocking STAT3 pathway and silencing HMGB1 reversed GC-EV-induced PD-L1 expression on neutrophils. GC-EV-elicited neutrophils suppressed T cell proliferation, activation, and function in vitro, which could be antagonized by a specific PD-L1 antibody. Furthermore, GC tissue-derived EVs also showed similar effects. Taken together, our results indicate that EVs from the GC microenvironment induce PD-L1 expression on neutrophils to suppress T-cell immunity, which provides a new insight into the pro-tumor roles of neutrophils in GC and sheds light on the multifaceted roles of EVs in orchestrating an immunosuppressive microenvironment.

Keywords: extracellular vesicles; gastric cancer; immune suppression; neutrophils; programmed death-ligand 1 (PD-L1).