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

• Main Authors: Yinghong Shi, Jiahui Zhang, Zheying Mao, Han Jiang, Wei Liu, Hui Shi, Runbi Ji, Wenrong Xu, Hui Qian, Xu Zhang
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2020-05-01
• Series: Frontiers in Oncology
• Subjects: extracellular vesicles; programmed death-ligand 1 (PD-L1); neutrophils; immune suppression; gastric cancer
• Online Access: https://www.frontiersin.org/article/10.3389/fonc.2020.00629/full

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.