Tumour-activated neutrophils in gastric cancer foster immune suppression and disease progression through GM-CSF-PD-L1 pathway

作者：Tingting Wang, Yongliang Zhao, Liu‐sheng Peng, Na Chen, Weisan Chen, Yi-pin Lv, Fangyuan Mao, Jinyu Zhang, Ping Cheng, Yong‐sheng Teng, Xiaolong Fu, Pei-wu Yu, Gang Guo, Ping Luo, Yuan Zhuang, Quanming Zou · 发表于：Gut · 年份：2017 · DOI：10.1136/gutjnl-2016-313075 · 被引用次数：537 · 研究领域：Immune cells in cancer、Neutrophil, Myeloperoxidase and Oxidative Mechanisms、Cancer Research and Treatments

Objective Neutrophils are prominent components of solid tumours and exhibit distinct phenotypes in different tumour microenvironments. However, the nature, regulation, function and clinical relevance of neutrophils in human gastric cancer (GC) are presently unknown. Design Flow cytometry analyses were performed to examine levels and phenotype of neutrophils in samples from 105 patients with GC. Kaplan-Meier plots for overall survival were performed using the log-rank test. Neutrophils and T cells were isolated, stimulated and/or cultured for in vitro and in vivo regulation and function assays. Results Patients with GC showed a significantly higher neutrophil infiltration in tumours. These tumour-infiltrating neutrophils showed an activated CD54 + phenotype and expressed high level immunosuppressive molecule programmed death-ligand 1 (PD-L1). Neutrophils activated by tumours prolonged their lifespan and strongly expressed PD-L1 proteins with similar phenotype to their status in GC, and significant correlations were found between the levels of PD-L1 and CD54 on tumour-infiltrating neutrophils. Moreover, these PD-L1 + neutrophils in tumours were associated with disease progression and reduced GC patient survival. Tumour-derived GM-CSF activated neutrophils and induced neutrophil PD-L1 expression via Janus kinase (JAK)-signal transducer and activator of transcription 3 (STAT3) signalling pathway. The activated PD-L1 + neutrophils effectively suppressed normal T-cell immunity in v...