Journal Article

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

Luo, Ping, Lv, Yi-pin, Chen, Na, Zhao, Yong-liang, Yu, Pei-wu, Zhang, Jin-yu, Cheng, Ping, Fu, Xiao-long, Zhuang, Yuan, Wang, Ting-ting, Zou, Quan-ming, Mao, Fang-yuan, Guo, Gang, Peng, Liu-sheng, Chen, Weisan, Teng, Yong-sheng

2017

Overview

ObjectiveNeutrophils 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.DesignFlow 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.ResultsPatients 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 vitro and contributed to the growth and progression of human GC in vivo; the effect could be reversed by blocking PD-L1 on these neutrophils.ConclusionsOur results illuminate a novel mechanism of PD-L1 expression on tumour-activated neutrophils in GC, and also provide functional evidence for these novel GM-CSF-PD-L1 pathways to prevent, and to treat this immune tolerance feature of GC.

• Publisher: BMJ Publishing Group Ltd and British Society of Gastroenterology,BMJ Publishing Group LTD,BMJ Publishing Group
• Subject: Animals / Apoptosis / B7-H1 Antigen - metabolism / Biomarkers, Tumor - metabolism / Case-Control Studies / Cohort Studies / Disease / Disease Progression / Female / Flow Cytometry / GASTRIC CANCER / Genotype & phenotype / Granulocyte-macrophage colony-stimulating factor / Granulocyte-Macrophage Colony-Stimulating Factor - metabolism / Humans / Immune Tolerance / Immunological tolerance / Janus kinase / Kaplan-Meier Estimate / Kinases / Leukocytes (neutrophilic) / Life span / Ligands / Liver cancer / Lung cancer / Lymphocytes / Lymphocytes T / Medical prognosis / Metastases / Mice / Mice, Inbred NOD / Mice, SCID / Microenvironments / Neutrophil Activation / Neutrophil Infiltration / Neutrophils / Neutrophils - immunology / Neutrophils - metabolism / Patients / PD-L1 protein / Phenotypes / Signal Transduction / Solid tumors / Stat3 protein / Stomach / Stomach Neoplasms - immunology / Stomach Neoplasms - mortality / Survival Rate / T-Lymphocytes - immunology / Transcription / Tumor microenvironment / Tumors