Article Text
Abstract
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 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.
Conclusions Our 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.
- GASTRIC CANCER
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Footnotes
YZ, T-tW and Y-lZ contributed equally.
Contributors Conception and design; data analysis; drafting the manuscript: YZ. Manuscript revision: YZ and WC. Statistical analysis: YZ, T-tW, Y-lZ, L-sP, NC, Y-pL, F-yM, J-yZ, PC, Y-sT, X-lF, P-wY and GG. Obtained funding: YZ, Y-lZ. Technical support: PL and Q-mZ. Final approval of submitted version: YZ.
Funding This work was supported by the National Key Research and Development Program of China (2016YFC1302200) and grant of National Natural Science Foundation of China (81402355 and 81372560).
Competing interests None declared.
Patient consent Obtained.
Ethics approval The biopsy specimens were obtained under protocols approved by the ethics committees of Southwest Hospital of Third Military Medical University and informed consent was obtained from all patients. All animal experiments were undertaken with approval from the Animal Ethical and Experimental Committee of Third Military Medical University.
Provenance and peer review Not commissioned; externally peer reviewed.