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

Abstract

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.

CCL15 Recruits Suppressive Monocytes to Facilitate Immune Escape and Disease Progression in Hepatocellular Carcinoma

“…As a confirmation, DNA demethylation agent heavily increased CCL15 expression in HCC cells. The results supported the notion that intrinsic characteristics of tumor cells could regulate the local immune microenvironment . Similar to the findings that TNF‐α stimulation could elevate CCL15 expression in human airway smooth muscle cells, we found that TNF‐α and IFN‐γ could also promote CCL15 production in HCC cells.…”

Chronic lymphocytic leukemia cells increase neutrophils survival and promote their differentiation into CD16highCD62Ldim immunosuppressive subset

“…e and f). These results suggest that, as reported in gastric cancer, neutrophils from CLL patients can impair T‐cell responses.…”

Neutrophils as myeloid‐derived suppressor cells

“…Another nonclassic mechanism that has been described is the interaction of programmed death‐ligand 1 (PD‐L1) on MDSCs and programmed cell death protein 1 (PD‐1) on T cells, which impairs the proliferation and cytokine production of T cells . PD‐L1 is under normal conditions not expressed on neutrophils, but can be induced by IFN‐γ and hypoxia, which are readily found in some cancers, or by tumour‐derived GM‐CSF . In fact, patients with gastric cancer have a high infiltration of neutrophils in tumours, which show an activated CD54+ phenotype, a high expression of PD‐L1 and were found to suppress normal T‐cell immunity in vitro .…”