Granulocyte-Macrophage Colony-Stimulating Factor-Activated Neutrophils Express B7-H4 That Correlates with Gastric Cancer Progression and Poor Patient Survival

Autor: Fang-yuan Mao, Liu-sheng Peng, Kun Fan, Yong-sheng Teng, Ping Cheng, Zong-Bao Yan, Zhi-Guo Shan, Yong-liang Zhao, Yuan Zhuang
Rok vydání: 2021
Předmět:
Article Subject
Neutrophils
Immunology
Naphthols
Neutrophil Activation
Immune tolerance
Flow cytometry
03 medical and health sciences
0302 clinical medicine
Stomach Neoplasms
Immune Tolerance
medicine
Humans
Immunology and Allergy
STAT3
Cells
Cultured
Janus Kinases
Neoplasm Staging
Sulfonamides
biology
medicine.diagnostic_test
Chemistry
Granulocyte-Macrophage Colony-Stimulating Factor
General Medicine
V-Set Domain-Containing T-Cell Activation Inhibitor 1
RC581-607
Intercellular Adhesion Molecule-1
Survival Analysis
Gene Expression Regulation
Neoplastic
Phenotype
Granulocyte macrophage colony-stimulating factor
Tumor progression
030220 oncology & carcinogenesis
Disease Progression
biology.protein
Cancer research
Immunologic diseases. Allergy
Signal transduction
Janus kinase
Ex vivo
Signal Transduction
Research Article
030215 immunology
medicine.drug
Zdroj: Journal of Immunology Research, Vol 2021 (2021)
Journal of Immunology Research
ISSN: 2314-7156
2314-8861
DOI: 10.1155/2021/6613247
Popis: Neutrophils are prominent components of gastric cancer (GC) tumors and exhibit distinct phenotypes in GC environment. However, the phenotype, regulation, and clinical relevance of neutrophils in human GC are presently unknown. Here, immunohistochemistry, real-time PCR, and flow cytometry analyses were performed to examine levels and phenotype of neutrophils in samples from 41 patients with GC, and also isolated, stimulated, and/or cultured neutrophils for in vitro regulation assays. Finally, we performed Kaplan-Meier plots for overall survival by using the log-rank test to evaluate the clinical relevance of neutrophils and their subsets. In our study, neutrophils in tumor tissues were significantly higher than those in nontumor tissues and were positively associated with tumor progression but negatively correlated with GC patient survival. Most intratumoral neutrophils showed an activated CD54+ phenotype and expressed high-level immunosuppressive molecule B7-H4. Tumor tissue culture supernatants from GC patients induced neutrophils to express CD54 and B7-H4 in both time-dependent and dose-dependent manners. Locally enriched CD54+ neutrophils and B7-H4+ neutrophils positively correlated with increased granulocyte-macrophage colony-stimulating factor (GM-CSF) detection ex vivo, and in vitro GM-CSF induced the expression of CD54 and B7-H4 on neutrophils in a time-dependent and dose-dependent manner. Moreover, GC tumor-derived GM-CSF activated neutrophils and induced neutrophil B7-H4 expression via Janus kinase (JAK)-signal transducer and activator of transcription 3 (STAT3) signaling pathway activation. Furthermore, higher intratumoral B7-H4+ neutrophil percentage/number was found in GC patients with advanced tumor node metastasis stage and reduced overall survival following surgery. Our results illuminate a novel regulating mechanism of B7-H4 expression on tumor-activated neutrophils in GC, suggesting that functional inhibition of these novel GM-CSF-B7-H4 pathways may be a suitable therapeutic strategy to treat the immune tolerance feature of GC.
Databáze: OpenAIRE
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