Activated neutrophils polarize protumorigenic interleukin‐17A‐producing T helper subsets through TNF‐α‐B7‐H2‐dependent pathway in human gastric cancer

Autor: Yong-liang Zhao, Wei-Ying Zhou, Jin-yu Zhang, Jun Chen, Liu-sheng Peng, Yong-sheng Teng, Yuan Zhuang, Fang-yuan Mao, Ping Cheng, Jin-Shan Liu, Quanming Zou, Ting-Ting Wang, Zhi-Guo Shan
Rok vydání: 2021
Předmět:
0301 basic medicine
Medicine (General)
Neutrophils
Medicine (miscellaneous)
Apoptosis
Mice
SCID
Neutrophil Activation
Flow cytometry
Inducible T-Cell Co-Stimulator Ligand
Mice
03 medical and health sciences
R5-920
0302 clinical medicine
Mice
Inbred NOD
Stomach Neoplasms
In vivo
Tumor Cells
Cultured
medicine
Animals
Humans
IL‐17A
B7‐H2
Research Articles
Cell Proliferation
biology
medicine.diagnostic_test
Tumor Necrosis Factor-alpha
Chemistry
gastric cancer
Interleukin-17
Chemotaxis
T-Lymphocytes
Helper-Inducer
Prognosis
Xenograft Model Antitumor Assays
In vitro
Gene Expression Regulation
Neoplastic
Survival Rate
030104 developmental biology
030220 oncology & carcinogenesis
CXCL6
biology.protein
Cancer research
Molecular Medicine
Female
Tumor necrosis factor alpha
Interleukin 17
Ex vivo
Research Article
Zdroj: Clinical and Translational Medicine
Clinical and Translational Medicine, Vol 11, Iss 6, Pp n/a-n/a (2021)
ISSN: 2001-1326
DOI: 10.1002/ctm2.484
Popis: Rationale Neutrophils constitute massive cellular constituents in inflammatory human gastric cancer (GC) tissues, but their roles in pathogenesis of inflammatory T helper (Th) subsets are still unknown. Methods Flow cytometry analysis and immunohistochemistry were used to analyze the responses and phenotypes of neutrophils in different samples from 51 patients with GC. Kaplan‐Meier plots and Multivariate analysis for the survival of patients were used by log‐rank tests and Cox proportional hazards models. Neutrophils and CD4+ T cells were purified and cultured for ex vivo, in vitro and in vivo regulation and function assays. Results GC patients exhibited increased tumoral neutrophil infiltration with GC progression and poor patient prognosis. Intratumoral neutrophils accumulated in GC tumors via CXCL6/CXCL8‐CXCR1‐mediated chemotaxis, and expressed activated molecule CD54 and co‐signaling molecule B7‐H2. Neutrophils induced by tumors strongly expressed CD54 and B7‐H2 in both dose‐ and time‐dependent manners, and a close correlation was obtained between the expressions of CD54 and B7‐H2 on intratumoral neutrophils. Tumor‐derived tumor necrosis factor‐α (TNF‐α) promoted neutrophil activation and neutrophil B7‐H2 expression through ERK‐NF‐κB pathway, and a significant correlation was found between the levels of TNF‐α and CD54+ or B7‐H2+ neutrophils in tumor tissues. Tumor‐infiltrating and tumor‐conditioned neutrophils effectively induced IL‐17A‐producing Th subset polarization through a B7‐H2‐dependent manner ex vivo and these polarized IL‐17A‐producing Th cells exerted protumorigenic roles by promoting GC tumor cell proliferation via inflammatory molecule IL‐17A in vitro, which promoted the progression of human GC in vivo; these effects could be reversed when IL‐17A is blocked. Moreover, increased B7‐H2+ neutrophils and IL‐17A in tumors were closely related to advanced GC progression and predicted poor patient survival. Conclusion We illuminate novel underlying mechanisms that TNF‐α‐activated neutrophils link B7‐H2 to protumorigenic IL‐17A‐producing Th subset polarization in human GC. Blocking this pathological TNF‐α‐B7‐H2‐IL‐17A pathway may be useful therapeutic strategies for treating GC.
Our results illuminate a novel mechanism that TNF‐α‐activated neutrophils link B7‐H2 to protumorigenic IL‐17A‐producing Th subset polarization in human GC. Blocking this pathological TNF‐α‐B7‐H2‐IL‐17A pathway may be useful therapeutic strategies for treating GC.
Databáze: OpenAIRE
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