Interleukin-17-Producing Neutrophils Link Inflammatory Stimuli to Disease Progression by Promoting Angiogenesis in Gastric Cancer.
Purpose:Elevated levels of neutrophils have been associated with poor survival in various cancers, but direct evidence supporting a role for neutrophils in the immunopathogenesis of human cancers is lacking.Experimental Design:A total of 573 patients with gastric cancer were enrolled in this study. Immunohistochemistry and real-time PCR were performed to analyze the distribution and clinical relevance of neutrophils in different microanatomic regions. The regulation and function of neutrophils were assessed bothin vitroandin vivoResults:Increased neutrophil counts in the peripheral blood were associated with poor prognosis in gastric cancer patients. In gastric cancer tissues, neutrophils were enriched predominantly in the invasive margin, and neutrophil levels were a powerful predictor of poor survival in patients with gastric cancer. IL17+neutrophils constitute a large portion of IL17-producing cells in human gastric cancer. Proinflammatory IL17 is a critical mediator of the recruitment of neutrophils into the invasive margin by CXC chemokines. Moreover, neutrophils at the invasive margin were a major source of matrix metalloproteinase-9, a secreted protein that stimulates proangiogenic activity in gastric cancer cells. Accordingly, high levels of infiltrated neutrophils at the invasive margin were positively correlated with angiogenesis progression in patients with gastric cancer.Conclusions:These data provide direct evidence supporting the pivotal role of neutrophils in gastric cancer progression and reveal a novel immune escape mechanism involving fine-tuned collaborative action between cancer cells and immune cells in the distinct tumor microenvironment.Clin Cancer Res; 23(6); 1575-85. ©2016 AACR.
Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.|Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China.
Tuan-Jie
TJ
Li
Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Yu-Ming
YM
Jiang
Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Yan-Feng
YF
Hu
German Cancer Research Center (DKFZ), Heidelberg, Germany.
Lei
L
Huang
Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Jiang
J
Yu
Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Li-Ying
LY
Zhao
Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Hai-Jun
HJ
Deng
Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Ting-Yu
TY
Mou
Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Hao
H
Liu
Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China. gzliguoxin@163.com keekee77@126.com yysysu@163.com.|Department of Hepatic Surgery, The 3 Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
Yang
Y
Yang
Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China. gzliguoxin@163.com keekee77@126.com yysysu@163.com.|Cell-gene Therapy Translational Medicine Research Center, The 3 Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
Qi
Q
Zhang
Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China. gzliguoxin@163.com keekee77@126.com yysysu@163.com.
Guo-Xin
GX
Li
D018952:Antigens, CD34 / Q000276:immunology; D019070:Cell Lineage / Q000276:immunology; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007249:Inflammation / Q000276:immunology* / Q000473:pathology; D020381:Interleukin-17 / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000276:immunology* / Q000473:pathology; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D013274:Stomach Neoplasms / Q000276:immunology* / Q000473:pathology; D059016:Tumor Microenvironment / Q000276:immunology; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology
D018952:Antigens, CD34; D020381:Interleukin-17; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A