Neutrophil Extracellular Traps Induced by IL8 Promote Diffuse Large B-cell Lymphoma Progression via the TLR9 Signaling
Neutrophil Extracellular Traps Induced by IL8 Promote Diffuse Large B-cell Lymphoma Progression via the TLR9 Signaling
复制标题
IL8 诱导的中性粒细胞胞外陷阱通过 TLR9 信号传导促进弥漫性大 B 细胞淋巴瘤进展
DOI：
10.1158/1078-0432.ccr-18-1226
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发表时间：
2019-03-15
影响因子：
11.5
通讯作者：
Jiang, Wenqi
中科院分区：
文献类型：
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作者：
Nie, Man;Yang, Linbin;Jiang, Wenqi
目的：超过30%的弥漫性大B细胞淋巴瘤（DLBCL）患者在一线治疗后经历治疗失败。神经元细胞外陷阱（NETs）是肿瘤微环境中的一种捕获病原体的结构，可促进自身免疫向淋巴瘤发生的转变。在这里，我们调查是否NET发挥新的作用DLBCL进展及其潜在的机制。实验设计：分别通过免疫荧光和ELISA检测DLBCL肿瘤样品和血浆中的NET。分析NETs与临床特征的相关性。通过一系列的体内外实验，探讨了NET对细胞增殖和迁移的影响及其机制，并对NET的形成机制进行了研究。结果：血浆和肿瘤组织中较高水平的NET与DLBCL患者的不良结局相关。此外，我们确定NET在体外增加细胞增殖和迁移，在体内增加肿瘤生长和淋巴结转移。机制上，DLBCL衍生的IL 8与其在中性粒细胞上的受体（CXCR 2）相互作用，导致通过Src、p38和ERK信号传导形成NET。新形成的NET直接上调DLBCL中的Toll样受体9（TLR 9）通路，随后激活NFκB、STAT 3和p38通路以促进肿瘤进展。更重要的是，在临床前模型中，破坏NET、阻断IL 8-CXCR 2轴或抑制TLR 9可以延缓肿瘤进展。结论：我们的数据揭示了DLBCL中肿瘤-NETs的积极相互作用，并表明NETs是一种有用的预后生物标志物，靶向这种新的串扰代表了这种具有挑战性的疾病的新治疗机会。
Purpose: More than 30% of patients with diffuse large B-cell lymphoma (DLBCL) experience treatment failure after first-line therapy. Neutrophil extracellular traps (NETs), a pathogen-trapping structure in tumor microenvironment, can promote the transition of autoimmunity to lymphomagenesis. Here, we investigate whether NETs play a novel role in DLBCL progression and its underlying mechanism. Experimental Design: NETs in DLBCL tumor samples and plasma were detected by immunofluorescence and ELISA, respectively. The correlation between NETs and clinical features were analyzed. The effects of NETs on cellular proliferation and migration and mechanisms were explored, and the mechanism of NET formation was also studied by a series of in vitro and in vivo assays. Results: Higher levels of NETs in plasma and tumor tissues were associated with dismal outcome in patients with DLBCL. Furthermore, we identified NETs increased cell proliferation and migration in vitro and tumor growth and lymph node dissemination in vivo. Mechanistically, DLBCL-derived IL8 interacted with its receptor (CXCR2) on neutrophils, resulting in the formation of NETs via Src, p38, and ERK signaling. Newly formed NETs directly upregulated the Toll-like receptor 9 (TLR9) pathways in DLBCL and subsequently activated NFκB, STAT3, and p38 pathways to promote tumor progression. More importantly, disruption of NETs, blocking IL8–CXCR2 axis or inhibiting TLR9 could retard tumor progression in preclinical models. Conclusions: Our data reveal a tumor–NETs aggressive interaction in DLBCL and indicate that NETs is a useful prognostic biomarker and targeting this novel cross-talk represents a new therapeutic opportunity in this challenging disease.