IL-17 induces antitumor immunity by promoting beneficial neutrophil recruitment and activation in esophageal squamous cell carcinoma
IL-17 induces antitumor immunity by promoting beneficial neutrophil recruitment and activation in esophageal squamous cell carcinoma
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IL-17 通过促进食管鳞状细胞癌中有益的中性粒细胞募集和激活来诱导抗肿瘤免疫
DOI：
10.1080/2162402x.2017.1373234
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发表时间：
2018-01-01
期刊：
影响因子：
7.2
通讯作者：
Xia, Jian-Chuan
中科院分区：
文献类型：
--
作者：
Chen, Chang-Long;Wang, Ying;Xia, Jian-Chuan
摘要白细胞介素（IL）-17在肿瘤免疫中的作用一直存在争议。我们以前的研究表明，IL-17产生细胞在食管鳞状细胞癌（ESCC）中的浸润通过招募CD 8 +T淋巴细胞、自然杀伤（NK）细胞和B淋巴细胞进入肿瘤微环境来诱导肿瘤保护性免疫。然而，IL-17调节肿瘤相关中性粒细胞的机制在ESCC中仍然难以捉摸。因此，在这项研究中，我们评估了髓过氧化物酶（MPO）+中性粒细胞的积累及其与ESCC肿瘤巢内IL-17产生细胞的相关性。我们还研究了IL-17对中性粒细胞的募集和抗肿瘤活性的影响。MPO+中性粒细胞浸润与IL-17+细胞密度呈正相关，提示ESCC患者预后良好。IL-17刺激ESCC肿瘤细胞释放更多的CXC趋化因子CXCL 2和CXCL 3，它们参与中性粒细胞迁移。此外，IL-17通过增强细胞毒性分子（包括活性氧（ROS）、MPO、TNF相关凋亡诱导配体（TRAIL）和IFN-γ）的产生来增强嗜中性粒细胞的直接杀伤能力。在小鼠中的实验表明，单独的IL-17可能不会影响荷瘤宿主中的肿瘤进展，但IL-17可以通过促进肿瘤部位的有益中性粒细胞浸润和活化来抑制肿瘤生长。随着新出现的证据表明靶向肿瘤相关中性粒细胞是抗肿瘤治疗的一种策略，我们的研究结果揭示了IL-17对ESCC中嗜中性粒细胞介导的抗肿瘤免疫的调节的积极贡献。这项研究提供了选择性调节中性粒细胞功能活动的机制的进一步理解，这可能是开发新的肿瘤免疫治疗的关键。
ABSTRACT Interleukin (IL)-17 has been reported to play a controversial role in tumor immunity. Our previous studies showed that infiltration of IL-17-producing cells in esophageal squamous cell carcinoma (ESCC) induced tumor protective immunity by recruiting CD8+T lymphocytes, natural killer (NK) cells, and B lymphocytes into the tumor microenvironment. However, the mechanism of IL-17 regulation of tumor-associated neutrophils remains elusive in ESCC. In this study, we therefore evaluated the accumulation of myeloperoxidase (MPO)+ neutrophils and its association with IL-17-producing cells within ESCC tumor nests. We also investigated the effects of IL-17 on the recruitment and antitumor activity of neutrophils. MPO+ neutrophil infiltration was found to predict a favorable prognosis in ESCC patients and was positively correlated with IL-17+ cell density. IL-17 stimulated ESCC tumor cells to release more of the CXC chemokines CXCL2 and CXCL3, which are involved in neutrophil migration. Furthermore, IL-17 potentiates the direct killing capability of neutrophils by enhancing the production of cytotoxic molecules, including reactive oxygen species (ROS), MPO, TNF-related apoptosis-inducing ligand (TRAIL), and IFN-γ. Experiments in mice suggested that IL-17 alone might not affect tumor progression in the tumor-bearing host, but IL-17 can inhibit tumor growth by promoting beneficial neutrophil infiltration and activation at tumor sites. As emerging evidence indicates that targeting tumor-associated neutrophils is a strategy for antitumor therapy, our findings reveal a positive contribution of IL-17 to the modulation of neutrophil-mediated antitumor immunity in ESCC. This study provides further understanding of the mechanisms that selectively regulate functional activities of neutrophils, which may be critical for developing new tumor immunotherapy.