CXCL5 as Regulator of Neutrophil Function in Cutaneous Melanoma
CXCL5 as Regulator of Neutrophil Function in Cutaneous Melanoma
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DOI：
10.1016/j.jid.2018.07.006
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发表时间：
2019-01-01
影响因子：
6.5
通讯作者：
Loewe, Robert
中科院分区：
文献类型：
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作者：
Forsthuber, Agnes L.;Lipp, Katharina;Loewe, Robert
趋化因子通过招募不同的免疫细胞群塑造肿瘤微环境，从而强烈影响疾病进展。先前，我们发现CXCL5在原发性黑色素瘤的晚期表达上调，这与肿瘤中中性粒细胞的存在有关。对各种组织中中性粒细胞群体的分析揭示了肿瘤相关中性粒细胞的独特表型。肿瘤相关中性粒细胞表达PD-L1、CXCR4、CCR5、Adam17和Nos2，并在t细胞增殖试验中具有免疫抑制作用。为了研究CXCL5和中性粒细胞在体内的影响，我们利用过表达CXCL5和对照黑色素瘤细胞系建立了同基因小鼠肿瘤移植模型。原发肿瘤的生长行为或血管形成不受CXCL5表达和中性粒细胞的单独影响。然而，与Poly（I: C）联合，肿瘤相关中性粒细胞能够减弱诱导的抗肿瘤t细胞反应。与对照肿瘤相比，过表达cxcl5的肿瘤肺转移减少。中性粒细胞耗竭逆转了这种效应。在体外，与肿瘤相关的中性粒细胞相比，未受刺激的肺源性中性粒细胞具有更高的活性氧水平，并且CXCL5刺激进一步增加了活性氧水平。总之，在黑色素瘤中，中性粒细胞发挥着受局部或全身因素影响的环境依赖性作用，并干扰激活获得性免疫系统的治疗。主动将中性粒细胞转换为抗肿瘤模式可能是一种新的治疗策略。
Chemokines mold the tumor microenvironment by recruiting distinct immune cell populations, thereby strongly influencing disease progression. Previously, we showed that CXCL5 expression is upregulated in advanced stages of primary melanomas, which correlates with the presence of neutrophils in the tumor. The analysis of neutrophil populations in various tissues revealed a distinct phenotype of tumor-associated neutrophils. Tumor-associated neutrophils expressed PD-L1, CXCR4, CCR5, Adam17, and Nos2 and were immunosuppressive in a T-cell proliferation assay. To investigate the impact of CXCL5 and neutrophils in vivo, we established a syngeneic mouse tumor transplantation model using CXCL5-overexpressing and control melanoma cell lines. Growth behavior or vascularization of primary tumors was not affected by CXCL5 expression and neutrophils alone. However, in combination with Poly(I: C), tumor-associated neutrophils were able to attenuate induced antitumoral T-cell responses. CXCL5-overexpressing tumors had reduced lung metastasis compared with control tumors. Neutrophil depletion reversed this effect. In vitro, unstimulated lung-derived neutrophils had higher levels of reactive oxygen species compared with tumor-associated neutrophils, and CXCL5 stimulation further increased reactive oxygen species levels. In summary, in melanoma, neutrophils play a context-dependent role that is influenced by local or systemic factors, and interfere with therapies activating the acquired immune system. Actively switching neutrophils into antitumorigenic mode might be a new therapeutic strategy.