The microenvironment of malignant melanomas defines the properties of tumor blood vessels and regulates infiltration and vascular dissemination of immune and cancer cells, respectively. Previous research in other cancer entities suggested the complement system as an essential part of the tumor microenvironment. Here, we confirm activation of the complement system in samples of melanoma patients and murine melanomas. We identified the tumor endothelium as the starting point of the complement cascade. Generation of complement-derived C5a promoted the recruitment of neutrophils. Upon contact with the vascular endothelium, neutrophils were further activated by complement membrane attack complexes (MACs). MAC-activated neutrophils release neutrophil extracellular traps (NETs). Close to the blood vessel wall, NETs opened the endothelial barrier as indicated by an enhanced vascular leakage. This facilitated the entrance of melanoma cells into the circulation and their systemic spread. Depletion of neutrophils or lack of MAC formation in complement component 6 (C6)–deficient animals protected the vascular endothelium and prevented vascular intravasation of melanoma cells. Our data suggest that inhibition of MAC-mediated neutrophil activation is a potent strategy to abolish hematogenous dissemination in melanoma.

中文翻译：

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被膜攻击复合物激活的中性粒细胞增加黑色素瘤血管的通透性

恶性黑色素瘤的微环境定义了肿瘤血管的特性，并分别调节免疫细胞和癌细胞的浸润和血管传播。先前对其他癌症实体的研究表明，补体系统是肿瘤微环境的重要组成部分。在这里，我们确认了黑色素瘤患者和小鼠黑色素瘤样本中补体系统的激活。我们将肿瘤内皮确定为补体级联的起点。补体衍生的 C5a 的产生促进了中性粒细胞的募集。与血管内皮细胞接触后，中性粒细胞被补体膜攻击复合物 (MAC) 进一步激活。MAC 激活的嗜中性粒细胞释放嗜中性粒细胞胞外陷阱 (NET)。靠近血管壁，NETs 打开了内皮屏障，如血管渗漏增强所示。这促进了黑色素瘤细胞进入循环及其全身扩散。在补体成分 6 (C6) 缺陷的动物中，中性粒细胞的耗竭或 MAC 形成的缺乏保护了血管内皮细胞并防止了黑色素瘤细胞的血管内渗。我们的数据表明，抑制 MAC 介导的中性粒细胞激活是消除黑色素瘤血源性传播的有效策略。