CCL15 Recruits Suppressive Monocytes to Facilitate Immune Escape and Disease Progression in Hepatocellular Carcinoma

作者：Longzi Liu, Zhao Zhang, Bo‐Hao Zheng, Yang Shi, Men Duan, Lijie Ma, Zhichao Wang, Liangqing Dong, Pingping Dong, Jie-Yi Shi, Shu Zhang, Zhen‐Bin Ding, Ai‐Wu Ke, Ya Cao, Xiaoming Zhang, Ruibin Xi, Jian Zhou, Jia Fan, Xiaoying Wang, Qiang Gao · 发表于：Hepatology · 年份：2018 · DOI：10.1002/hep.30134 · 被引用次数：150 · 研究领域：Immune cells in cancer、Chemokine receptors and signaling、Immunotherapy and Immune Responses

Chemokines play a key role in orchestrating the recruitment and positioning of myeloid cells within the tumor microenvironment. However, the tropism regulation and functions of these cells in hepatocellular carcinoma (HCC) are not completely understood. Herein, by scrutinizing the expression of all chemokines in HCC cell lines and tissues, we found that CCL15 was the most abundantly expressed chemokine in human HCC. Further analyses showed that CCL15 expression was regulated by genetic, epigenetic, and microenvironmental factors, and negatively correlated with patient clinical outcome. In addition to promoting tumor invasion in an autocrine manner, CCL15 specifically recruited CCR1 + cells toward HCC invasive margin, approximately 80% of which were CD14 + monocytes. Clinically, a high density of marginal CCR1 + CD14 + monocytes positively correlated with CCL15 expression and was an independent index for dismal survival. Functionally, these tumor‐educated monocytes directly accelerated tumor invasion and metastasis through bursting various pro‐tumor factors and activating signal transducer and activator of transcription 1/3, extracellular signal‐regulated kinase 1/2, and v‐akt murine thymoma viral oncogene homolog signaling in HCC cells. Meanwhile, tumor‐derived CCR1 + CD14 + monocytes expressed significantly higher levels of programmed cell death‐ligand 1, B7‐H3, and T‐cell immunoglobulin domain and mucin domain‐3 that may lead to immune suppression. Transcriptome sequencing ...