MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, P. R. China; State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China.
MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, P. R. China.
J Hepatol. 2020 Oct;73(4):906-917. doi: 10.1016/j.jhep.2020.05.004. Epub 2020 May 12.
BACKGROUND & AIMS: Neutrophils are one of the most abundant components in human hepatocellular carcinoma (HCC) and have been shown to play important roles in regulating disease progression. However, neutrophils are very short-lived cells in circulation, and mechanisms regulating their accumulation and functions in HCC are not yet fully understood.
Monocytes were purified from non-tumor or paired tumor tissues of patients with HCC, and their production of neutrophil-attracting chemokines was evaluated. Mechanisms regulating the expression of CXCL2/8 by tumor monocytes, and the role of tumor monocyte-derived chemokines and cytokines in modulating neutrophil accumulation and functions were studied with both ex vivo analyses and in vitro experiments.
Monocyte-derived CXCL2 and CXCL8 were major factors in regulating the recruitment of neutrophils into tumor milieus. These chemokines, in addition to tumor-derived soluble factors, could inhibit apoptosis and sustain survival of neutrophils, thus leading to neutrophil accumulation in tumor tissues. Moreover, monocyte-derived TNF-α acted synergistically with tumor-derived soluble factors to induce the production of the pro-metastasis factor OSM by neutrophils. Further, the glycolytic switch in tumor-infiltrating monocytes mediated their production of CXCL2 and CXCL8 via the PFKFB3-NF-κB signaling pathway. Accordingly, levels of PFKFB3, CXCL2/CXCL8 production in monocytes and infiltration of OSM-producing neutrophils were positively correlated in human HCC tissues.
Our results unveiled a previously unappreciated link between monocytes and neutrophils in human HCC, identifying possible targets that could be therapeutically exploited in the future.
Neutrophils constitute a major but poorly understood component of human hepatocellular carcinoma (HCC). Herein, we unveil a novel mechanism by which metabolic switching in monocytes promotes the accumulation of neutrophils in the tumors of patients with HCC. Both monocyte-produced chemokines and signals from the tumor microenvironment promote the production of the pro-metastatic factor OSM by neutrophils. These data identify potential targets for immune-based anticancer therapies for HCC.
中性粒细胞是人类肝细胞癌（HCC）中最丰富的成分之一，已被证明在调节疾病进展中发挥重要作用。然而，中性粒细胞在循环中是非常短命的细胞，调节其在 HCC 中的积累和功能的机制尚未完全理解。
从 HCC 患者的非肿瘤或配对肿瘤组织中纯化单核细胞，并评估其产生中性粒细胞趋化因子的能力。通过体外分析和体外实验研究了肿瘤单核细胞调节 CXCL2/8 表达的机制，以及肿瘤单核细胞衍生的趋化因子和细胞因子在调节中性粒细胞积累和功能中的作用。
单核细胞衍生的 CXCL2 和 CXCL8 是调节中性粒细胞募集到肿瘤环境中的主要因素。这些趋化因子除了肿瘤来源的可溶性因子外，还可以抑制中性粒细胞凋亡并维持其存活，从而导致肿瘤组织中中性粒细胞的积累。此外，单核细胞衍生的 TNF-α与肿瘤来源的可溶性因子协同作用，诱导中性粒细胞产生促转移因子 OSM。此外，肿瘤浸润单核细胞的糖酵解转换通过 PFKFB3-NF-κB 信号通路介导其 CXCL2 和 CXCL8 的产生。因此，在人类 HCC 组织中，PFKFB3 水平、单核细胞中 CXCL2/CXCL8 的产生以及产生 OSM 的中性粒细胞的浸润呈正相关。
我们的结果揭示了人类 HCC 中单核细胞和中性粒细胞之间以前未被认识的联系，确定了可能成为未来治疗靶点的潜在目标。
中性粒细胞构成了人类肝细胞癌（HCC）的一个主要但尚未被充分理解的成分。在此，我们揭示了一种新的机制，即单核细胞的代谢转换促进了 HCC 患者肿瘤中中性粒细胞的积累。单核细胞产生的趋化因子和肿瘤微环境中的信号都促进了中性粒细胞产生促转移因子 OSM。这些数据为 HCC 的免疫抗癌治疗确定了潜在的靶点。
