PDF(Pubmed)
Abstract：
The liver harbors a diverse array of immune cells during both health and disease. The specific roles of these cells in nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC) remain unclear. Using a systems immunology approach, we demonstrate that reciprocal cell-cell communications function through dominant-subdominant pattern of ligand-receptor homeostatic pathways. In the healthy control, hepatocyte-dominated homeostatic pathways induce local immune responses to maintain liver homeostasis. Chronic intake of a Western diet (WD) alters hepatocytes and induces hepatic stellate cell (HSC), cancer cell and NKT cell-dominated interactions during NAFLD. During HCC, monocytes, hepatocytes, and myofibroblasts join the dominant cellular interactions network to restore liver homeostasis. Dietary correction during NAFLD results in nonlinear outcomes with various cellular rearrangements. When cancer cells and stromal cells dominate hepatic interactions network without inducing homeostatic immune responses, HCC progression occurs. Conversely, myofibroblast and fibroblast-dominated network orchestrates monocyte-dominated HCC-preventive immune responses. Tumor immune surveillance by 75% of immune cells successfully promoting liver homeostasis can create a tumor-inhibitory microenvironment, while only 5% of immune cells manifest apoptosis-inducing functions, primarily for facilitating homeostatic liver cell turnover rather than direct tumor killing. These data suggest that an effective immunotherapy should promote liver homeostasis rather than direct tumor killing.
摘要：
在健康和疾病期间，肝脏都有各种各样的免疫细胞。这些细胞在非酒精性脂肪性肝病（NAFLD）和肝细胞癌（HCC）中的具体作用尚不清楚。使用系统免疫学方法，我们证明了相互的细胞间通讯功能是通过配体-受体稳态途径的显性-亚显性模式实现的.在健康的控制下，肝细胞主导的稳态途径诱导局部免疫反应，以维持肝脏稳态。慢性摄入西方饮食（WD）改变肝细胞和诱导肝星状细胞（HSC），NAFLD期间癌细胞和NKT细胞主导的相互作用。在HCC期间，单核细胞,肝细胞，和肌成纤维细胞加入显性细胞相互作用网络以恢复肝脏稳态。NAFLD期间的饮食校正导致各种细胞重排的非线性结果。当癌细胞和基质细胞主导肝脏相互作用网络而不诱导稳态免疫反应时，发生HCC进展。相反，肌成纤维细胞和成纤维细胞为主的网络协调单核细胞为主的HCC预防性免疫反应。肿瘤免疫监视通过75%的免疫细胞成功促进肝脏稳态可以创造一个抑制肿瘤的微环境，而只有5%的免疫细胞表现出诱导凋亡的功能，主要用于促进稳态肝细胞周转，而不是直接杀死肿瘤。这些数据表明，有效的免疫疗法应促进肝脏稳态，而不是直接杀死肿瘤。
