Reduced CD160 Expression Contributes to Impaired NK-cell Function and Poor Clinical Outcomes in Patients with HCC
Reduced CD160 Expression Contributes to Impaired NK-cell Function and Poor Clinical Outcomes in Patients with HCC
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CD160 表达减少会导致 HCC 患者 NK 细胞功能受损和临床结果不佳
DOI：
10.1158/0008-5472.can-18-1049
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发表时间：
2018-12-01
期刊：
影响因子：
11.2
通讯作者：
Sun, Cheng
中科院分区：
文献类型：
--
作者：
Sun, Haoyu;Xu, Jing;Sun, Cheng
我们以前报道过自然杀伤（NK）细胞数量和功能的缺陷在肝细胞癌（HCC）的进展中起重要作用。然而，这种现象背后的机制仍然不清楚。在这项研究中，我们分析了279例HCC患者和20例健康肝脏的瘤周和瘤内组织中肝内NK细胞上CD 160的表达。我们观察到肿瘤内NK细胞CD 160表达减少，肿瘤细胞内CD 160细胞密度较低的患者表现出更严重的疾病和更高的复发率。流式细胞术分选的原发性肝内CD 160（+）和健康肝脏的CD 160（+）NK细胞的高分辨率微阵列和基因集富集分析表明，人CD 160（+）NK细胞表现出功能活化、高IFN γ产生和NK介导的免疫。此外，分选的瘤周和瘤内CD 160（+）NK细胞的总体转录组学分析显示，瘤内CD 160（+）NK细胞比瘤周CD 160（+）NK细胞更耗尽，并且产生更少的IFN γ。高水平的TGFb 1干扰CD 160（+）NK细胞产生IFN γ，阻断该干扰可使CD 160（+）NK细胞中IFN γ的产生恢复至正常水平。这些发现表明，CD 160（+）NK细胞数量的减少，以及TGF β 1对CD 160（+）NK细胞功能的损害，有助于肿瘤免疫逃逸。此外，恢复CD 160的表达和阻断TGF β 1似乎是一种有希望的治疗肝癌的策略。意义：这些发现表明，减少肿瘤微环境中CD 160（+）NK细胞的数量和功能有助于HCC的免疫逃逸;阻断TGF β 1恢复CD 160（+）NK细胞的IFN γ产生。http://cancerres.aacrjournals.org/content/canres/78/23/6581/F1.large.jpg (C)2018年AACR。
We previously reported that deficiencies in natural killer (NK)-cell number and function play an important role in the progression of hepatocellular carcinoma (HCC). However, the mechanisms underlying this phenomenon remain obscure. In this study, we analyzed the expression of CD160 on intrahepatic NK cells by evaluating peritumoral and intratumoral tissues of 279 patients with HCC and 20 healthy livers. We observed reduced expression of CD160 on intratumoral NK cells, and patients with lower CD160 cell densities within tumor cells exhibited worse disease and a higher recurrence rate. High-resolution microarray and gene set enrichment analysis of flow cytometry-sorted primary intrahepatic CD160(+) and CD160(+) NK cells of healthy livers indicated that human CD160(+) NK cells exhibited functional activation, high IFN gamma production, and NK-mediated immunity. In addition, global transcriptomic analysis of sorted peritumoral and intratumoral CD160(+) NK cells revealed that intratumoral CD160(+) NK cells are more exhausted than peritumoral CD160(+) NK cells and produce less IFN gamma. High levels of TGFb1 interfered with production of IFN gamma by CD160(+) NK cells, blocking of which specifically restored IFN gamma production in CD160(+) NK cells to normal levels. These findings indicate that reduced numbers of CD160(+) NK cells, together with the functional impairment of CD160(+) NK cells by TGFb1, contribute to tumor immune escape. In addition, restoring the expression of CD160 and blocking TGFb1 appear a promising therapeutic strategy against liver cancer.Significance: These findings show that reduced number and function of CD160(+) NK cells in the tumor microenvironment contributes to immune escape of HCC; blocking TGFb1 restores IFN gamma production of CD160(+) NK cells.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/23/6581/F1.large.jpg. (C) 2018 AACR.