Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, China.
Institute of Immunology, University of Science and Technology of China, Hefei, China.
Cancer Res. 2018 Dec 1;78(23):6581-6593. doi: 10.1158/0008-5472.CAN-18-1049. Epub 2018 Sep 19.
: 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 tumors 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 IFNγ 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 IFNγ. High levels of TGFβ1 interfered with production of IFNγ by CD160 NK cells, blocking of which specifically restored IFNγ 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 TGFβ1, contribute to tumor immune escape. In addition, restoring the expression of CD160 and blocking TGFβ1 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 TGFβ1 restores IFNγ production of CD160 NK cells. http://cancerres.aacrjournals.org/content/canres/78/23/6581/F1.large.jpg.
我们之前报道称，自然杀伤 (NK)-细胞数量和功能的缺陷在肝细胞癌 (HCC) 的进展中发挥着重要作用。然而，这一现象背后的机制尚不清楚。在这项研究中，我们通过评估 279 例 HCC 患者和 20 例健康肝脏的肿瘤周围和肿瘤内组织，分析了肝内 NK 细胞上 CD160 的表达。我们观察到肿瘤内 NK 细胞上 CD160 的表达减少，并且肿瘤内 CD160 细胞密度较低的患者疾病预后更差，复发率更高。对健康肝脏中经流式细胞术分选的原发性肝内 CD160 和 CD160 NK 细胞进行高分辨率微阵列和基因集富集分析表明，人类 CD160 NK 细胞表现出功能激活、高 IFNγ 产生和 NK 介导的免疫。此外，对分选的肿瘤周围和肿瘤内 CD160 NK 细胞进行的全转录组分析表明，肿瘤内 CD160 NK 细胞比肿瘤周围 CD160 NK 细胞更耗竭，产生的 IFNγ 更少。高水平的 TGFβ1 干扰 CD160 NK 细胞产生 IFNγ，阻断 TGFβ1 可特异性将 CD160 NK 细胞中的 IFNγ 产生恢复至正常水平。这些发现表明，CD160 NK 细胞数量减少，以及 TGFβ1 对 CD160 NK 细胞功能的损害，导致肿瘤免疫逃逸。此外，恢复 CD160 的表达并阻断 TGFβ1 似乎是一种有前途的肝癌治疗策略。意义：这些发现表明肿瘤微环境中 CD160 NK 细胞数量和功能的减少导致 HCC 免疫逃逸；阻断 TGFβ1 可恢复 CD160 NK 细胞 IFNγ 的产生。http://cancerres.aacrjournals.org/content/canres/78/23/6581/F1.large.jpg。
