Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Transplantation, Chinese Academy of Medical Sciences, Nanjing, Jiangsu Province, 210029, China; School of Medicine, Southeast University, Nanjing, Jiangsu Province, 210009, China.
Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Transplantation, Chinese Academy of Medical Sciences, Nanjing, Jiangsu Province, 210029, China.
Cancer Lett. 2024 Jun 28;592:216909. doi: 10.1016/j.canlet.2024.216909. Epub 2024 Apr 26.
Natural killer (NK) cells exert an indispensable role in innate immune responses against cancer progression, however NK cell dysfunction has been rarely reported in hepatocellular carcinoma (HCC). This study sought to uncover the immunoregulatory mechanisms of tumor-infiltrating NK cells in HCC. A consensus NK cell-based signature (NKS) was constructed using integrative machine learning algorithms based on multi-omics data of HCC patients. HCC tumors had lower numbers of infiltrating NK cells than para-tumor normal liver tissues. Based on the NK cell-associated genes, the NKS was built for HCC prognostic prediction and clinical utilities. Drug targets and novel compounds were then identified for high-NKS groups. RAC1 was confirmed as the hub gene in the NKS genes. RAC1 was upregulated in HCC tumors and positively correlated with shorter survival time. RAC1 overexpression in NK-92 cells facilitated the cancer-killing capacity by the anticancer cytotoxic effectors and the upregulated NKG2D. The survival time of PDX-bearing mice was also prolonged upon NK-92 cells. Mechanistically, RAC1 interacted with STAT3 and facilitated its activation, thereby enabling its binding to the promoter region of NKG2D and functioning as a transcriptional regulator in NK-92 via molecular docking, Co-IP assay, CHIP and luciferase experiments. Collectively, our study describes a novel function of RAC1 in potentiating NK cell-mediated cytotoxicity against HCC, highlighting the clinical utilities of NKS score and RAC1 NK cell subset in HCC immunotherapy.
自然杀伤 (NK) 细胞在对抗癌症进展的先天免疫反应中发挥着不可或缺的作用，然而在肝细胞癌 (HCC) 中很少报道 NK 细胞功能障碍。本研究旨在揭示肿瘤浸润 NK 细胞在 HCC 中的免疫调节机制。使用基于 HCC 患者多组学数据的集成机器学习算法构建了基于共识的 NK 细胞特征 (NKS)。HCC 肿瘤中的浸润 NK 细胞数量低于肿瘤旁正常肝组织。基于与 NK 细胞相关的基因，构建了用于 HCC 预后预测和临床应用的 NKS。然后确定了高 NKS 组的药物靶点和新型化合物。RAC1 被确认为 NKS 基因中的枢纽基因。RAC1 在 HCC 肿瘤中上调，与较短的生存时间呈正相关。NK-92 细胞中 RAC1 的过表达通过抗癌细胞毒性效应物和上调的 NKG2D 促进了癌细胞杀伤能力。NK-92 细胞也延长了 PDX 荷瘤小鼠的存活时间。在机制上，RAC1 与 STAT3 相互作用并促进其激活，从而使其能够与 NKG2D 的启动子区域结合，并通过分子对接、Co-IP 测定、CHIP 和荧光素酶实验在 NK-92 中作为转录调节剂发挥作用。总之，我们的研究描述了 RAC1 在增强 NK 细胞介导的对 HCC 的细胞毒性作用中的新功能，突出了 NKS 评分和 RAC1 NK 细胞亚群在 HCC 免疫治疗中的临床应用。
