Liver Cancer Institute, Zhongshan Hospital, State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, PR China; Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai, 200032, PR China.
Liver Cancer Institute, Zhongshan Hospital, State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, PR China; Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai, 200032, PR China; Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, PR China.
Cancer Lett. 2022 Aug 10;541:215750. doi: 10.1016/j.canlet.2022.215750. Epub 2022 May 21.
Immune checkpoint blockade (ICB) therapy is an important treatment option for individuals with cancer, but it has certain limitations. Identifying a better target that can overcome tumor immune escape and stimulate T cell activity is critical. This research aimed to delve into the molecular mechanism underlying the immunoregulatory function of metadherin (MTDH), which is a novel and potential therapeutic target in hepatocellular cancer (HCC). A small interfering RNA library was screened using the luciferase reporter assay and PD-L1 promoter. The Cancer Genome Atlas database and HCC tissues were used to investigate the relationship between MTDH and PD-L1. The association between MTDH and β-catenin/lymphoid enhancer binding factor (LEF-1) was discovered by co-immunoprecipitation. The chromatin immunoprecipitation assay was used to investigate the interaction of MTDH with the PD-L1 promoter when LEF-1 expression was silenced. Locked nucleic acid antisense oligonucleotides (ASOs) were used to inhibit MTDH. We utilized in vitro co-cultures and in vivo syngeneic tumor development experiments to confirm the effectiveness of MTDH ASO combined with PD-1 monoclonal antibody (mAb). MTDH was demonstrated to be a PD-L1 modulator. MTDH increased PD-L1 expression and upregulated PD-L1 transcriptional activity through β-catenin/LEF-1 signaling. More importantly, MTDH ASO improved the anti-PD-1 response and increased cytotoxic T-cell infiltration in PD-1 mAb-treated malignancies. MTDH effectively predicts the therapeutic efficacy of ICB therapy. Our results imply that combining MTDH ASO with PD-1 mAb could be a promising therapeutic strategy for HCC. In addition, MTDH is a potential novel biomarker for predicting the effectiveness of immune checkpoint inhibitor treatment.
免疫检查点阻断（ICB）疗法是癌症患者的重要治疗选择，但它有一定的局限性。确定更好的靶点以克服肿瘤免疫逃逸并刺激 T 细胞活性至关重要。本研究旨在深入研究黏附蛋白（MTDH）的免疫调节功能的分子机制，MTDH 是肝细胞癌（HCC）的一个新的潜在治疗靶点。使用荧光素酶报告基因检测和 PD-L1 启动子对小干扰 RNA 文库进行筛选。利用癌症基因组图谱数据库和 HCC 组织研究 MTDH 与 PD-L1 之间的关系。通过共免疫沉淀发现 MTDH 与 β-连环蛋白/淋巴增强因子结合因子（LEF-1）之间的关联。通过染色质免疫沉淀检测当 LEF-1 表达沉默时 MTDH 与 PD-L1 启动子的相互作用。使用锁定核酸反义寡核苷酸（ASO）抑制 MTDH。我们利用体外共培养和体内同基因肿瘤发展实验来证实 MTDH ASO 与 PD-1 单克隆抗体（mAb）联合的有效性。MTDH 被证明是 PD-L1 的调节剂。MTDH 通过 β-连环蛋白/LEF-1 信号通路增加 PD-L1 的表达和上调 PD-L1 的转录活性。更重要的是，MTDH ASO 改善了 PD-1 mAb 治疗恶性肿瘤中的抗 PD-1 反应并增加了细胞毒性 T 细胞浸润。MTDH 可有效预测 ICB 治疗的疗效。我们的结果表明，将 MTDH ASO 与 PD-1 mAb 联合使用可能是 HCC 的一种有前途的治疗策略。此外，MTDH 是预测免疫检查点抑制剂治疗效果的潜在新型生物标志物。
