Wong Kah Keng, Ab Hamid Suzina Sheikh
Department of Immunology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia.
Tissue Bank Unit, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia.
PLoS One. 2025 Feb 25;20(2):e0307048. doi: 10.1371/journal.pone.0307048. eCollection 2025.
The clinical application of cellular immunotherapy in hepatocellular carcinoma (HCC) is impeded by the lack of a cell surface target frequently expressed in HCC cells and with minimal presence in normal tissues to reduce on-target, off-tumor toxicity. To address this, an in silico multomics analysis was conducted to identify an optimal therapeutic target in HCC. A longlist of genes (n = 12,948) expressed in HCCs according to The Human Protein Atlas database were examined. Eight genes were shortlisted to identify one with the highest expression in HCCs, without being shed into circulation, and with restrictive expression profile in other normal human tissues. A total of eight genes were shortlisted and subsequently ranked according to the combination of their transcript and protein expression levels in HCC cases (n = 791) derived from four independent datasets. TM4SF4 was the top-ranked target with the highest expression in HCCs. TM4SF4 showed more favorable expression profile with significantly lower expression in normal human tissues but more highly expressed in HCC compared with seven other common HCC therapeutic targets. Furthermore, scRNA-seq and immunohistochemistry datasets showed that TM4SF4 was absent in immune cell populations but highly expressed in the bile duct canaliculi of hepatocytes, regions inaccessible to immune cells. In scRNA-seq dataset of HCCs, TM4SF4 expression was positively associated with mitochondrial components and oxidative phosphorylation Gene Ontologies in HCC cells (n = 15,787 cells), suggesting its potential roles in mitochondrial-mediated oncogenic effects in HCC. Taken together, TM4SF4 is proposed as a promising cell surface target in HCC due to its high expression in HCC cells with restricted expression profile in non-cancerous tissues, and association with HCC oncogenic pathways.
细胞免疫疗法在肝细胞癌（HCC）中的临床应用受到阻碍，因为缺乏在HCC细胞中频繁表达且在正常组织中表达极少的细胞表面靶点，以减少脱靶性肿瘤外毒性。为了解决这一问题，进行了一项计算机多组学分析，以确定HCC中的最佳治疗靶点。根据人类蛋白质图谱数据库，对在HCC中表达的一长串基因（n = 12,948）进行了检查。筛选出八个基因，以确定其中在HCC中表达最高、不释放到循环中且在其他正常人体组织中表达受限的基因。总共筛选出八个基因，随后根据它们在来自四个独立数据集的HCC病例（n = 791）中的转录本和蛋白质表达水平组合进行排名。TM4SF4是排名最高的靶点，在HCC中表达最高。与其他七个常见的HCC治疗靶点相比，TM4SF4表现出更有利的表达谱，在正常人体组织中的表达显著降低，但在HCC中表达更高。此外，单细胞RNA测序（scRNA-seq）和免疫组织化学数据集显示，TM4SF4在免疫细胞群体中不存在，但在肝细胞的胆小管中高度表达，而免疫细胞无法到达这些区域。在HCC的scRNA-seq数据集中，TM4SF4表达与HCC细胞（n = 15,787个细胞）中的线粒体成分和氧化磷酸化基因本体呈正相关，表明其在HCC线粒体介导的致癌作用中的潜在作用。综上所述，TM4SF4被认为是HCC中有前景的细胞表面靶点，因为它在HCC细胞中高表达，在非癌组织中表达受限，且与HCC致癌途径相关。
