Li Tong, Xu Xin, Guo Mengzhou, Guo Jing, Nakayama Kiyoko, Ren Zhenggang, Zhang Lan
Liver Cancer Institute & Key Laboratory of Carcinogenesis and Cancer Invasion, Zhongshan Hospital, Fudan University, Shanghai, China.
Department of Gastroenterology, Zhongshan Hospital Xuhui Branch, Fudan University, Shanghai, China.
Heliyon. 2024 May 27;10(11):e31881. doi: 10.1016/j.heliyon.2024.e31881. eCollection 2024 Jun 15.
Only a minority of hepatocellular carcinoma (HCC) patients can benefit from systemic regimens. Macrophages, which abundantly infiltrate in HCC, could mediate tumour microenvironment remodelling and immune escape, proving to be powerful weapons in combating HCC. Thus, a deeper understanding of macrophages is necessary for improving existing antitumour treatments.
With a series of bioinformatic approaches, we comprehensively explored the role of macrophage-related genes in human HCCs from multiple single-cell and bulk RNA sequencing datasets. Unsupervised clustering was performed to cluster the macrophage marker genes (MMGs). GSVA and functional enrichment analysis were used to elucidate the functional differences among the MMG-associated clusters. Subsequently, a component analysis algorithm was used to construct a Macrosig score, and the prognosis, biological characteristics, mutation profile, TME cell infiltration status and drug response of patients with different Macrosig scores were further analysed.
We identified 13 MMGs in 574 HCC samples, based on which three MMG-associated clusters were defined. Overall survival time, clinicopathological features and immune infiltration scores differed among the different clusters. On this basis, 12 hub genes were identified among these clusters; subsequently, a scoring system was constructed to determine the Macrosig score. Importantly, patients with low-Macrosig scores, characterized by increased immune infiltration, increased mutation frequency and increased immune checkpoint expression, including CTLA-4, LAG3, PDCD1 and TIGIT, exhibited enhanced efficacy of immunotherapy when validated in an external database. Moreover, a low-Macrosig score indicates increased sensitivity to AZD.2281, A.443654, ABT.263, ABT.888, AG.014699 and ATRA, while a high Macrosig score indicates increased sensitivity to AZD6482, AKT inhibitor VIII, AS601245, AZ628, AZD.0530 and AZD6244.
A novel scoring system was constructed to guide more effective prognostic evaluation and tailoring therapeutic regimens for HCC patients.
只有少数肝细胞癌（HCC）患者能从全身治疗方案中获益。巨噬细胞大量浸润于HCC中，可介导肿瘤微环境重塑和免疫逃逸，是对抗HCC的有力武器。因此，深入了解巨噬细胞对于改进现有的抗肿瘤治疗至关重要。
通过一系列生物信息学方法，我们从多个单细胞和批量RNA测序数据集中全面探索了巨噬细胞相关基因在人类HCC中的作用。进行无监督聚类以对巨噬细胞标记基因（MMGs）进行聚类。使用基因集变异分析（GSVA）和功能富集分析来阐明MMG相关簇之间的功能差异。随后，使用一种成分分析算法构建巨噬细胞特征评分（Macrosig评分），并进一步分析不同Macrosig评分患者的预后、生物学特征、突变谱、肿瘤微环境（TME）细胞浸润状态和药物反应。
我们在574例HCC样本中鉴定出13个MMGs，并据此定义了三个MMG相关簇。不同簇之间的总生存时间、临床病理特征和免疫浸润评分存在差异。在此基础上，在这些簇中鉴定出12个核心基因；随后构建了一个评分系统来确定Macrosig评分。重要的是，低Macrosig评分的患者在外部数据库验证时表现出免疫治疗疗效增强，其特征为免疫浸润增加、突变频率增加以及免疫检查点表达增加，包括细胞毒性T淋巴细胞相关蛋白4（CTLA-4）、淋巴细胞活化基因3蛋白（LAG3）、程序性死亡蛋白1（PDCD1）和T细胞免疫球蛋白和ITIM结构域（TIGIT）。此外，低Macrosig评分表明对AZD.2281、A.443654、ABT.263、ABT.888、AG.014699和全反式维甲酸（ATRA）的敏感性增加，而高Macrosig评分表明对AZD6482、AKT抑制剂VIII、AS601245、AZ628、AZD.0530和AZD6244的敏感性增加。
构建了一种新的评分系统，以指导对HCC患者进行更有效的预后评估和制定个性化治疗方案。
