Immune infiltration landscape and potential drug-targeted implications for hepatocellular carcinoma with 'progression/hyper-progression' recurrence.

Annals of medicine Pub Date : 2025-12-01 Epub Date: 2025-01-27 DOI:10.1080/07853890.2025.2456113
Jing-Xuan Xu, Yue-Xiang Su, Yuan-Yuan Chen, Yi-Yue Huang, Zu-Shun Chen, Yu-Chong Peng, Lu-Nan Qi
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Abstract

Background and aims: Hepatocellular carcinoma (HCC) recurrence was previously characterized into four types, and patients with progression/hyper-progression recurrence (type III-IV) have an extremely poor prognosis. However, the immune background of resectable HCC, particularly in patients who experience recurrence, remains underexplored. Therefore, this study aimed to describe the immune landscape of resectable HCC, especially postoperative type III-IV recurrent HCC, and explore potential immune-targeted anti-relapse strategies for treated populations.

Methods: The differences in gene expression in patients with recurrent HCC (type I-II (solitary or multi-intrahepatic oligo recurrence) vs. type III-IV) were investigated using bulk sequencing. Multiple immune infiltration methods (single-sample gene set enrichment analysis (GSEA), Microenvironment Cell Populations-counter and ESTIMATE) were used, and patients were divided into four groups to identify four distinct immune subtypes: immune-enrichment/matrix-poor (IE1), immune-enrichment/matrix-rich (IE2), immune intermediate/matrix-rich (ITM) and immune desert/matrix-poor (ID). Co-expression and protein interaction analyses were used to identify characteristic genes in ITM closely associated with type III-IV recurrence, which was matched with drug targets for Huaier granules (HG) and lenvatinib. Virtual docking was used to identify potential therapeutic targets, and the results were verified using single-nuclei RNA sequencing and histological analysis.

Results: ITM was closely related to type III-IV recurrence and exhibited immunotherapy potential. The potential efficacy of inhibiting CCNA2, VEGFA, CXCL8, PLK2, TIMP1, ITGB2, ALDOA, ANXA5 and CSK in ITM reversal was determined. Molecular docking demonstrated that the proteins of these genes could bind to HG or lenvatinib. The immunohistochemical findings demonstrated differential VEGFA (p < .01) and PLK2 (p < .001) expression in ITM type and ID in type III-IV recurrent HCC.

Conclusions: Three primary immunotypes of resectable HCC (IE2, ITM and ID) were identified, and HG and lenvatinib could potentially overcome immune checkpoint blockade (ICB) resistance in ITM patients with HCC, particularly those classified as type III-IV.

肝细胞癌“进展/超进展”复发的免疫浸润景观和潜在的药物靶向意义
背景与目的:肝细胞癌(HCC)复发既往分为四种类型,进展/超进展复发(III-IV型)患者预后极差。然而,可切除肝细胞癌的免疫背景,特别是复发患者的免疫背景,仍未得到充分研究。因此,本研究旨在描述可切除HCC的免疫景观,特别是术后III-IV型复发HCC,并探索治疗人群潜在的免疫靶向抗复发策略。方法:采用批量测序方法研究复发性HCC (I-II型(单发或多发肝内寡核苷酸复发)与III-IV型)患者基因表达的差异。采用多种免疫浸润方法(单样本基因集富集分析(GSEA)、微环境细胞群计数(Microenvironment Cell population -counter)和ESTIMATE),将患者分为四组,以鉴定四种不同的免疫亚型:免疫富集/基质贫乏(IE1)、免疫富集/基质丰富(IE2)、免疫中间/基质丰富(ITM)和免疫荒漠/基质贫乏(ID)。通过共表达和蛋白相互作用分析,我们确定了ITM中与III-IV型复发密切相关的特征基因,这些基因与怀尔颗粒(HG)和lenvatinib的药物靶点相匹配。虚拟对接用于识别潜在的治疗靶点,并通过单核RNA测序和组织学分析验证结果。结果:ITM与III-IV型复发密切相关,具有免疫治疗潜力。测定抑制CCNA2、VEGFA、CXCL8、PLK2、TIMP1、ITGB2、ALDOA、ANXA5和CSK在ITM逆转中的潜在功效。分子对接表明,这些基因的蛋白可以与HG或lenvatinib结合。结论:确定了可切除HCC的三种主要免疫类型(IE2, ITM和ID), HG和lenvatinib可能克服ITM HCC患者的免疫检查点阻断(ICB)耐药,特别是III-IV型。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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