ABHD17C调节乐伐替尼抑制肝细胞癌的疗效

摘要(中文译文)

仑伐替尼是肝细胞癌（HCC）的一线治疗药物，但其临床疗效受到耐药性的限制。ABHD17C是一种参与HCC进展的去棕榈酰化酶，尚未在仑伐替尼应答中受到研究。本研究旨在确定ABHD17C是否调控仑伐替尼在HCC中的抗肿瘤疗效。通过分析已发表的单细胞RNA测序（scRNA-seq）数据，表征ABHD17C在HCC肿瘤微环境中的表达。在HCC细胞系中进行功能实验，评估仑伐替尼及ABHD17C调控的作用。研究结果通过HCC异种移植小鼠模型和患者来源的肿瘤类器官进行验证。scRNA-seq分析显示，ABHD17C与免疫抑制性肿瘤微环境相关，其特征为CD8⁺ T细胞浸润减少、T细胞耗竭增加以及细胞间通讯异常。体外实验中，仑伐替尼抑制HCC细胞的增殖、迁移和侵袭，同时诱导凋亡和细胞周期阻滞。这些效应被ABHD17C过表达显著减弱，而被ABHD17C敲低所增强。体内实验中，过表达ABHD17C的异种移植瘤对仑伐替尼的应答较差，表现为肿瘤生长增加和凋亡减少。同样，在患者来源的类器官中，ABHD17C过表达削弱了仑伐替尼的疗效。值得注意的是，仑伐替尼降低了类器官中ABHD17C的表达，提示可能存在反馈调节。ABHD17C促进免疫抑制性肿瘤微环境并减弱仑伐替尼在HCC中的抗肿瘤效应。靶向ABHD17C可能是增强仑伐替尼敏感性并改善治疗结局的潜在策略。

Abstract

Lenvatinib is a first-line therapy for hepatocellular carcinoma (HCC), but its clinical efficacy is limited by drug resistance. ABHD17C, a depalmitoylation enzyme involved in HCC progression, has not been investigated in lenvatinib response. This study aimed to determine whether ABHD17C regulates the anti-tumor efficacy of lenvatinib in HCC. Published single-cell RNA sequencing (scRNA-seq) data were analyzed to characterize ABHD17C expression in the HCC tumor microenvironment. Functional assays were performed in HCC cell lines to evaluate the effects of lenvatinib and ABHD17C modulation. The findings were validated using HCC xenograft mouse models and patient-derived tumor organoids. scRNA-seq analysis showed that ABHD17C is associated with an immunosuppressive tumor microenvironment characterized by reduced CD8⁺ T cell infiltration, increased T cell exhaustion, and abnormal intercellular communication. In vitro, lenvatinib inhibited proliferation, migration, and invasion while inducing apoptosis and cell cycle arrest in HCC cells. These effects were significantly attenuated by ABHD17C overexpression but enhanced by ABHD17C depletion. In vivo, ABHD17C-overexpressing xenografts were less responsive to lenvatinib, exhibiting increased tumor growth and reduced apoptosis. Similarly, in patient-derived organoids, ABHD17C overexpression diminished lenvatinib efficacy. Notably, lenvatinib reduced ABHD17C expression in organoids, suggesting potential feedback regulation. ABHD17C promotes an immunosuppressive tumor microenvironment and attenuates the anti-tumor effects of lenvatinib in HCC. Targeting ABHD17C may represent a potential strategy to enhance lenvatinib sensitivity and improve therapeutic outcomes.

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