背景:免疫检查点阻断(ICB)的治疗潜力遍及各种癌症;然而,其治疗肝细胞癌(HCC)的有效性经常受到固有和已发展的耐药性的削弱。
目的:本研究探讨了将安洛替尼(一种广谱酪氨酸激酶抑制剂)与程序性死亡-1(PD-1)阻断相结合的有效性,并为更有效的治疗HCC策略提供了机制见解。
方法:使用患者来源的器官型组织球体和原位HCC小鼠模型,我们评估了安洛替尼联合PD-1阻断的有效性.对肿瘤免疫微环境和潜在机制的影响使用飞行时间质量细胞计数评估,RNA测序,和跨细胞系的蛋白质组学,小鼠模型,和HCC患者样本。
结果:在临床前模型中,安洛替尼与抗PD-1抗体的组合增强了针对HCC的免疫应答。安洛替尼通过VEGFR2/AKT/HIF-1α信号轴显著抑制转铁蛋白受体(TFRC)的表达。CD8+T细胞浸润到肿瘤微环境中与TFRC的低表达相关。安洛替尼还增加了趋化因子CXCL14的水平,这对于吸引CD8+T细胞至关重要。CXCL14成为TFRC的下游效应物,TFRC沉默后表现出表达升高。重要的是,低TFRC表达也与更好的预后相关,增强对联合治疗的敏感性,和肝癌患者抗PD-1治疗的良好反应。
结论:我们的发现强调了安洛替尼通过靶向TFRC和增强CXCL14介导的CD8+T细胞浸润来增强抗PD-1免疫治疗在HCC中的疗效的潜力。这项研究有助于开发新的肝癌治疗策略,强调精准医学在肿瘤学中的作用。
结论:在HCC临床前模型中证明了安洛替尼和抗PD-1免疫疗法的协同作用。安洛替尼通过VEGFR2/AKT/HIF-1α途径抑制TFRC表达。CXCL14通过TFRC抑制上调促进CD8+T细胞募集。TFRC成为评估晚期HCC患者预后和预测基于抗PD-1疗法反应的潜在生物标志物。
BACKGROUND: The therapeutic potential of immune checkpoint blockade (ICB) extends across various cancers; however, its effectiveness in treating hepatocellular carcinoma (HCC) is frequently curtailed by both inherent and developed resistance.
OBJECTIVE: This research explored the effectiveness of integrating anlotinib (a broad-spectrum tyrosine kinase inhibitor) with programmed death-1 (PD-1) blockade and offers mechanistic insights into more effective strategies for treating HCC.
METHODS: Using patient-derived organotypic tissue spheroids and orthotopic HCC mouse models, we assessed the effectiveness of anlotinib combined with PD-1 blockade. The impact on the tumour immune microenvironment and underlying mechanisms were assessed using time-of-flight mass cytometry, RNA sequencing, and proteomics across cell lines, mouse models, and HCC patient samples.
RESULTS: The combination of anlotinib with an anti-PD-1 antibody enhanced the immune response against HCC in preclinical models. Anlotinib remarkably suppressed the expression of transferrin receptor (TFRC) via the VEGFR2/AKT/HIF-1α signaling axis. CD8+ T-cell infiltration into the tumour microenvironment correlated with low expression of TFRC. Anlotinib additionally increased the levels of the chemokine CXCL14, crucial for attracting CD8+ T cells. CXCL14 emerged as a downstream effector of TFRC, exhibiting elevated expression following the silencing of TFRC. Importantly, low TFRC expression was also associated with a better prognosis, enhanced sensitivity to combination therapy, and a favourable response to anti-PD-1 therapy in patients with HCC.
CONCLUSIONS: Our findings highlight anlotinib\'s potential to augment the efficacy of anti-PD-1 immunotherapy in HCC by targeting TFRC and enhancing CXCL14-mediated CD8+ T-cell infiltration. This study contributes to developing novel therapeutic strategies for HCC, emphasizing the role of precision medicine in oncology.
CONCLUSIONS: Synergistic effects of anlotinib and anti-PD-1 immunotherapy demonstrated in HCC preclinical models. Anlotinib inhibits TFRC expression via the VEGFR2/AKT/HIF-1α pathway. CXCL14 upregulation via TFRC suppression boosts CD8+ T-cell recruitment. TFRC emerges as a potential biomarker for evaluating prognosis and predicting response to anti-PD-1-based therapies in advanced HCC patients.