Inhibition of PCSK9 enhances the anti-hepatocellular carcinoma effects of TCR-T cells and anti-PD-1 immunotherapy.

IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY International Journal of Biological Sciences Pub Date : 2024-07-15 eCollection Date: 2024-01-01 DOI:10.7150/ijbs.93668
Weikang Xu, Minli Hu, Xinyu Lu, Yueqiong Lao, Na Ma, Yiyue Wang, Jing Li, Xingyuan Chen, Shiming Liu, Jing Liu, Wei Zhu, Hui Yang
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Abstract

T cells play important roles in antitumor immunity. However, given that the hepatocellular carcinoma (HCC) tumor microenvironment confers resistance to T cell-based immunotherapies, novel strategies to boost T cell-mediated antitumor efficacy are urgently needed for the treatment of HCC. Here, we show that high proprotein convertase subtilisin/kexin type9 (PCSK9) expression was negatively associated with HCC patient's overall survival and markers of CD8+ T cells. Pharmacological inhibition of PCSK9 enhanced tumor-specific killing and downregulated PD-1 expression of AFP-specific TCR-T. Inhibition of PCSK9 significantly enhances the anti-HCC efficacy of TCR-T cells and anti-PD-1 immunotherapy in vivo. Moreover, PCSK9 inhibitor suppressed HCC growth dependent on CD8+ T cells. Mechanically, pharmacological inhibition of PCSK9 promoted low-density lipoprotein receptor (LDLR)-mediated activation of mTORC1 signaling in CD8+ T cells. LDLR deficiency was shown to impair cellular mTORC1 signaling and the anti-HCC function of CD8 T cells. On the basis of our findings in this study, we propose a potential metabolic intervention strategy that could be used to enhance the antitumor effects of immunotherapy for HCC.

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抑制 PCSK9 可增强 TCR-T 细胞和抗 PD-1 免疫疗法的抗肝细胞癌效果。
T 细胞在抗肿瘤免疫中发挥着重要作用。然而,鉴于肝细胞癌(HCC)肿瘤微环境会对基于 T 细胞的免疫疗法产生抗药性,因此治疗 HCC 急需提高 T 细胞介导的抗肿瘤疗效的新策略。在这里,我们发现高丙脯氨酸转化酶亚基酶/kexin9型(PCSK9)表达与HCC患者的总生存期和CD8+ T细胞标记物呈负相关。药理抑制PCSK9可增强肿瘤特异性杀伤力,并下调AFP特异性TCR-T的PD-1表达。抑制PCSK9能显著提高TCR-T细胞和体内抗PD-1免疫疗法的抗HCC疗效。此外,PCSK9抑制剂还能抑制依赖于CD8+ T细胞的HCC生长。从机制上讲,药理抑制PCSK9可促进CD8+ T细胞中低密度脂蛋白受体(LDLR)介导的mTORC1信号激活。研究表明,缺乏 LDLR 会损害细胞的 mTORC1 信号传导和 CD8 T 细胞的抗HCC 功能。根据本研究的发现,我们提出了一种潜在的代谢干预策略,可用于增强 HCC 免疫疗法的抗肿瘤效果。
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来源期刊
International Journal of Biological Sciences
International Journal of Biological Sciences 生物-生化与分子生物学
CiteScore
16.90
自引率
1.10%
发文量
413
审稿时长
1 months
期刊介绍: The International Journal of Biological Sciences is a peer-reviewed, open-access scientific journal published by Ivyspring International Publisher. It dedicates itself to publishing original articles, reviews, and short research communications across all domains of biological sciences.
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