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

• Published in: International journal of biological sciences 2024-01, Vol.20 (10), p.3942-3955
• Main Authors: Xu, Weikang, Hu, Minli, Lu, Xinyu, Lao, Yueqiong, Ma, Na, Wang, Yiyue, Li, Jing, Chen, Xingyuan, Liu, Shiming, Liu, Jing, Zhu, Wei, Yang, Hui
• Format: Article
• Language: English
• Subjects: Animals; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - immunology; Carcinoma, Hepatocellular - metabolism; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Humans; Immunotherapy - methods; Liver Neoplasms - drug therapy; Liver Neoplasms - immunology; Liver Neoplasms - metabolism; Male; Mice; Mice, Inbred C57BL; PCSK9 Inhibitors; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - metabolism; Proprotein Convertase 9 - metabolism; Receptors, Antigen, T-Cell - metabolism; Research Paper; Tumor Microenvironment
• ISSN: 1449-2288; 1449-2288
• DOI: 10.7150/ijbs.93668

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 . 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.