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

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

  • Int J Biol Sci. 2024 Jul 15;20(10):3942-3955. doi: 10.7150/ijbs.93668.
Weikang Xu 1,  Minli Hu 1,  Xinyu Lu 2,  Yueqiong Lao 1,  Na Ma 3,  Yiyue Wang 2,  Jing Li 1,  Xingyuan Chen 1,  Shiming Liu 4,  Jing Liu 5,  Wei Zhu 2,  Hui Yang 1
Affiliations

Affiliations

  • 1 Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510220, China.
  • 2 Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China; State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China, Ministry of Education; Guangdong Provincial Key Laboratory of Viral Hepatitis Research; Guangdong Provincial Clinical Research Center for Viral Hepatitis; Guangdong Institute of Hepatology. Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
  • 3 Department of Pathology, The First People's Hospital of Foshan, Foshan 528000, China.
  • 4 Guangzhou Institute of Cardiovascular Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510220, China.
  • 5 Department of Hematology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510220, China.
PMID: 39113701 DOI: 10.7150/ijbs.93668
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.

Keywords

TCR-engineered T cell (TCR-T); hepatocellular carcinoma (HCC); low-density lipoprotein receptor (LDLR); proprotein convertase subtilisin/kexin 9 (PCSK9).

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