2. Academic Validation
  3. Potentiating CD8+ T cell antitumor activity by inhibiting PCSK9 to promote LDLR-mediated TCR recycling and signaling

Potentiating CD8+ T cell antitumor activity by inhibiting PCSK9 to promote LDLR-mediated TCR recycling and signaling

  • Protein Cell. 2021 Apr;12(4):240-260. doi: 10.1007/s13238-021-00821-2.
Juanjuan Yuan  # 1 2 3,  Ting Cai  # 1 2 3,  Xiaojun Zheng  # 2 4 3,  Yangzi Ren  # 2 4,  Jingwen Qi 2 3,  Xiaofei Lu 2 3,  Huihui Chen 2 3,  Huizhen Lin 2 3,  Zijie Chen 2 3,  Mengnan Liu 2 3,  Shangwen He 2 3,  Qijun Chen 2 3,  Siyang Feng 2 3,  Yingjun Wu 2 3,  Zhenhai Zhang 5,  Yanqing Ding 6 7 8,  Wei Yang 9 10 11
Affiliations

Affiliations

  • 1 Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan, 528308, China.
  • 2 Guangdong Provincial Key Laboratory of Molecular Oncologic Pathology, Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China.
  • 3 Guangdong Provincial Key Laboratory of Molecular Oncologic Pathology, Southern Medical University, Guangzhou, 510515, China.
  • 4 Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
  • 5 Center for Precision Medicine, Guangdong Provincial People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510030, China. [email protected].
  • 6 Guangdong Provincial Key Laboratory of Molecular Oncologic Pathology, Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China. [email protected].
  • 7 Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. [email protected].
  • 8 Guangdong Provincial Key Laboratory of Molecular Oncologic Pathology, Southern Medical University, Guangzhou, 510515, China. [email protected].
  • 9 Guangdong Provincial Key Laboratory of Molecular Oncologic Pathology, Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China. [email protected].
  • 10 Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. [email protected].
  • 11 Guangdong Provincial Key Laboratory of Molecular Oncologic Pathology, Southern Medical University, Guangzhou, 510515, China. [email protected].
  • # Contributed equally.
PMID: 33606190 DOI: 10.1007/s13238-021-00821-2
Abstract

Metabolic regulation has been proven to play a critical role in T cell antitumor immunity. However, Cholesterol metabolism as a key component of this regulation remains largely unexplored. Herein, we found that the low-density lipoprotein receptor (LDLR), which has been previously identified as a transporter for Cholesterol, plays a pivotal role in regulating CD8+ T cell antitumor activity. Besides the involvement of Cholesterol uptake which is mediated by LDLR in T cell priming and clonal expansion, we also found a non-canonical function of LDLR in CD8+ T cells: LDLR interacts with the T-cell receptor (TCR) complex and regulates TCR recycling and signaling, thus facilitating the effector function of cytotoxic T-lymphocytes (CTLs). Furthermore, we found that the tumor microenvironment (TME) downregulates CD8+ T cell LDLR level and TCR signaling via tumor cell-derived proprotein convertase subtilisin/kexin type 9 (PCSK9) which binds to LDLR and prevents the recycling of LDLR and TCR to the plasma membrane thus inhibits the effector function of CTLs. Moreover, genetic deletion or pharmacological inhibition of PCSK9 in tumor cells can enhance the antitumor activity of CD8+ T cells by alleviating the suppressive effect on CD8+ T cells and consequently inhibit tumor progression. While previously established as a hypercholesterolemia target, this study highlights PCSK9/LDLR as a potential target for Cancer Immunotherapy as well.

Keywords

CD8+ T cells; LDLR; PCSK9; TCR; cancer immunotherapy; tumor microenvironment.

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