Potentiating CD8<sup>+</sup> T cell antitumor activity by inhibiting PCSK9 to promote LDLRmediated TCR recycling and signaling

doi:10.1007/s13238-021-00821-2

Protein Cell

2021, Vol. 12

Issue (4) : 240-260 https://doi.org/10.1007/s13238-021-00821-2

RESEARCH ARTICLE

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

Juanjuan Yuan^1,^2,⁴, Ting Cai^1,^2,⁴, Xiaojun Zheng^2,^3,⁴, Yangzi Ren^2,³, Jingwen Qi^2,⁴, Xiaofei Lu^2,⁴, Huihui Chen^2,⁴, Huizhen Lin^2,⁴, Zijie Chen^2,⁴, Mengnan Liu^2,⁴, Shangwen He^2,⁴, Qijun Chen^2,⁴, Siyang Feng^2,⁴, Yingjun Wu^2,⁴, Zhenhai Zhang⁵(

), Yanqing Ding^2,^3,⁴(

), Wei Yang^2,^3,⁴(

)

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. Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
⁴. Guangdong Provincial Key Laboratory of Molecular Oncologic Pathology, 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

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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 cellderived 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 LDLR PCSK9 TCR CD8⁺ T cells tumor microenvironment cancer immunotherapy

Corresponding Author(s): Zhenhai Zhang,Yanqing Ding,Wei Yang

Issue Date: 10 May 2021

Cite this article:

Juanjuan Yuan,Ting Cai,Xiaojun Zheng, et al. Potentiating CD8⁺ T cell antitumor activity by inhibiting PCSK9 to promote LDLRmediated TCR recycling and signaling[J]. Protein Cell, 2021, 12(4): 240-260.

URL:

https://academic.hep.com.cn/pac/EN/10.1007/s13238-021-00821-2
https://academic.hep.com.cn/pac/EN/Y2021/V12/I4/240

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