Ting Cai
Xiaojun Zheng
Yangzi Ren
Jingwen Qi
Xiaofei Lu
Huihui Chen
Huizhen Lin
Zijie Chen
Mengnan Liu
Shangwen He
Qijun Chen
Siyang Feng
Yingjun Wu
Zhenhai Zhang
Yanqing Ding
Wei Yang
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
Funds: The imaging works were performed at the SMU Central Laboratory of Southern Medical University and Department of Pathology of Nanfang Hospital. We thank Chenqi Xu for the discussion at the early stage of this project. W.Y. is funded by National Key R&D Program of China (MOST, No. 2018YFA0800404), NSFC grants (No. 81822036 and 31770931), Guangdong Natural Science Funds for Distinguished Young Scholar (No. 2017A030306030). Y.D. is funded by NSFC grant (No. 81972754) and National Key R&D Program of China (MOST, No. 2015CB554002). J.Y. is funded by NSFC grant (No. 82001658), China Postdoctoral Science Foundation (No. BX20190148 and 2019M662973) and Guangdong Basic and Applied Basic Research Foundation (No. 2019A1515110015). T.C. is funded by NSFC grant (No. 82001745), China Postdoctoral Science Foundation (No. 2020M672544) and Guangdong Basic and Applied Basic Research Foundation (No. 2019A1515110052). X.Z. is funded by NSFC grant (No. 31800730), China Postdoctoral Science Foundation (No. 2017M622730), Natural Science Foundation of Guangdong Province (No. 2018030310293) and Guangdong Basic and Applied Basic Research Foundation (No. 2020A1515011246).
Received Date: 2020-12-21
Rev Recd Date:2020-12-31
Abstract
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
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