| Autor: |
Xiaojun Zheng, Yanqing Ding, Zhenhai Zhang, Huihui Chen, Shangwen He, Siyang Feng, Zijie Chen, Xiaofei Lu, Yinjun Wu, Wei Yang, Ting Cai, Qijun Chen, Juanjuan Yuan, Mengnan Liu, Yangzi Ren, Huizhen Lin, Jinwen Qi |
| Rok vydání: |
2020 |
| Předmět: |
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| DOI: |
10.1101/2020.12.03.403121 |
| Popis: |
Metabolic regulation has proven to play a critical role in T cell antitumor immunity. Cholesterol metabolism is a key component of this response but remains largely unexplored. Herein, we found that the LDL receptor (LDLR), which has been previously identified as a transporter for cholesterol and fatty acids, plays a pivotal role in regulating CD8+ T cell antitumor activity, with the genetic ablation of LDLR significantly attenuating CD8+ T cell activation and clonal expansion. Additionally, we found that LDLR interacts with the T-cell receptor (TCR) signalosome and regulates TCR signaling, facilitating CD8+ T cell activation and effector function. Furthermore, we found that the tumor microenvironment downregulates CD8+ T cell LDLR levels and TCR signaling via tumor cell-derived PCSK9, which binds and prevents the recycling of LDLR and TCR into the plasma membrane. Our findings indicate that genetic deletion or pharmacological inhibition of PCSK9 in tumor cells can enhance the antitumor activity of CD8+ T cells by alleviating the tumor microenvironment’s suppressive effect on CD8+ T cells and consequently inhibit tumor progression. While previously established as a hyperlipidemia target, this study highlights PCSK9 as a potential target for cancer immunotherapy as well. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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