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Inhibition of PCSK9 potentiates immune checkpoint therapy for cancer

Author

Listed:
  • Xinjian Liu

    (Duke University Medical Center
    Sun Yat-sen University)

  • Xuhui Bao

    (Duke University Medical Center)

  • Mengjie Hu

    (Duke University Medical Center)

  • Hanman Chang

    (Duke University Medical Center)

  • Meng Jiao

    (Duke University Medical Center)

  • Jin Cheng

    (Shanghai Jiaotong University School of Medicine)

  • Liyi Xie

    (Fudan University Shanghai Cancer Center)

  • Qian Huang

    (Shanghai Jiaotong University School of Medicine)

  • Fang Li

    (Duke University Medical Center)

  • Chuan-Yuan Li

    (Duke University Medical Center
    Duke University Medical Center
    Duke University Medical Center)

Abstract

Despite its success in achieving the long-term survival of 10–30% of treated individuals, immune therapy is still ineffective for most patients with cancer1,2. Many efforts are therefore underway to identify new approaches that enhance such immune ‘checkpoint’ therapy3–5 (so called because its aim is to block proteins that inhibit checkpoint signalling pathways in T cells, thereby freeing those immune cells to target cancer cells). Here we show that inhibiting PCSK9—a key protein in the regulation of cholesterol metabolism6–8—can boost the response of tumours to immune checkpoint therapy, through a mechanism that is independent of PCSK9’s cholesterol-regulating functions. Deleting the PCSK9 gene in mouse cancer cells substantially attenuates or prevents their growth in mice in a manner that depends on cytotoxic T cells. It also enhances the efficacy of immune therapy that is targeted at the checkpoint protein PD1. Furthermore, clinically approved PCSK9-neutralizing antibodies synergize with anti-PD1 therapy in suppressing tumour growth in mouse models of cancer. Inhibiting PCSK9—either through genetic deletion or using PCSK9 antibodies—increases the expression of major histocompatibility protein class I (MHC I) proteins on the tumour cell surface, promoting robust intratumoral infiltration of cytotoxic T cells. Mechanistically, we find that PCSK9 can disrupt the recycling of MHC I to the cell surface by associating with it physically and promoting its relocation and degradation in the lysosome. Together, these results suggest that inhibiting PCSK9 is a promising way to enhance immune checkpoint therapy for cancer.

Suggested Citation

  • Xinjian Liu & Xuhui Bao & Mengjie Hu & Hanman Chang & Meng Jiao & Jin Cheng & Liyi Xie & Qian Huang & Fang Li & Chuan-Yuan Li, 2020. "Inhibition of PCSK9 potentiates immune checkpoint therapy for cancer," Nature, Nature, vol. 588(7839), pages 693-698, December.
  • Handle: RePEc:nat:nature:v:588:y:2020:i:7839:d:10.1038_s41586-020-2911-7
    DOI: 10.1038/s41586-020-2911-7
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    Citations

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    Cited by:

    1. Yanan Liu & Longmiao Hu & Zhengzhen Wu & Kun Yuan & Guangliang Hong & Zhengke Lian & Juanjuan Feng & Na Li & Dali Li & Jiemin Wong & Jiekai Chen & Mingyao Liu & Jiangping He & Xiufeng Pang, 2023. "Loss of PHF8 induces a viral mimicry response by activating endogenous retrotransposons," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Zhen Lu & Jinyun Chen & Pengfei Yu & Matthew J. Atherton & Jun Gui & Vivek S. Tomar & Justin D. Middleton & Neil T. Sullivan & Sunil Singhal & Subin S. George & Ashley G. Woolfork & Aalim M. Weljie & , 2022. "Tumor factors stimulate lysosomal degradation of tumor antigens and undermine their cross-presentation in lung cancer," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    3. Wenfeng Ren & Zilong Xu & Yating Chang & Fei Ju & Hongning Wu & Zhiqi Liang & Min Zhao & Naizhen Wang & Yanhua Lin & Chenhang Xu & Shengming Chen & Yipeng Rao & Chaolong Lin & Jianxin Yang & Pingguo L, 2024. "Pharmaceutical targeting of OTUB2 sensitizes tumors to cytotoxic T cells via degradation of PD-L1," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    4. Zhaoqi Shu & Minghe Fan & Bo Tu & Zhiheng Tang & Haojie Wang & Haimeng Li & Hengchao Li & Meng Yuan & Jingru Bai & Sihan Huo & Lina Wang & Wei-Guo Zhu & Wei Wang & Xiaoyun Liu & Shaokun Shu & Ying Zha, 2023. "The Lin28b/Wnt5a axis drives pancreas cancer through crosstalk between cancer associated fibroblasts and tumor epithelium," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    5. Chi Chun Wong & Jian-Lin Wu & Fenfen Ji & Wei Kang & Xiqing Bian & Huarong Chen & Lam-Shing Chan & Simson Tsz Yat Luk & Samuel Tong & Jiaying Xu & Qiming Zhou & Dabin Liu & Hao Su & Hongyan Gou & Alvi, 2022. "The cholesterol uptake regulator PCSK9 promotes and is a therapeutic target in APC/KRAS-mutant colorectal cancer," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    6. Wanzun Lin & Li Chen & Haojiong Zhang & Xianxin Qiu & Qingting Huang & Fangzhu Wan & Ziyu Le & Shikai Geng & Anlan Zhang & Sufang Qiu & Long Chen & Lin Kong & Jiade J. Lu, 2023. "Tumor-intrinsic YTHDF1 drives immune evasion and resistance to immune checkpoint inhibitors via promoting MHC-I degradation," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    7. Lianmei Tan & Tao Yin & Handan Xiang & Liuyang Wang & Poorva Mudgal & Junying Chen & Yi Ding & Guoping Wang & Bryan Jian Wei Lim & Yuqi Huang & De Huang & Yaosi Liang & Peter B. Alexander & Kun Xiang , 2024. "Aberrant cytoplasmic expression of UHRF1 restrains the MHC-I-mediated anti-tumor immune response," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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