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Inhibition of PCSK9 potentiates immune checkpoint therapy for cancer

机译：PCSK9抑制癌症免疫检查点治疗的抑制作用

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摘要

Despite its success in achieving the long-term survival of 10-30% of treated individuals, immune therapy is still ineffective for most patients with cancer~(1,2). Many efforts are therefore underway to identify new approaches that enhance such immune 'checkpoint' therapy~(3-5)(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 metabolism~(6-8)-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.
机译：尽管其成功实现了10-30％治疗的人的长期存活，但免疫治疗对大多数癌症患者仍然无效〜（1,2）。因此，许多努力识别增强这种免疫力“检查点”治疗的新方法〜（3-5）（所谓的，因为它的目的是阻止抑制T细胞中检查点信号传导途径的蛋白质，从而释放那些免疫细胞靶向癌症细胞）。在这里，我们表明抑制胆固醇代谢调节中的PCSK9-A关键蛋白 - 通过独立于PCSK9的胆固醇调节功能的机制提升肿瘤对免疫检查点治疗的反应。删除小鼠癌细胞中的PCSK9基因基本上衰减或以取决于细胞毒性T细胞的方式衰减或防止它们在小鼠中的生长。它还增强了在检查点蛋白PD1上靶向的免疫疗法的功效。此外，临床批准的PCSK9中和抗体在抑制癌小鼠模型中抑制肿瘤生长的抗PD1治疗。通过遗传缺失或使用PCSK9抗体来抑制PCSK9 - 增加主要组织相容性蛋白类I（MHC I）蛋白在肿瘤细胞表面上的表达，促进细胞毒性T细胞的鲁棒肿瘤渗透。机械地，通过物理上与其促进其在溶酶体中的迁移和降解，我们发现PCSK9可以破坏MHC I的再循环到细胞表面。这些结果表明，抑制pcsk9是增强癌症免疫检查点治疗的有希望的方法。

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  • 来源
    《Nature》 |2020年第7839期|693-698|共6页
  • 作者

    Xinjian Liu; Xuhui Bao; Mengjie Hu; Hanman Chang; Meng Jiao; Jin Cheng; Liyi Xie; Qian Huang; Fang Li; Chuan-Yuan Li;

  • 作者单位

    Department of Dermatology Duke University Medical Center|Department of Biochemistry Molecular Cancer Research Center School of Medicine Sun Yat-sen University;

    Department of Dermatology Duke University Medical Center;

    Department of Dermatology Duke University Medical Center;

    Department of Dermatology Duke University Medical Center;

    Department of Dermatology Duke University Medical Center;

    Molecular Diagnostic Laboratory of Cancer Center Shanghai General Hospital Shanghai Jiaotong University School of Medicine;

    Department of Radiation Oncology Fudan University Shanghai Cancer Center;

    Molecular Diagnostic Laboratory of Cancer Center Shanghai General Hospital Shanghai Jiaotong University School of Medicine;

    Department of Dermatology Duke University Medical Center;

    Department of Dermatology Duke University Medical Center|Department of Pharmacology and Cancer Biology Duke University Medical Center|Duke Cancer Institute Duke University Medical Center;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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