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Inhibition of PCSK9 potentiates immune checkpoint therapy for cancer
Nature ( IF 64.8 ) Pub Date : 2020-11-11 , DOI: 10.1038/s41586-020-2911-7
Xinjian Liu 1, 2 , Xuhui Bao 1 , Mengjie Hu 1 , Hanman Chang 1 , Meng Jiao 1 , Jin Cheng 3 , Liyi Xie 4 , Qian Huang 3 , Fang Li 1 , Chuan-Yuan Li 1, 5, 6
Affiliation  

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. Inhibiting the PCSK9 protein, a regulator of cholesterol metabolism, enhances immune checkpoint therapy in mouse models of cancer, in a manner that depends on the regulation of antigen-presenting MHC I molecules.

中文翻译:

抑制 PCSK9 可增强癌症的免疫检查点治疗

尽管免疫疗法成功地使 10-30% 接受治疗的个体获得了长期存活,但对大多数癌症患者来说,免疫疗法仍然无效 1 , 2 。因此,正在进行许多努力来确定增强这种免疫“检查点”疗法 3 - 5 的新方法(之所以这么称呼,是因为其目的是阻断抑制 T 细胞检查点信号通路的蛋白质,从而释放这些免疫细胞以靶向癌细胞)。在这里,我们表明抑制 PCSK9——一种调节胆固醇代谢 6-8 的关键蛋白——可以通过一种独立于 PCSK9 的胆固醇调节功能的机制来增强肿瘤对免疫检查点治疗的反应。删除小鼠癌细胞中的 PCSK9 基因会以依赖于细胞毒性 T 细胞的方式显着减弱或阻止它们在小鼠中的生长。它还增强了针对检查点蛋白 PD1 的免疫疗法的功效。此外,临床批准的 PCSK9 中和抗体与抗 PD1 疗法协同抑制癌症小鼠模型中的肿瘤生长。通过基因缺失或使用 PCSK9 抗体抑制 PCSK9 会增加肿瘤细胞表面主要组织相容性蛋白 I 类 (MHC I) 蛋白的表达,促进细胞毒性 T 细胞的强大肿瘤内浸润。从机制上讲,我们发现 PCSK9 可以通过与 MHC I 物理结合并促进其在溶酶体中的重新定位和降解来破坏 MHC I 到细胞表面的再循环。总之,这些结果表明抑制 PCSK9 是增强癌症免疫检查点治疗的一种有前途的方法。抑制 PCSK9 蛋白,
更新日期:2020-11-11
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