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虽然免疫检查点（PD-1或PD-L1）抑制剂成功实现了10%～30%的癌症患者长期生存，不过对于大多数癌症患者仍然无效。因此，科学家们正努力寻找增强这些免疫检查点抑制剂疗效的新方法。 2020年11月11日，全球自然科学三大旗舰期刊之一、英国《自然》正刊在线发表美国杜克大学、中国中山大学医学院分子肿瘤研究中心、上海交通大学医学院附属第一人民医院、复旦大学附属肿瘤医院的研究报告，发现依洛尤单抗（瑞百安，美国安进出品，2018年7月31日进入中国内陆）或阿利西尤单抗（波立达，法国赛诺菲出品，2019年12月26日进入中国内陆）之类胆固醇代谢抑制剂可显著增强三阴性乳腺癌等恶性肿瘤的免疫检查点抑制剂疗效。 该研究证实，抑制胆固醇代谢调节关键蛋白质PCSK9，可显著增强免疫检查点抑制剂对小鼠三阴性乳腺癌细胞4T1或人类三阴性乳腺癌细胞MDA-MB-231等恶性肿瘤细胞的疗效，其作用机制并不依靠PCSK9的胆固醇调节功能。PCSK9通过与低密度脂蛋白受体结合，可降低肝脏从血液清除低密度脂蛋白胆固醇的能力。依洛尤单抗或阿利西尤单抗通过抑制PCSK9与低密度脂蛋白受体的结合，可增加能够清除血液低密度脂蛋白的低密度脂蛋白受体数量，从而减少低密度脂蛋白胆固醇。 如果删除小鼠癌细胞的PCSK9编码基因，可通过杀伤型T淋巴细胞，大大减弱或阻止癌细胞的生长，还可显著增强免疫检查点PD-1抑制剂的疗效。 此外，已获批准用于临床的PCSK9中和抗体（依洛尤单抗、阿利西尤单抗）联合PD-1抑制剂对于抑制小鼠肿瘤生长具有协同作用。 抑制PCSK9（通过基因删除或PCSK9抗体）可提高肿瘤细胞表面主要组织相容性复合体MHCI表达水平，从而促进杀伤型T淋巴细胞向肿瘤内浸润。 根据机制分析，PCSK9可与MHCI物理结合，并促进MHCI进入溶酶体被降解，从而破坏MHCI向细胞表面再循环。 因此，该研究结果表明，抑制PCSK9有望成为增强三阴性乳腺癌等恶性肿瘤免疫检查点抑制剂疗效的新方法。 Nature. 2020 Nov 11. Online ahead of print. Inhibition of PCSK9 potentiates immune checkpoint therapy for cancer. Xinjian Liu, Xuhui Bao, Mengjie Hu, Hanman Chang, Meng Jiao, Jin Cheng, Liyi Xie, Qian Huang, Fang Li, Chuan-Yuan Li. Duke University Medical Center, Durham, NC, USA; Molecular Cancer Research Center, School of Medicine, Sun Yat-sen University, Shenzhen, Guangdong, China; Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Fudan University Shanghai Cancer Center, Shanghai, China. 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. Many efforts are therefore underway to identify new approaches that enhance such immune 'checkpoint' therapy (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—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. DOI: 10.1038/s41586-020-2911-7
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