Nat Chem Biol:国内肿瘤免疫疗法新突破!肿瘤防御系统有望彻底被瓦解!

2018-11-07 佚名 转化医学网

国内肿瘤免疫疗法创新研究传喜讯!上海交通大学医学院附属仁济医院消化科许杰研究团队揭示了肿瘤免疫治疗的靶标程序性死亡配体-1(PD-L1)的调控机制,并设计了新的靶向方法。相关论文11月5日发表于《自然·化学生物学》。

国内肿瘤免疫疗法创新研究传喜讯!上海交通大学医学院附属仁济医院消化科许杰研究团队揭示了肿瘤免疫治疗的靶标程序性死亡配体-1(PD-L1)的调控机制,并设计了新的靶向方法。相关论文11月5日发表于《自然·化学生物学》。

目前研究者正在对靶向分子进行代谢和毒理试验,该方法利用HIP1R的功能从细胞内部降解PD-L1,就像从“肿瘤”城堡内部攻击卫兵的“特洛伊木马”,有望更彻底地瓦解肿瘤细胞的防御。该论文通讯作者是仁济医院消化科许杰,第一作者是上海交通大学医学院博士研究生王焕彬。

许杰做了一个比喻:PD-L1蛋白保护肿瘤细胞逃避免疫细胞的杀伤,就像城堡的“卫兵”;既往方法是用抗体从细胞外部靶向PD-L1,但是城堡内的“卫兵”(细胞内的PD-L1)还会补充上来,可能再次形成抵抗;新的方法利用HIP1R的功能从细胞内部降解PD-L1,就像从城堡内部攻击卫兵的“特洛伊木马”,有望更彻底地瓦解肿瘤细胞的防御。


李楚舒绘制  HIP1R如特洛伊木马般瓦解肿瘤细胞的"守卫"PD-L1

近年来癌症的免疫治疗方法获得高度关注,尤其是肿瘤免疫检查点阻断剂,该领域的两位重要研究者詹姆斯-艾利森和本庶佑还获得2018年诺贝尔生理学或医学奖。

肿瘤免疫检查点阻断剂例如抗程序性死亡-1(PD-1)受体及其程序性死亡配体(PD-L1)的抗体药物,主要是通过克服患者体内的免疫抑制,重新激活患者自身的免疫细胞来杀伤肿瘤。美国食品和药品监督管理局已批准了 PD-1 抗体在治疗黑色素瘤等恶性肿瘤中的应用,目前PD-1 抗体药物在我国也已获批上市。

然而PD-1抑制剂在未经选择的实体瘤患者中,有效率只有10%-30%;而起初具有良好治疗效果的患者,随着药物的长期使用也可能产生耐药。

现有的抗体药物能结合并阻断肿瘤细胞表面的PD-L1,但近期研究发现肿瘤细胞的PD-L1还存在于细胞内的循环内体、高尔基体和微囊泡上。癌细胞内的PD-L1具备促癌的功能,还会对细胞表面失活的PD-L1进行补充和更新,这可能是抗体药物失效的原因之一。


许杰课题组

许杰课题组通过肿瘤基因组学筛选发现了PD-L1与HIP1R的显着关联,并通过一系列的实验研究证明,HIP1R促进PD-L1从溶酶体途径的降解,也就是把PD-L1蛋白质运送到细胞内的“回收站”进行彻底清除。失去了PD-L1的保护后,肿瘤细胞就会被体内的T细胞杀伤。研究者根据HIP1R调控PD-L1的方式设计了PD-LYSO多肽,能靶向PD-L1至溶酶体降解,并促进免疫细胞对肿瘤细胞的杀伤。

这项研究为肿瘤免疫治疗提供了新的思路和方法,为提升治疗效果、改善疾病预后提供了非常有意义的参考和借鉴。

原始出处:Huanbin Wang, Han Yao, Chushu Li, et al. HIP1R targets PD-L1 to lysosomal degradation to alter T cell–mediated cytotoxicity.Nat Chem Biol. 05 November 2018

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    2019-06-12 sunylz
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    2019-07-25 liye789132251
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    2019-08-26 zxxiang
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    2018-11-08 15938038573红旗飘飘

    已学习并已分享

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    2018-11-07 123fd467m06暂无昵称

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    2018-11-07 kafei

    学习了谢谢

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