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Cell:刷新认知!癌细胞竟会放出“无人攻击机”,远程破坏免疫系统总部

2019-04-05 佚名 学术经纬

今天,顶尖学术期刊《细胞》上发表了一篇重量级的论文。来自加州大学旧金山分校(UCSF)的科学家们发现,我们现有关于癌症免疫疗法的认知,很有可能是不完善的……其实不用这些科学家提醒,我们就知道现在的免疫疗法存在短板。“在黑色素瘤等最佳治疗案例中,免疫检查点抑制剂也只能对20%-30%的患者生效。在类似于前列腺癌等其他癌症里,缓解率只有个位数,”本研究的负责人Robert Blelloch教授说道:“

今天,顶尖学术期刊《细胞》上发表了一篇重量级的论文。来自加州大学旧金山分校(UCSF)的科学家们发现,我们现有关于癌症免疫疗法的认知,很有可能是不完善的……其实不用这些科学家提醒,我们就知道现在的免疫疗法存在短板。“在黑色素瘤等最佳治疗案例中,免疫检查点抑制剂也只能对20%-30%的患者生效。在类似于前列腺癌等其他癌症里,缓解率只有个位数,”本研究的负责人Robert Blelloch教授说道:“这表明大部分患者(对免疫疗法)没有反应,我们想要知道为什么。”

依照现有的疾病模型,免疫疗法的一大核心在于PD-1/PD-L1。前者是免疫T细胞表面上的一类受体,后者则由癌细胞分泌。两者结合之后,就会让免疫T细胞偃旗息鼓,放任癌细胞生长。而现有的一类重磅免疫疗法,便是抑制PD-1与PD-L1的结合,从而激活免疫T细胞,让它们重新对癌细胞发起攻击。然而正如上文中提到的那样,大部分癌症患者对免疫疗法并没有反应。后续分析发现,这些患者体内,癌细胞表面的PD-L1水平往往极低。对于这个现象,科学家们做出了一个令人信服的解释——由于PD-L1水平不足,针对PD-1/PD-L1的疗法自然不会生效。

这个解释错了,而且可能错得离谱。

在这项发表在《细胞》的研究中,科学家们决定重新检验这一疾病模型。和先前很多人一样,他们发现那些难治的癌症病例中,癌细胞表面的PD-L1蛋白水平极低。这看起来和其他研究没有什么两样。然而进一步的分析则表明,事情没有这么简单——研究人员们也发现,在这些癌细胞内,编码PD-L1的mRNA水平极高,表明这些癌细胞正在源源不断地生产PD-L1,来抑制免疫细胞活性。

那么这些被癌细胞大量生产出来的PD-L1,究竟跑到哪儿去了?


一些难治的癌症细胞里,PD-L1的mRNA水平(左)与蛋白质水平(右)不成比例

答案令人惊讶!原来,癌细胞在生产完大量PD-L1后,会把这些免疫抑制性分子装进“外泌体”。外泌体就好像是癌细胞释放的无人机一样,离开癌细胞后会进入血液循环,最终抵达淋巴结。而淋巴结恰恰是免疫细胞被激活的场所!换句话说,这些难治的癌细胞已经不满足于在抗癌第一线与免疫细胞斗智斗勇。它们直接对免疫系统总部发起“斩首行动”,从源头对免疫细胞的活性进行破坏!


许多PD-L1通过外泌体走遍全身

而接下来一系列精心设计的实验,完美证实外泌体就是免疫疗法失效的关键。首先,研究人员们获得了一种免疫疗法不起效的前列腺癌小鼠模型。当他们把这些前列腺癌细胞注射到健康小鼠体内后,马上观察到了肿瘤的快速生长。然而当科学家们利用CRISPR基因编辑技术,删除了两条和外泌体生产有关的基因后,注射入小鼠体内的癌细胞就无法形成肿瘤。也就是说,尽管癌细胞本身还是能合成大量PD-L1,但只要无法通过外泌体将PD-L1运往身体各处,小鼠的免疫系统就不会受到抑制。癌细胞也会很快被免疫系统清除。随后,研究人员们又做了进一步实验。先前我们提到,那些由于CRISPR基因编辑而失去外泌体生产能力的癌细胞,无法在小鼠体内形成肿瘤。然而,只要同时注射带有PD-L1的外泌体,就会限制免疫系统的活性。原本会很快被清除的癌细胞,也能就此在体内落地生根,形成肿瘤。


小鼠模型中,抑制外泌体形成,或是抑制PD-L1,都会缩小肿瘤(左),延长小鼠的生存期(右)

直肠癌的小鼠模型中,研究人员们观察到了类似的现象。在这些小鼠中,存在两类PD-L1,一类存在于癌细胞表面,他们能被现有的免疫疗法所抑制;另一类则是存在于外泌体中,免疫疗法对它们不起效。倘若使用组合疗法,同时抑制PD-L1,并阻止外泌体的生成,就能让小鼠活得更久。

“从两类不同的癌症模型中获得的数据带来了一种全新的治疗方法。无论是否与现有的免疫检查点抑制剂进行组合,只要抑制外泌体里的PD-L1释放,就有望克服大部分患者对免疫疗法无反应的现象。” Blelloch教授评论道。


本研究的图示

除了创新疗法之外,这项研究还有望带来癌症疫苗!研究人员们指出,既然无法形成外泌体的癌细胞无法抑制免疫系统,它们在体内就会被免疫系统主动攻击。而这些免疫反应可能让免疫系统“形成记忆”,对同样的癌细胞产生免疫力。动物实验也证明了这一设想的可行性。科学家们首先在小鼠体内植入了经过CRISPR基因编辑,无法产生外泌体的癌细胞。90天后,研究人员们又植入了带有同样遗传背景,没有经过编辑的普通癌细胞。原本,这些癌细胞会迅速在小鼠体内形成肿瘤。然而经过前一批癌细胞的训练后,免疫系统已经学会了如何识别这些异物,立即做出反应,对它们进行清除。“免疫系统在接触到无法生成外泌体PD-L1的癌细胞后,形成了抗肿瘤的记忆。只要免疫系统有这种记忆,就不会再受到此类PD-L1的影响。” Blelloch教授补充道。

这项研究给我们带来了关于免疫疗法的全新洞见,也揭示了过去我们对癌症免疫疗法的认知有多么不足。目前在临床上,尚没有针对外泌体PD-L1的疗法。考虑到外泌体在抑制免疫疗法中的重要意义,将来,它有望成为研究人员们的关注热点。我们期待这一发现能够带来更多抗癌疗法,造福全球病患!

原始出处:

Mauro Poggio,et al.Suppression of Exosomal PD-L1 Induces Systemic Anti-tumor Immunity and Memory.Cell.VOLUME 177, ISSUE 2, P414-427.E13, APRIL 04, 2019

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    2019-04-24 维他命
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    2019-06-08 125a1eefm88暂无昵称

    厉害了我的哥

    0

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    2019-04-07 yxch36
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    2019-04-06 gakkilovesky

    s

    0

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    2019-04-05 蝴蝶A

    免疫疗法,外泌体

    0

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