Nat Med :癌细胞扩散到肝脏会更糟糕,邹伟平团队揭示背后原因,并提出治疗手段

2021-01-08 Bio生物世界 Bio生物世界

转移扩散,是许多晚期癌症的表现之一,同时也是最难以治愈的情况。界时,患者的癌细胞的附着能力下降甚至完全丧失,与此同时,其迁移能力增强,导致癌细胞从原生部位随血液或淋巴系统转移到其他身体部位。

转移扩散,是许多晚期癌症的表现之一,同时也是最难以治愈的情况。界时,患者的癌细胞的附着能力下降甚至完全丧失,与此同时,其迁移能力增强,导致癌细胞从原生部位随血液或淋巴系统转移到其他身体部位,最终形成新的肿瘤。

更可怕的是,在这种情况下,患者就如同被宣判死刑,几乎无法治愈。其中,肝脏是癌症转移的常见部位,且临床研究表明,癌细胞扩散到肝脏的肿瘤患者往往会表现出更糟糕的预后,但这一现象背后的具体机制却一直的不到解释。

2021年1月4日,美国密歇根大学邹伟平教授研究团队在 Nature Medicine 杂志上发表了题为:Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination (肝转移通过巨噬细胞介导的T细胞消除抑制免疫治疗效果)的研究论文。

这项研究表明,肝转移瘤可以利用宿主外周免疫耐受机制,通过CD8+ T细胞缺失引起获得性免疫治疗耐药性。研究人员还发现,肝脏定向放射疗法结合免疫治疗可以恢复免疫细胞的功能,改善癌症转移患者的预后。

目前尚不清楚癌细胞转移到特定器官是否通过损害全身抗肿瘤免疫和限制免疫治疗的疗效而导致癌症死亡率的增加。肝脏是癌症转移的常见部位,在自身免疫性疾病、病毒感染和器官移植的情况下,肝脏可促进免疫耐受。

肝脏免疫耐受的机制包括导致T细胞无能的无效免疫突触、调节性T细胞诱导或效应T细胞消除。然而,在癌症背景下,这些肝脏免疫耐受机制的重要性还没有明确定义。

在这项研究中,研究团队统计分析了718名在密歇根大学罗格尔癌症中心接受免疫治疗的癌症患者的数据。

这些患者属于不同的癌症类型,包括非小细胞肺癌、黑色素瘤、尿路上皮癌和肾细胞癌等,并且他们的癌细胞已经扩散到不同器官,例如肝和肺。

研究人员发现,那些癌细胞扩散到肝脏的患者对免疫治疗的反应更差——与癌症扩散但没有扩散到肝脏的类似患者相比,这些患者全身的癌症更多。

对此,本研究的通讯作者和主要领导者邹伟平教授表示:“肝脏正在启动一种全身免疫抑制机制,该机制发生在肝脏,但我们看到的是它对全身都产生影响。”

肝转移与癌症患者免疫治疗效果降低相关

更令人意外的是,研究人员发现接受化疗或靶向治疗的肝转移患者的预后并不比接受其他类型转移的患者差。这表明,发生癌细胞肝转移的患者仅对免疫疗法不敏感——这是免疫疗法特有的。

为了探究这一现象的具体机制,研究人员观察了肝转移瘤的微环境,发现肿瘤正在“吸走”CD8+ T细胞——一种本应用来攻击癌症的免疫细胞。更糟糕的是,不仅肝脏中的T细胞被清除,而且还在全身创造了一个免疫沙漠。

肝转移引起抗原特异性T细胞的全身丢失

这也意味着,肝转移瘤患者的免疫系统无法被激活来对抗任何部位的肿瘤。

那我们又该如何去治疗肝转移瘤患者呢?

在肝转移瘤小鼠模型中,研究人员使用肝脏定向放射治疗可消除免疫抑制的肝巨噬细胞,增加肝T细胞存活率。随着T细胞的恢复,免疫检查点抑制剂就能够激活免疫系统来消除全身的肿瘤。

放疗重塑肝脏免疫微环境,消除肝转移引起的免疫治疗耐药性

总而言之,这项研究发现,肝转移瘤患者的免疫治疗反应更差,并且与肝脏免疫耐受的机制,联合使用放射疗法和免疫疗法会增加患者的T细胞存活率,从而恢复肝脏癌转移患者对免疫疗法的敏感性。

该研究的另一位通讯作者Michael Green 表示:“免疫疗法已经改变了许多癌症的治疗策略,但癌细胞转移到肝脏的癌症患从免疫疗法中获益甚微,这项研究表明,可以用放射疗法逆转这种耐药性,这有可能对这些患者的预后产生真正有用的影响。”

原始出处:

Jiali Yu , Michael D Green, Shasha Li, et al.Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination.Nat Med . 2021 Jan 4.doi: 10.1038/s41591-020-1131-x. 

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    2021-01-10 liye789132251
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    2021-01-10 yxch36
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    2021-01-08 ms7000001350918467

    写的很好 很详细

    0

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    2021-01-08 zb1235672

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