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两篇Science连发，揭示癌症发病新机制，竟是健全的免疫系统“背锅”

2021-09-26 梅斯医学 MedSci原创

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自然进化的肿瘤必须应付功能齐全的免疫系统，以躲避人体的攻击。过去一直认为，免疫系统是肿瘤的天敌，但最近，科学家利用免疫系统完善的小鼠模型发现，完好的免疫系统竟然会助纣为虐！

自然进化的肿瘤必须应付功能齐全的免疫系统，以躲避人体的攻击。过去一直认为，免疫系统是肿瘤的天敌，但最近，科学家利用免疫系统完善的小鼠模型发现，完好的免疫系统竟然会助纣为虐！
来源：搜狐网
一般来说，免疫系统会将肿瘤细胞视为异类，并启动一系列的攻击反应，旨在消除肿瘤。但Science新近发表的文章却表明，免疫系统会对肿瘤进行选择，帮助筛选出富含有抑癌基因突变的肿瘤细胞，进而帮助肿瘤细胞朝着更强的方向演化。
doi: 10.1126/science.abg5784.
 
在这之前，对抑癌基因突变的研究主要集中在它们对肿瘤细胞表型的影响上，例如促进增殖或逃避细胞凋亡。这些表型可能是一些抑癌基因失活后出现的，是肿瘤细胞的内在特性，与是否存在免疫细胞无关。
 
然而，越来越多的研究发现，某些抑癌基因在体外试验和裸鼠（缺乏完整的免疫系统）中没有显示出什么功能，而在免疫力完好的小鼠中能表现出功能。这些都提示抑癌基因失活与免疫促进有关，这或许是抑癌基因新的功能。
研究人员以乳腺癌细胞作为切入点，对大约7500个基因进行了 CRISPR突变编辑。然后将这些细胞分别植入免疫功能良好的野生型小鼠和免疫缺陷小鼠中，通过监测野生型小鼠与免疫缺陷小鼠中肿瘤的生长，可以识别出在免疫系统完善的情况下，肿瘤生长所需的基因。
 
 doi: 10.1126/science.abg5784.
 
结果出乎意料的是，在野生型小鼠肿瘤中发现了更多的抑癌基因突变富集。这就说明，宿主完善的免疫系统促使了肿瘤细胞的适应性改变，这种改变的结果就是抑癌基因的突变失活。
 
为了说明抑癌基因的显著变化是因为免疫系统才出现的，研究人员还比较了传统2D培养的肿瘤细胞系，这种培养体系中没有免疫细胞的加入。结果更加表明，如果没有完善的免疫系统的帮助，肿瘤细胞中抑癌基因突变不会富集得如此明显。
 
doi: 10.1126/science.abg5784.
 
这个结果说明，免疫系统的压力会使得肿瘤细胞得到更强的生存能力，也可以说，免疫系统是肿瘤的帮凶。这个结论颠覆了以往的观点，也更加表明肿瘤细胞具有强大的适应能力。
 
接下来，研究人员换用结肠癌细胞进行了下一步实验，目的是想证明免疫系统“助纣为虐”的现象在多数肿瘤中都是存在的。结果证实了作者的猜想，野生型小鼠中突变的抑癌基因富集了几乎12倍，在免疫缺陷小鼠中仅富集了1.8倍。
 
doi: 10.1126/science.abg5784.
 
下一步，研究人员以抑癌基因 GNA13为例，试图说明免疫和抑癌基因间的关联机制。他们发现，当GNA13下降时，趋化因子CCL2的分泌会增加。CCL2是一种已知的骨髓细胞募集剂，可以招募M2巨噬细胞和骨髓源性抑制细胞，而它们都有促进肿瘤的作用。
 
体内实验发现，与对照相比，GNA13敲除的肿瘤在免疫缺陷小鼠中生长时，其生长速度没有明显变化。但在野生型小鼠中，GNA13敲除则显著促进了肿瘤的生长。这些结果支持GNA13的失活通过调节免疫而发挥促肿瘤功能。
doi: 10.1126/science.abg5784.
 
另有一些基因如Cul3，体外发现其突变失活后肿瘤的生长会减慢，但在野生型动物中这种失活突变却被肿瘤所青睐，因为它对免疫逃逸有积极作用。这些发现说明了，在免疫细胞的参与下，抑癌基因对整体肿瘤的存活可能有相反的影响。
 
看到这里，大家一定好奇，免疫系统是如何导致抑癌基因突变的富集呢？
 
可惜的是，对于这个问题，目前仍然没有答案。
但至少我们可以肯定的是，一味地增强免疫并不是最佳的抗癌手段，肿瘤具有很强的适应能力，甚至会化敌为友。
 
doi: 10.1126/science.abl5376.
 
这项研究的深刻启发是，肿瘤研究不能忽视细胞间的相互作用。传统的2D培养和裸鼠实验具有很大的局限性，甚至会导致错误结论。
 
抑癌基因与免疫微环境也不是割裂开来的，未来的研究更需要整体观和系统的方法。
 
另外，经典的免疫疗法在某些肿瘤中效果不理想，这篇文章开拓了免疫治疗的视野，提示我们，免疫检查点抑制剂联合一些抑癌基因的靶向治疗或许会有意想不到的效果。
 
参考文献
1.Martin TD, et al. The adaptive immune system is a major driver of selection for tumor suppressor gene inactivation. Science. 2021; 373(6561):1327-1335. doi: 10.1126/science.abg5784.
2.Ho WJ, et al. Opposing roles of the immune system in tumors. Science. 2021; 373(6561):1306-1307. doi: 10.1126/science.abl5376.

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    2021-09-28 jichang

    #SCIE#

    0

  2. [GetPortalCommentsPageByObjectIdResponse(id=1376354, encodeId=9b6c13e63549c, content=<a href='/topic/show?id=2949159989d' target=_blank style='color:#2F92EE;'>#SCIE#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=25, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=15998, encryptionId=2949159989d, topicName=SCIE)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=17a3387, createdName=jichang, createdTime=Tue Sep 28 00:39:26 CST 2021, time=2021-09-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1054938, encodeId=b1611054938d3, content=涨知识了, beContent=null, objectType=article, channel=null, level=null, likeNumber=52, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=16705611430, createdName=ms5000000315862721, createdTime=Sun Sep 26 11:25:29 CST 2021, time=2021-09-26, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1054936, encodeId=c85f10549369f, content=开拓眼界，看来任何事情都是有的度，增加免疫力也是。, beContent=null, objectType=article, channel=null, level=null, likeNumber=55, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=ace25259634, createdName=147fc793m53(暂无昵称), createdTime=Sun Sep 26 11:16:59 CST 2021, time=2021-09-26, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1054949, encodeId=f752105494971, content=真心不错, beContent=null, objectType=article, channel=null, level=null, likeNumber=53, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20210926/57c8060194d54470bb9443e19539b764/7a2369c8edb7447499c3f8ffe1750477.jpg, createdBy=8edf5615057, createdName=ms2000000198716627, createdTime=Sun Sep 26 12:40:47 CST 2021, time=2021-09-26, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1054941, encodeId=0d4910549413c, content=不错, beContent=null, objectType=article, channel=null, level=null, likeNumber=56, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=8cde5515465, createdName=doctor.lin, createdTime=Sun Sep 26 11:51:11 CST 2021, time=2021-09-26, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1054897, encodeId=a7b0105489e5d, content=观点独特, beContent=null, objectType=article, channel=null, level=null, likeNumber=48, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=92a11943582, createdName=ALY, createdTime=Sun Sep 26 09:59:39 CST 2021, time=2021-09-26, status=1, ipAttribution=)]
    2021-09-26 ms5000000315862721

    涨知识了

    0

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    2021-09-26 147fc793m53(暂无昵称)

    开拓眼界，看来任何事情都是有的度，增加免疫力也是。

    0

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    2021-09-26 ms2000000198716627

    真心不错

    0

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    2021-09-26 doctor.lin

    不错

    0

  6. [GetPortalCommentsPageByObjectIdResponse(id=1376354, encodeId=9b6c13e63549c, content=<a href='/topic/show?id=2949159989d' target=_blank style='color:#2F92EE;'>#SCIE#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=25, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=15998, encryptionId=2949159989d, topicName=SCIE)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=17a3387, createdName=jichang, createdTime=Tue Sep 28 00:39:26 CST 2021, time=2021-09-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1054938, encodeId=b1611054938d3, content=涨知识了, beContent=null, objectType=article, channel=null, level=null, likeNumber=52, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=16705611430, createdName=ms5000000315862721, createdTime=Sun Sep 26 11:25:29 CST 2021, time=2021-09-26, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1054936, encodeId=c85f10549369f, content=开拓眼界，看来任何事情都是有的度，增加免疫力也是。, beContent=null, objectType=article, channel=null, level=null, likeNumber=55, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=ace25259634, createdName=147fc793m53(暂无昵称), createdTime=Sun Sep 26 11:16:59 CST 2021, time=2021-09-26, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1054949, encodeId=f752105494971, content=真心不错, beContent=null, objectType=article, channel=null, level=null, likeNumber=53, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20210926/57c8060194d54470bb9443e19539b764/7a2369c8edb7447499c3f8ffe1750477.jpg, createdBy=8edf5615057, createdName=ms2000000198716627, createdTime=Sun Sep 26 12:40:47 CST 2021, time=2021-09-26, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1054941, encodeId=0d4910549413c, content=不错, beContent=null, objectType=article, channel=null, level=null, likeNumber=56, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=8cde5515465, createdName=doctor.lin, createdTime=Sun Sep 26 11:51:11 CST 2021, time=2021-09-26, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1054897, encodeId=a7b0105489e5d, content=观点独特, beContent=null, objectType=article, channel=null, level=null, likeNumber=48, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=92a11943582, createdName=ALY, createdTime=Sun Sep 26 09:59:39 CST 2021, time=2021-09-26, status=1, ipAttribution=)]
    2021-09-26 ALY

    观点独特

    0