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>> Nature:&肿瘤免疫治疗新靶点：Wnt/beta-catenin
Nature:&肿瘤免疫治疗新靶点：Wnt/beta-catenin
来源：生物谷
日讯/生物谷BIOON/--5月11日，来自芝加哥大学的研究人员将他们的最新研究成果在线发表在了Nature 杂志上。他们发现，黑色素瘤细胞可以通过产生大量的beta-catenin，从而将它们自己与免疫系统的抗癌前线武器－T细胞屏蔽。他们还发现了，beta-catenin是如何阻止T细胞浸润到肿瘤细胞，从而减弱免疫治疗效果的。最后，研究人员们提出建议，该如何绕开这个障碍。黑色素瘤的治疗在研发出了免疫疗法之后，有了革命性的改观。这些治疗策略包括阻断激活T细胞上的免疫抑制受体，例如，利用抗CTLA-4，PD-1和PD-L1的单 抗。然而，仅仅一部分的患者对这些治疗有效，他们常常是在治疗前，已经存在有T细胞的抗肿瘤反应，因为在肿瘤的微环境中可以检测到CD8T细胞的浸润。而没有T细胞浸润的黑色素瘤患者，常常是对免疫疗法抵抗耐药的。为了研究清楚是什么细胞信号传导通路，破坏了T细胞浸润到黑色素瘤，研究人员们比较了黑色素瘤的病人样本。这些样本中，91名病人是没有T细胞浸润的，106名病人是有T细胞浸润且引发了炎症的。通过对这两组样本的分析，研究人员发现，激活的beta-catenin信号在两组间有最大的差异。49%的无T细胞浸润的样本呈现出高水平的beta-catenin活性，且6个beta-catenin的靶基因也有显著的升高。而在T细胞浸润组，仅4％的肿瘤样本表现出了相似的信号模式。接下来，研究人员利用小鼠黑色素瘤模型发现，beta-catenin高表达的癌症细胞确实是可以阻止T细胞进入到肿瘤的微环境中，而且还可以降低CD103+树突状细胞（DC）的数量。DC细胞是对外来入侵者的清道夫，如病原体或是肿瘤细胞。当DC细胞发现有有害的微生物或是细胞损伤时，它们会把这些危险信号传递到淋巴结，递呈给T细胞，T细胞就会向肿瘤浸润。研究人员发现，没有beta-catenin的肿瘤细胞可以产生免疫信号分子CCL4，这个分子可以吸引CD103+DC。但是，表达高水平beta-catenin的肿瘤细胞可以抑制CCL4 的表达，因此，没有吸引来CD103+DC细胞，也没有T细胞向肿瘤的浸润。最后，研究人员将Flt－3配体诱导的骨髓DC打入无T细胞浸润的小鼠肿瘤模型，对黑色素瘤有一定的治疗效果，但如果再联合使用抗CTLA－4和PD-L1单抗后，抑瘤效果显著增加。这项研究发现，肿瘤内高表达的beta-catenin可能是黑色素瘤抵抗免疫治疗的机制之一。研究结果提示我们，对于那些对免疫治疗抵抗的患者，直接注射病人自身的CD103+DC细胞，或是先利用放疗引起肿瘤的炎症，接下来再联合使用免疫治疗，效果可能会更好。（生物谷)本文系生物谷原创编译整理，欢迎转载！转载请注明来源并附原文链接。更多资讯请下载。谢谢！
doi: 10.1038/nature14404PMC:PMID:Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunityStefani Spranger, Riyue Bao，Thomas F. GajewskiMelanoma treatment is being revolutionized by the development of effective immunotherapeutic approaches. These strategies include blockade of immune-inhibitory receptors on activated T for example, using monoclonal antibodies against CTLA-4, PD-1, and PD-L1. However, only a subset of patients responds to these treatments, and data suggest that therapeutic benefit is preferentially achieved in patients with a pre-existing T-cell response against their tumour, as evidenced by a baseline CD8+ T-cell infiltration within the tumour microenvironment6. Understanding the molecular mechanisms that underlie the presence or absence of a spontaneous anti-tumour T-cell response in subsets of cases, therefore, should enable the development of therapeutic solutions for patients lacking a T-cell infiltrate. Here we identify a melanoma-cell-intrinsic oncogenic pathway that contributes to a lack of T-cell infiltration in melanoma. Molecular analysis of human metastatic melanoma samples revealed a correlation between activation of the WNT/β-catenin signalling pathway and absence of a T-cell gene expression signature. Using autochthonous mouse melanoma models, we identified the mechanism by which tumour-intrinsic active β-catenin signalling results in T-cell exclusion and resistance to anti-PD-L1/anti-CTLA-4 monoclonal antibody therapy. Specific oncogenic signals, therefore, can mediate cancer immune evasion and resistance to immunotherapies, pointing to new candidate targets for immune potentiation.
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