Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity
Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity
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DOI：
10.1038/nature14404
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发表时间：
2015-07-09
期刊：
影响因子：
64.8
通讯作者：
Gajewski, Thomas F.
中科院分区：
文献类型：
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作者：
Spranger, Stefani;Bao, Riyue;Gajewski, Thomas F.
随着有效免疫治疗方法的发展，黑色素瘤的治疗正在发生革命性的变化(1，2)。这些策略包括阻断激活的T细胞上的免疫抑制受体；例如，使用抗CTLA-4、PD-1和PD-L1的单抗(参考文献3-5)。然而，只有一小部分患者对这些治疗有反应，数据表明，先前存在针对肿瘤的T细胞反应的患者优先获得治疗益处，肿瘤微环境中的基线CD8(+)T细胞渗透证明了这一点(6，7)。因此，了解在部分病例中存在或不存在自发的抗肿瘤T细胞反应的分子机制，应该能够为缺乏T细胞浸润的患者开发治疗方案。在这里，我们确定了一种黑色素瘤细胞固有的致癌途径，导致黑色素瘤中缺乏T细胞的渗透。对人类转移性黑色素瘤样本的分子分析显示，WNT/β-连环蛋白信号通路的激活与T细胞基因表达特征的缺失之间存在相关性。利用自体小鼠黑色素瘤模型(8，9)，我们确定了肿瘤固有的活性β-连环蛋白信号导致T细胞排斥和对抗PD-L1/抗CTLA-4单抗治疗产生抵抗的机制。因此，特定的致癌信号可以介导癌症免疫逃避和对免疫疗法的抵抗，为免疫增强指明了新的候选靶点。
Melanoma treatment is being revolutionized by the development of effective immunotherapeutic approaches(1,2). These strategies include blockade of immune-inhibitory receptors on activated T cells; for example, using monoclonal antibodies against CTLA-4, PD-1, and PD-L1 (refs 3-5). 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 microenvironment(6,7). 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/beta-catenin signalling pathway and absence of a T-cell gene expression signature. Using autochthonous mouse melanoma models(8,9) we identified the mechanism by which tumour-intrinsic active beta-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.