TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis
TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis
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DOI：
10.1038/nature25492
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发表时间：
2018-02-22
期刊：
影响因子：
64.8
通讯作者：
Batlle, Eduard
中科院分区：
文献类型：
--
作者：
Tauriello, Daniele V. F.;Palomo-Ponce, Sergio;Batlle, Eduard
大多数结直肠癌患者死于疾病扩散到其他器官的结果。然而，尚未发现与转移性结直肠癌相关的流行突变(1，2)。相反，肿瘤微环境的特殊特征，如缺乏T细胞渗透(3)、1型T辅助细胞(T(H)1)活性低和免疫细胞毒性降低(2)或转化生长因子β水平升高(4)预测了结直肠癌患者的不良结局。在这里，我们通过携带肠道干细胞中四种主要结直肠癌突变的条件等位基因的小鼠，分析了遗传变化和肿瘤微环境之间的相互作用。四重突变小鼠出现转移性肠道肿瘤，表现出人类微卫星稳定型结直肠癌的关键特征，包括低突变负担(5)、T细胞排斥(3)和转化生长因子β激活的间质(4、6、7)。抑制PD-1-PD-L1免疫检查点在该模型系统中引起有限的反应。相比之下，抑制转化生长因子β释放出强大而持久的细胞毒性T细胞对肿瘤细胞的反应，从而防止转移。在进行性肝转移疾病的小鼠中，阻断转化生长因子β信号使肿瘤对抗PD-1-PD-L1治疗敏感。我们的数据显示，肿瘤微环境中转化生长因子β的增加代表了免疫逃避的主要机制，促进了T细胞排斥并阻止了Thi效应表型的获得。因此，针对转化生长因子β信号的免疫疗法可能在治疗晚期结直肠癌患者中有广泛的应用。
Most patients with colorectal cancer die as a result of the disease spreading to other organs. However, no prevalent mutations have been associated with metastatic colorectal cancers(1,2). Instead, particular features of the tumour microenvironment, such as lack of T-cell infiltration(3), low type 1 T-helper cell (T(H)1) activity and reduced immune cytotoxicity(2) or increased TGF beta levels(4) predict adverse outcomes in patients with colorectal cancer. Here we analyse the interplay between genetic alterations and the tumour microenvironment by crossing mice bearing conditional alleles of four main colorectal cancer mutations in intestinal stem cells. Quadruple-mutant mice developed metastatic intestinal tumours that display key hallmarks of human microsatellite-stable colorectal cancers, including low mutational burden(5), T-cell exclusion(3) and TGF beta-activated stroma(4,6,7). Inhibition of the PD-1-PD-L1 immune checkpoint provoked a limited response in this model system. By contrast, inhibition of TGF beta unleashed a potent and enduring cytotoxic T-cell response against tumour cells that prevented metastasis. In mice with progressive liver metastatic disease, blockade of TGF beta signalling rendered tumours susceptible to anti-PD-1-PD-L1 therapy. Our data show that increased TGF beta in the tumour microenvironment represents a primary mechanism of immune evasion that promotes T-cell exclusion and blocks acquisition of the THI-effector phenotype. Immunotherapies directed against TGF beta signalling may therefore have broad applications in treating patients with advanced colorectal cancer.