IFN-γ is required for cytotoxic T cell-dependent cancer genome immunoediting.
IFN-γ is required for cytotoxic T cell-dependent cancer genome immunoediting.
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DOI：
10.1038/ncomms14607
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发表时间：
2017-02-24
影响因子：
16.6
通讯作者：
Smyth MJ
中科院分区：
文献类型：
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作者：
Takeda K;Nakayama M;Hayakawa Y;Kojima Y;Ikeda H;Imai N;Ogasawara K;Okumura K;Thomas DM;Smyth MJ
在癌症进展期间发生的遗传进化使肿瘤异质性成为可能，从而促进肿瘤适应性、治疗抗性和转移潜力。已知免疫应答选择（免疫编辑）显示免疫逃避特性的肿瘤细胞。在这里，我们解决了IFN-γ在介导免疫编辑过程中的作用。我们观察到，在几种小鼠肿瘤模型中，例如表达HA的4 T1乳腺癌细胞、表达OVA的EG 7淋巴瘤细胞和天然表达突变的细胞外信号调节激酶（ERK）抗原的CMS 5 MCA诱导的纤维肉瘤细胞，抗原特异性细胞毒性T细胞（CTL）的体内作用仅在肿瘤微环境中存在IFN-γ的情况下导致耐药癌细胞克隆的出现。此外，我们表明，肿瘤暴露于体内产生IFN-γ的抗原特异性CTL会导致与DNA损伤反应和DNA编辑/修复基因表达调节相关的拷贝数改变（CNA）。这些结果表明，增强的遗传不稳定性可能是CTL和IFN-γ免疫编辑肿瘤的机制之一，由于遗传进化而改变了它们的免疫抗性。T细胞介导的抗肿瘤免疫应答导致在称为免疫编辑的过程中出现免疫抗性群体。在这里，作者表明免疫编辑与肿瘤细胞基因组重排的增加有关，这需要细胞毒性T细胞和IFNγ暴露。
Genetic evolution that occurs during cancer progression enables tumour heterogeneity, thereby fostering tumour adaptation, therapeutic resistance and metastatic potential. Immune responses are known to select (immunoedit) tumour cells displaying immunoevasive properties. Here we address the role of IFN-γ in mediating the immunoediting process. We observe that, in several mouse tumour models such as HA-expressing 4T1 mammary carcinoma cells, OVA-expressing EG7 lymphoma cells and CMS5 MCA-induced fibrosarcoma cells naturally expressing mutated extracellular signal-regulated kinase (ERK) antigen, the action of antigen-specific cytotoxic T cell (CTL) in vivo results in the emergence of resistant cancer cell clones only in the presence of IFN-γ within the tumour microenvironment. Moreover, we show that exposure of tumours to IFN-γ-producing antigen-specific CTLs in vivo results in copy-number alterations (CNAs) associated with DNA damage response and modulation of DNA editing/repair gene expression. These results suggest that enhanced genetic instability might be one of the mechanisms by which CTLs and IFN-γ immunoedits tumours, altering their immune resistance as a result of genetic evolution. T cell mediated anti-tumour immune responses result in the emergence of an immune-resistant population in a process called immunoediting. Here, the authors show that immunoediting is associated with an increase in genomic rearrangements of tumour cells that requires both cytotoxic T cells and IFNγ exposure.