Division of Cell Biology, Biomedical Research Center, Graduate School of Medicine, Juntendo University, Bunkyo-ku, Tokyo 113-8421, Japan.
Department of Biofunctional Micribiota, Graduate School of Medicine, Juntendo University, Bunkyo-ku, Tokyo 113-8421, Japan.
Nat Commun. 2017 Feb 24;8:14607. doi: 10.1038/ncomms14607.
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.
遗传进化在癌症进展过程中发生，使肿瘤具有异质性，从而促进肿瘤适应、治疗抵抗和转移潜能。免疫反应已知会选择具有免疫逃避特性的肿瘤细胞（免疫编辑）。在这里，我们探讨了 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，如表达 HA 的 4T1 乳腺癌细胞、表达 OVA 的 EG7 淋巴瘤细胞和 CMS5 MCA 诱导的纤维肉瘤细胞，这些细胞天然表达突变型细胞外信号调节激酶（ERK）抗原，在肿瘤微环境中存在 IFN-γ 的情况下，抗原特异性细胞毒性 T 细胞（CTL）在体内的作用导致耐药癌细胞克隆的出现。此外，我们还表明，体内暴露于 IFN-γ 产生的抗原特异性 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 编辑肿瘤的机制之一，导致其免疫抵抗因遗传进化而改变。
