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.

中文翻译：

---

IFN-γ是细胞毒性T细胞依赖性癌症基因组免疫编辑所必需的。

在癌症进展过程中发生的遗传进化使肿瘤具有异质性，从而促进了肿瘤适应性，治疗抗性和转移潜力。已知免疫反应会选择（免疫编辑）表现出免疫逃避特性的肿瘤细胞。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，例如表达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自然表达突变的细胞外信号调节激酶（ERK）抗原，抗原-仅在肿瘤微环境中存在IFN-γ的情况下，体内特异性细胞毒性T细胞（CTL）才会导致耐药性癌细胞克隆的出现。而且，我们表明，体内肿瘤暴露于产生IFN-γ的抗原特异性CTL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变化（CNA）。这些结果表明，遗传不稳定性的增强可能是CTL和IFN-γ免疫编辑肿瘤，改变其免疫抵抗力的机制之一，这是遗传进化的结果。