为了使癌症进展，它们必须逃避 CD8 T 细胞或其他免疫机制的消除。 CD8 T 细胞识别并杀死展示与 MHC I 分子结合的免疫原性肿瘤肽的肿瘤细胞。癌症逃避这种杀伤的方法之一是减少 MHC I 分子的表达，并且在肿瘤中经常观察到 MHC I 的丢失。肿瘤上 MHC I 复合物的丢失有多种不同的机制，目前尚不清楚是否存在经常发生的特定机制，如果存在，则在什么类型的癌症中发生。同样重要的是要了解 MHC I 的损失是否是可逆的，以及这种损失和/或其恢复将如何影响对免疫治疗的反应。在这里，我们研究了 IRF1 和 IRF2 丢失的问题，IRF1 和 IRF2 是驱动 MHC I 途径基因表达和一些杀伤机制的转录因子。对 TCGA RNAseq 中的所有人类癌症进行了 IRF2 和 IRF2 依赖性基因转录本的生物信息学分析数据库。 IRF2 蛋白-DNA 结合在 ChIPseq 数据库中进行分析。 CRISRPcas9 用于敲除人类和小鼠黑色素瘤细胞中的 IRF1 和 IRF2 基因，并在体外和体内分析所得表型。转录组分析显示，在几乎所有类型的人类癌症中，相当一部分病例中 IRF2 表达均降低。当这种情况发生时，CD8 T 细胞识别所需的 IRF2 调节基因的表达会相应减少。为了测试这些 IRF2 相关性的因果关系以及 IRF2 丢失的后果，我们对源自患者的黑色素瘤和小鼠黑色素瘤中的 IRF2 进行了基因编辑。 IRF2 基因编辑的黑色素瘤减少了 MHC I 通路中基因转录物的表达，并降低了细胞表面 MHC I 复合物的水平。 Caspase 7（一种参与 CD8 T 细胞杀伤肿瘤的 IRF2 靶基因）的水平也降低了。 IRF2 的缺失导致人类和小鼠黑色素瘤对检查点抑制剂的免疫治疗产生耐药性。重要的是，这些影响是可逆的。用干扰素刺激 IRF2 缺陷的黑色素瘤诱导功能同源转录因子 IRF1 的表达，然后恢复 MHC I 通路和对 CPI 的反应。我们的研究表明，大多数类型癌症中的一部分病例下调 IRF2，并且这可以让癌症逃脱免疫控制。这可能会导致对检查点阻断免疫疗法的耐药性，并且用目前可用的生物制剂是可逆的。

In order for cancers to progress, they must evade elimination by CD8 T cells or other immune mechanisms. CD8 T cells recognize and kill tumor cells that display immunogenic tumor peptides bound to MHC I molecules. One of the ways that cancers can escape such killing is by reducing expression of MHC I molecules, and loss of MHC I is frequently observed in tumors. There are multiple different mechanisms that can underly the loss of MHC I complexes on tumor and it is currently unclear whether there are particular mechanisms that occur frequently and, if so, in what types of cancers. Also of importance to know is whether the loss of MHC I is reversible and how such loss and/or its restoration would impact responses to immunotherapy. Here, we investigate these issues for loss of IRF1 and IRF2, which are transcription factors that drive expression of MHC I pathway genes and some killing mechanisms.Bioinformatics analyses of IRF2 and IRF2-dependent gene transcripts were performed for all human cancers in the TCGA RNAseq database. IRF2 protein-DNA-binding was analyzed in ChIPseq databases. CRISRPcas9 was used to knock out IRF1 and IRF2 genes in human and mouse melanoma cells and the resulting phenotypes were analyzed in vitro and in vivo.Transcriptomic analysis revealed that IRF2 expression was reduced in a substantial subset of cases in almost all types of human cancers. When this occurred there was a corresponding reduction in the expression of IRF2-regulated genes that were needed for CD8 T cell recognition. To test cause and effect for these IRF2 correlations and the consequences of IRF2 loss, we gene-edited IRF2 in a patient-derived melanoma and a mouse melanoma. The IRF2 gene-edited melanomas had reduced expression of transcripts for genes in the MHC I pathway and decreased levels of MHC I complexes on the cell surface. Levels of Caspase 7, an IRF2 target gene involved in CD8 T cell killing of tumors, were also reduced. This loss of IRF2 caused both human and mouse melanomas to become resistant to immunotherapy with a checkpoint inhibitor. Importantly, these effects were reversible. Stimulation of the IRF2-deficient melanomas with interferon induced the expression of a functionally homologous transcription factor, IRF1, which then restored the MHC I pathway and responsiveness to CPI.Our study shows that a subset of cases within most types of cancers downregulates IRF2 and that this can allow cancers to escape immune control. This can cause resistance to checkpoint blockade immunotherapy and is reversible with currently available biologics.