PDF(Pubmed)
Abstract：
Type I interferon (IFN-I) and IFN-γ foster antitumor immunity by facilitating T cell responses. Paradoxically, IFNs may promote T cell exhaustion by activating immune checkpoints. The downstream regulators of these disparate responses are incompletely understood. Here, we describe how interferon regulatory factor 1 (IRF1) orchestrates these opposing effects of IFNs. IRF1 expression in tumor cells blocks Toll-like receptor- and IFN-I-dependent host antitumor immunity by preventing interferon-stimulated gene (ISG) and effector programs in immune cells. In contrast, expression of IRF1 in the host is required for antitumor immunity. Mechanistically, IRF1 binds distinctly or together with STAT1 at promoters of immunosuppressive but not immunostimulatory ISGs in tumor cells. Overexpression of programmed cell death ligand 1 (PD-L1) in Irf1-/- tumors only partially restores tumor growth, suggesting multifactorial effects of IRF1 on antitumor immunity. Thus, we identify that IRF1 expression in tumor cells opposes host IFN-I- and IRF1-dependent antitumor immunity to facilitate immune escape and tumor growth.
摘要：
I型干扰素(IFN-I)和IFN-γ通过促进T细胞应答来促进抗肿瘤免疫。矛盾的是,IFN可以通过激活免疫检查点来促进T细胞耗尽。这些完全不同的响应的下游调节器还没有被完全理解。这里,我们描述了干扰素调节因子1(IRF1)如何协调IFN的这些相反作用.肿瘤细胞中的IRF1表达通过阻止免疫细胞中干扰素刺激的基因（ISG）和效应程序来阻断Toll样受体和IFN-I依赖性宿主抗肿瘤免疫。相比之下,IRF1在宿主中的表达是抗肿瘤免疫所必需的。机械上,IRF1在肿瘤细胞中的免疫抑制而非免疫刺激ISG的启动子处明显结合或与STAT1结合。在Irf1-/-肿瘤中程序性细胞死亡配体1（PD-L1）的过表达仅部分恢复肿瘤生长，提示IRF1对抗肿瘤免疫的多因素作用。因此，我们确定IRF1在肿瘤细胞中的表达与宿主IFN-I和IRF1依赖性抗肿瘤免疫相反，以促进免疫逃逸和肿瘤生长。
