Princess Margaret Cancer Center, University Health Network, Toronto, ON, M5G 2M9 Canada.
Princess Margaret Cancer Center, University Health Network, Toronto, ON, M5G 2M9 Canada.
Immunity. 2022 Dec 13;55(12):2369-2385.e10. doi: 10.1016/j.immuni.2022.10.020. Epub 2022 Nov 11.
Type I and II interferons (IFNs) stimulate pro-inflammatory programs that are critical for immune activation, but also induce immune-suppressive feedback circuits that impede control of cancer growth. Here, we sought to determine how these opposing programs are differentially induced. We demonstrated that the transcription factor interferon regulatory factor 2 (IRF2) was expressed by many immune cells in the tumor in response to sustained IFN signaling. CD8 T cell-specific deletion of IRF2 prevented acquisition of the T cell exhaustion program within the tumor and instead enabled sustained effector functions that promoted long-term tumor control and increased responsiveness to immune checkpoint and adoptive cell therapies. The long-term tumor control by IRF2-deficient CD8 T cells required continuous integration of both IFN-I and IFN-II signals. Thus, IRF2 is a foundational feedback molecule that redirects IFN signals to suppress T cell responses and represents a potential target to enhance cancer control.
I 型和 II 型干扰素（IFNs）刺激促炎程序，这对免疫激活至关重要，但也诱导免疫抑制反馈回路，阻碍对癌症生长的控制。在这里，我们试图确定这些相反的程序是如何被不同诱导的。我们证明，转录因子干扰素调节因子 2（IRF2）在肿瘤中被许多免疫细胞表达，以响应持续的 IFN 信号。CD8 T 细胞特异性缺失 IRF2 可防止肿瘤内 T 细胞衰竭程序的获得，而是能够维持效应功能，促进长期肿瘤控制，并增加对免疫检查点和过继细胞疗法的反应性。IRF2 缺陷的 CD8 T 细胞的长期肿瘤控制需要持续整合 IFN-I 和 IFN-II 信号。因此，IRF2 是一种基础性的反馈分子，它将 IFN 信号重定向以抑制 T 细胞反应，代表了增强癌症控制的潜在靶点。
