The transcription factor IRF2 drives interferon-mediated CD8+ T cell exhaustion to restrict anti-tumor immunity

Type I Interferons (IFN-I) stimulate pro-inflammatory programs critical for immune activation, but also induce immune-suppressive feedback circuits that contribute to the failure of cancer control. Yet, how IFN-Is differentially induce these opposing programs remains enigmatic. We establish that the transcription factor Interferon Regulatory Factor 2 (IRF2) is a central feedback molecule attenuating IFN signaling and driving CD8 T cell exhaustion in the tumor microenvironment. IRF2 inhibits CD8 T cell effector function in response to sustained interferon signaling by programming T cell exhaustion. Lineage-specific deletion of IRF2 limits CD8 T cells exhaustion to maintain effector functions, thereby enabling long-term tumor control, and increased responsiveness to immune-checkpoint and adoptive cell therapies. Long-term tumor control by IRF2-deficient CD8 T cells is dependent on continuous integration of both IFN-I and IFN? signals, which in the absence of IRF2, potentiate sustained effector function instead of exhaustion. Thus, IRF2 redirects IFN signalling to drive T cell exhaustion and prevent tumor control. For AB-Seq experiment, MC38 Tumor-infitrating CD8 T cells from WT (Tumor WT), Irf2-/- (Tumor IRF2KO) mice. For scATAC-Seq experiment, MC38 Tumor-infitrating CD8 T cells from WT (Tumor WT), Irf2-/- (Tumor Irf2-/-) mice, as well as MC38 Tumor-infitrating CD8 T cells from mice that only lack IRF2 expression in the CD8 T cells (termed Tumor CD8-IRF2cKO mice) together with their controls Tumor CD8-IRF2cWT). For CUT&Tag - Naive isolated CD8+ T cells were isolated and invitro activated using anti-CD3 and Anti-CD28 and subjecte to either anti-IRF2 or IgG antibodies.

I型干扰素（Type I Interferons, IFN-I）可激活促炎程序以介导免疫活化，但同时也会诱导免疫抑制性反馈通路，这正是癌症免疫治疗失败的重要诱因之一。然而，IFN-I如何差异性调控这两类相互拮抗的程序至今仍未阐明。本研究证实，转录因子干扰素调节因子2（Interferon Regulatory Factor 2, IRF2）是关键的反馈调控分子，可衰减干扰素信号通路，并在肿瘤微环境中诱导CD8 T细胞耗竭。IRF2通过编程T细胞耗竭，在持续干扰素信号刺激下抑制CD8 T细胞的效应功能。特异性敲除IRF2可限制CD8 T细胞耗竭，维持其效应功能，从而实现长期的肿瘤控制，并提升免疫检查点治疗与过继性细胞治疗的响应性。IRF2缺陷型CD8 T细胞所介导的长期肿瘤控制，依赖于对IFN-I与II型干扰素（IFN-γ）信号的持续整合；在IRF2缺失的情况下，该信号整合会维持持续的效应功能而非诱导T细胞耗竭。综上，IRF2会重定向干扰素信号通路以驱动T细胞耗竭，从而阻碍肿瘤的有效控制。对于AB-Seq实验，样本为野生型（Tumor WT）、Irf2全敲除（Tumor IRF2KO）小鼠的MC38肿瘤浸润CD8 T细胞。针对scATAC-Seq实验，样本包括野生型（Tumor WT）、Irf2全敲除（Tumor Irf2-/-）小鼠的MC38肿瘤浸润CD8 T细胞，以及仅在CD8 T细胞中缺失IRF2表达的小鼠（命名为Tumor CD8-IRF2cKO小鼠），同时设置其对应野生型对照（Tumor CD8-IRF2cWT）。针对CUT&Tag实验：分离初始CD8+ T细胞，体外通过抗CD3与抗CD28抗体激活后，分别使用抗IRF2抗体或IgG抗体进行处理。