College of Pharmacy, Seoul National University, Seoul 08826, South Korea; Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, South Korea.
College of Pharmacy, Seoul National University, Seoul 08826, South Korea.
Cell Rep. 2021 Dec 21;37(12):110138. doi: 10.1016/j.celrep.2021.110138.
Tumor DNA-damage response (DDR) has an important role in driving type-I interferon (IFN)-mediated host antitumor immunity, but it is not clear how tumor DNA damage is interconnected with the immune response. Here, we report the role of IFN-γ-inducible protein 16 (IFI16) in DNA repair, which amplifies the stimulator of IFN genes (STING)-type-I IFN signaling, particularly in triple-negative breast cancer (TNBC). IFI16 is rapidly induced and accumulated to the histone-evicted DNA at double-stranded breakage (DSB) sites, where it inhibits recruitment of DDR factors. Subsequently, IFI16 increases the release of DNA fragments to the cytoplasm and induces STING-mediated type-I IFN production. Synergistic cytotoxic and immunomodulatory effects of doxorubicin and type-I IFNs are decreased upon IFI16 depletion in vivo. Furthermore, IFI16 expression correlates with improved clinical outcome in patients with TNBC treated with chemotherapy. Together, our findings suggest that type-I IFNs and IFI16 could offer potential therapeutic strategies for TNBC.
肿瘤 DNA 损伤反应 (DDR) 在驱动 I 型干扰素 (IFN) 介导的宿主抗肿瘤免疫中起着重要作用，但尚不清楚肿瘤 DNA 损伤如何与免疫反应相互关联。在这里，我们报告了 IFN-γ诱导蛋白 16 (IFI16) 在 DNA 修复中的作用，它可放大干扰素基因刺激物 (STING)-I 型 IFN 信号，特别是在三阴性乳腺癌 (TNBC) 中。IFI16 被快速诱导并积累到双链断裂 (DSB) 部位的组蛋白逐出的 DNA 上，在那里它抑制 DDR 因子的募集。随后，IFI16 增加 DNA 片段向细胞质的释放，并诱导 STING 介导的 I 型 IFN 产生。在体内敲除 IFI16 后，阿霉素和 I 型 IFN 的协同细胞毒性和免疫调节作用降低。此外，IFI16 的表达与接受化疗治疗的 TNBC 患者的临床预后改善相关。总之，我们的研究结果表明，I 型 IFN 和 IFI16 可为 TNBC 提供潜在的治疗策略。
