Agency for Science, Technology, and Research (A*STAR), Genome Institute of Singapore, 138672 Singapore.
The Sixth Affiliated Hospital, Sun Yat-sen University, 510275 Guangzhou, China.
Proc Natl Acad Sci U S A. 2022 Aug 2;119(31):e2201376119. doi: 10.1073/pnas.2201376119. Epub 2022 Jul 25.
Relapse to anti-HER2 monoclonal antibody (mAb) therapies, such as trastuzumab in HER2 breast cancer (BC), is associated with residual disease progression due to resistance to therapy. Here, we identify interferon-γ inducible protein 16 (IFI16)-dependent STING signaling as a significant determinant of trastuzumab responses in HER2 BC. We show that down-regulation of immune-regulated genes (IRG) is specifically associated with poor survival of HER2, but not other BC subtypes. Among IRG, IFI16 is identified as a direct target of EZH2, the underexpression of which leads to deficient STING activation and downstream CXCL10/11 expression in response to trastuzumab treatment. Dual inhibition of EZH2 and histone deacetylase (HDAC) significantly activates IFI16-dependent immune responses to trastuzumab. Notably, a combination of a novel histone methylation inhibitor with an HDAC inhibitor induces complete tumor eradication and long-term T cell memory in a HER2 BC mouse model. Our findings demonstrate an epigenetic regulatory mechanism suppressing the expression of the IFI16-CXCL10/11 signaling pathway that provides a survival advantage to HER2 BC to confer resistance to trastuzumab treatment.
抗 HER2 单克隆抗体（mAb）治疗的复发，如 HER2 乳腺癌（BC）中的曲妥珠单抗，与因治疗耐药而导致的残留疾病进展有关。在这里，我们确定干扰素-γ诱导蛋白 16（IFI16）依赖性 STING 信号作为曲妥珠单抗在 HER2 BC 中反应的重要决定因素。我们表明，免疫调节基因（IRG）的下调与 HER2 但不是其他 BC 亚型的不良生存特别相关。在 IRG 中，IFI16 被鉴定为 EZH2 的直接靶标，其表达下调导致 STING 激活不足，并导致曲妥珠单抗治疗后 CXCL10/11 的表达减少。EZH2 和组蛋白去乙酰化酶（HDAC）的双重抑制可显著激活曲妥珠单抗治疗的 IFI16 依赖性免疫反应。值得注意的是，新型组蛋白甲基化抑制剂与 HDAC 抑制剂的组合可在 HER2 BC 小鼠模型中诱导完全肿瘤消除和长期 T 细胞记忆。我们的研究结果表明，一种抑制 IFI16-CXCL10/11 信号通路表达的表观遗传调控机制为 HER2 BC 提供了生存优势，从而导致对曲妥珠单抗治疗的耐药性。
