Pattarayan Dhamotharan, Wang Yue, Wang Zehua, Li Sihan, Wang Xiaofei, Chen Yuang, Wang Yifei, Chen Chien-Yu, Bhuniya Avishek, Yadav Ghanshyam Singh, Xie Wen, Kammula Udai S, Li Song, Zhang Min, Yang Da
Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA.
UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Sci Signal. 2025 Aug 12;18(899):eadr9131. doi: 10.1126/scisignal.adr9131.
Increases in retroelement-derived double-stranded RNAs (dsRNAs) in various types of cancer cells facilitate the activation of antitumor immune responses. The long noncoding RNA EPIC1 interacts with the histone methyltransferase EZH2 and contributes to tumor immune evasion. Here, we found that EPIC1 in tumor cells suppressed cytoplasmic dsRNA accumulation, type I interferon (IFN) responses, and antitumor immunity. In various cancer cell lines, knockdown of EPIC1 stimulated the production of dsRNA from retroelements and an antiviral-like type I IFN response that activated immune cells. EPIC1 inhibited the expression of LINE, SINE, and LTR retroelements that were also repressed by EZH2, suggesting a potential role for the EPIC1-EZH2 interaction in regulating dsRNA production. In a humanized mouse model, in vivo delivery of EPIC1-targeting oligonucleotides enhanced dsRNA accumulation in breast cancer xenografts, reduced tumor growth, and increased the infiltration of T cells and inflammatory macrophages into tumors. Furthermore, EPIC1 knockdown improved the therapeutic efficacy of the immunotherapy drug pembrolizumab, a PD-1 inhibitor, in the humanized mouse model. Together, our findings establish EPIC1 as a key regulator of dsRNA-mediated type I IFN responses and highlight its potential as a therapeutic target to improve the efficacy of immunotherapy.
各种类型癌细胞中逆转录元件衍生的双链RNA（dsRNA）增加有助于激活抗肿瘤免疫反应。长链非编码RNA EPIC1与组蛋白甲基转移酶EZH2相互作用，促进肿瘤免疫逃逸。在此，我们发现肿瘤细胞中的EPIC1抑制细胞质dsRNA积累、I型干扰素（IFN）反应和抗肿瘤免疫。在各种癌细胞系中，敲低EPIC1可刺激逆转录元件产生dsRNA，并激活免疫细胞的抗病毒样I型IFN反应。EPIC1抑制了LINE、SINE和LTR逆转录元件的表达，这些元件也受到EZH2的抑制，这表明EPIC1-EZH2相互作用在调节dsRNA产生中具有潜在作用。在人源化小鼠模型中，体内递送靶向EPIC1的寡核苷酸可增强乳腺癌异种移植瘤中的dsRNA积累，减少肿瘤生长，并增加T细胞和炎性巨噬细胞向肿瘤的浸润。此外，在人源化小鼠模型中，敲低EPIC1可提高免疫治疗药物帕博利珠单抗（一种PD-1抑制剂）的治疗效果。总之，我们的研究结果确定EPIC1是dsRNA介导的I型IFN反应的关键调节因子，并突出了其作为改善免疫治疗疗效的治疗靶点的潜力。
