Lee Jaewoo, Lee Youngju, Xu Li, White Rebekah, Sullenger Bruce A
Department of Surgery, Duke University, Durham, NC 27710, USA; Duke Translational Research Institute, Duke University, Durham, NC 27710, USA.
Department of Surgery, Duke University, Durham, NC 27710, USA; Duke Translational Research Institute, Duke University, Durham, NC 27710, USA.
Mol Ther. 2017 Jun 7;25(6):1295-1305. doi: 10.1016/j.ymthe.2017.03.014. Epub 2017 Mar 31.
Activation of the RNA-sensing pattern recognition receptor (PRR) in cancer cells leads to cell death and cytokine expression. This cancer cell death releases tumor antigens and damage-associated molecular patterns (DAMPs) that induce anti-tumor immunity. However, these cytokines and DAMPs also cause adverse inflammatory and thrombotic complications that can limit the overall therapeutic benefits of PRR-targeting anti-cancer therapies. To overcome this problem, we generated and evaluated two novel and distinct ssRNA molecules (immunogenic cell-killing RNA [ICR]2 and ICR4). ICR2 and ICR4 differentially stimulated cell death and PRR signaling pathways and induced different patterns of cytokine expression in cancer and innate immune cells. Interestingly, DAMPs released from ICR2- and ICR4-treated cancer cells had distinct patterns of stimulation of innate immune receptors and coagulation. Finally, ICR2 and ICR4 inhibited in vivo tumor growth as effectively as poly(I:C). ICR2 and ICR4 are potential therapeutic agents that differentially induce cell death, immune stimulation, and coagulation when introduced into tumors.
癌细胞中RNA传感模式识别受体（PRR）的激活会导致细胞死亡和细胞因子表达。这种癌细胞死亡会释放肿瘤抗原和损伤相关分子模式（DAMP），从而诱导抗肿瘤免疫。然而，这些细胞因子和DAMP也会引起不良的炎症和血栓形成并发症，这可能会限制靶向PRR的抗癌疗法的总体治疗益处。为了克服这个问题，我们生成并评估了两种新型且不同的单链RNA分子（免疫原性细胞杀伤RNA [ICR]2和ICR4）。ICR2和ICR4以不同方式刺激细胞死亡和PRR信号通路，并在癌细胞和先天免疫细胞中诱导不同的细胞因子表达模式。有趣的是，从经ICR2和ICR4处理的癌细胞释放的DAMP对先天免疫受体和凝血的刺激模式不同。最后，ICR2和ICR4在体内抑制肿瘤生长的效果与聚肌胞苷酸（poly(I:C)）一样有效。ICR2和ICR4是潜在的治疗剂，当引入肿瘤时，它们会以不同方式诱导细胞死亡、免疫刺激和凝血。
