肿瘤细胞治疗研究
英文原题：Bacterial RNA downregulates MHC-I in tumor cell lines, promoting NK response and delaying tumor growth.
我们建立的MHC-I下调模型（通过bacRNA或合成hTLR8激动剂）可作为促进抗肿瘤反应的治疗策略。
免疫治疗开启了癌症治疗的新时代。癌症免疫治疗的临床目标是激活宿主免疫系统，以提供针对恶性肿瘤的被动或主动免疫。我们此前已证明，流产布鲁氏菌（Ba）RNA 通过 TLR8 依赖机制下调人单核细胞/巨噬细胞中 IFN- 诱导的 MHC-I 表面表达。其他细菌 RNA 可以模拟这一现象。肿瘤中 NK 细胞的存在和活性与患者更好的生存相关，这支持了这些细胞在抗肿瘤免疫应答中至关重要的证据。因此，我们推测细菌 RNA（bacRNA）可用于调节肿瘤中的 MHC-I 表达，以增强 NK 细胞应答。因此，本研究的目的是探讨 bacRNA 在实体瘤中的免疫调节作用。我们首先在 IFN- 存在下，用 bacRNA 刺激人胶质母细胞瘤 U251 和 LN-229、结直肠腺癌 HT-29、乳腺癌 MCF-7 以及小鼠黑色素瘤 B16-OVA 细胞。我们的实验表明，bacRNA 降低了所有肿瘤细胞系中 IFN- 诱导的 MHC-I 表面表达。此外，hTLR8 激动剂 ORN06/LyoVec 模拟了 bacRNA 的作用，表明 MHC-I 的降低可能由 TLR8 介导。另外，bacRNA 介导的 MHC-I 减少与 NK 细胞毒性增加相关。最后，与未处理小鼠相比，使用 bacRNA 或 ORN06 激动剂治疗导致肿瘤内免疫细胞浸润和活化增加。此外，bacRNA 在 B16 黑色素瘤模型中延缓了肿瘤生长。总体而言，我们建立的 MHC-I 下调模型（通过 bacRNA 或合成 hTLR8 激动剂）可作为促进抗肿瘤应答的治疗策略。
Immunotherapy has introduced a new era in cancer treatment. The clinical goal of cancer immunotherapy is to prime the host immune system to provide passive or active immunity against malignant tumors. We have previously demonstrated that Brucella abortus (Ba) RNA downregulates IFN- -induced MHC-I surface expression in human monocytes/macrophages via a TLR8-dependent mechanism. Other bacterial RNAs can mimic this phenomenon. The presence and activity of NK cells in tumors have been correlated with better patient survival, supporting the evidence that these cells are essential in the immune response against tumors. So, we postulated that bacterial RNA (bacRNA) can be used to modulate MHC-I expression in tumors to enhance the NK cell response. Hence, the aim of this study was to investigate the immunomodulatory role of bacRNA in solid tumors. We first stimulated human glioblastomas U251 and LN-229, colorectal adenocarcinoma HT-29, breast cancer MCF-7, and murine melanoma B16-OVA cells with bacRNA in the presence of IFN- . Our experiments demonstrated that bacRNA diminished IFN- -induced MHC-I surface expression in all tumor cell lines. Moreover, the hTLR8 agonist ORN06/LyoVec mimicked the effect of bacRNA, indicating that MHC-I reduction would be mediated by TLR8. In addition, the decrease in MHC-I mediated by bacRNA correlated with increased NK cytotoxicity. Finally, treatment with either bacRNA or the ORN06 agonist resulted in greater immune cell infiltration and activation within the tumor compared to untreated mice. Furthermore, bacRNA delayed tumor growth in the B16 melanoma model. Overall, our established model of MHC-I downregulation (either by bacRNA or synthetic hTLR8 agonists) could be used as a therapeutic strategy to promote anti-tumor responses.
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