转座元件通过 RIG-I 介导的病毒感应途径增强放射治疗诱导的细胞免疫反应。

Transposable elements potentiate radiotherapy-induced cellular immune reactions via RIG-I-mediated virus-sensing pathways.

机构信息

Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Chiba, Japan.

Division of Radiation Oncology and Particle Therapy, National Cancer Center Hospital East, Chiba, Japan.

出版信息

Commun Biol. 2023 Aug 5;6(1):818. doi: 10.1038/s42003-023-05080-x.

Radiotherapy (RT) plus immunotherapy is a promising modality; however, the therapeutic effects are insufficient, and the molecular mechanism requires clarification to further develop combination therapies. Here, we found that the RNA virus sensor pathway dominantly regulates the cellular immune response in NSCLC and ESCC cell lines. Notably, transposable elements (TEs), especially long terminal repeats (LTRs), functioned as key ligands for the RNA virus sensor RIG-I, and the mTOR-LTR-RIG-I axis induced the cellular immune response and dendritic cell and macrophage infiltration after irradiation. Moreover, RIG-I-dependent immune activation was observed in ESCC patient tissue. scRNA sequencing and spatial transcriptome analysis revealed that radiotherapy induced the expression of LTRs, and the RNA virus sensor pathway in immune and cancer cells; this pathway was also found to mediate tumour conversion to an immunological hot state. Here, we report the upstream and ligand of the RNA virus sensor pathway functions in irradiated cancer tissues.

放射治疗（RT）联合免疫疗法是一种很有前途的治疗方法；然而，其治疗效果仍不充分，其分子机制需要阐明，以进一步开发联合治疗方法。在这里，我们发现 RNA 病毒传感器通路在 NSCLC 和 ESCC 细胞系中主导调节细胞免疫反应。值得注意的是，转座元件（TEs），特别是长末端重复（LTRs），作为 RNA 病毒传感器 RIG-I 的关键配体发挥作用，mTOR-LTR-RIG-I 轴在照射后诱导细胞免疫反应和树突状细胞和巨噬细胞浸润。此外，在 ESCC 患者组织中观察到依赖于 RIG-I 的免疫激活。单细胞 RNA 测序和空间转录组分析表明，放射治疗诱导了免疫和癌细胞中 LTRs 和 RNA 病毒传感器通路的表达；该通路也被发现介导肿瘤转化为免疫热状态。在这里，我们报道了 RNA 病毒传感器通路在辐照癌组织中的上游和配体的作用。