Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Chiba, Japan.
Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan.
Cancer Sci. 2022 Apr;113(4):1352-1361. doi: 10.1111/cas.15297. Epub 2022 Feb 20.
Radiotherapy (RT) combined with immune checkpoint inhibitors has recently produced outstanding results and is expected to be adaptable for various cancers. However, the precise molecular mechanism by which immune reactions are induced by fractionated RT is still controversial. We aimed to investigate the mechanism of the immune response regarding multifractionated, long-term radiation, which is most often combined with immunotherapy. Two human esophageal cancer cell lines, KYSE-450 and OE-21, were irradiated by fractionated irradiation (FIR) daily at a dose of 3 Gy in 5 d/wk for 2 weeks. Western blot analysis and RNA sequencing identified type I interferon (IFN) and the stimulator of IFN genes (STING) pathway as candidates that regulate immune response by FIR. We inhibited STING, IFNAR1, STAT1, and IFN regulatory factor 1 (IRF1) and investigated the effects on the immune response in cancer cells and the invasion of surrounding immune cells. We herein revealed type I IFN-dependent immune reactions and the positive feedback of STING, IRF1, and phosphorylated STAT1 induced by FIR. Knocking out STING, IFNAR1, STAT1, and IRF1 resulted in a poorer immunological response than that in WT cells. The STING-KO KYSE-450 cell line showed significantly less invasion of PBMCs than the WT cell line under FIR. In the analysis of STING-KO cells and migrated PBMCs, we confirmed the occurrence of STING-dependent immune activation under FIR. In conclusion, we identified that the STING-IFNAR1-STAT1-IRF1 axis regulates immune reactions in cancer cells triggered by FIR and that the STING pathway also contributes to immune cell invasion of cancer cells.
放疗（RT）联合免疫检查点抑制剂最近取得了显著的效果，预计可适用于多种癌症。然而，分次 RT 诱导免疫反应的确切分子机制仍存在争议。我们旨在研究最常与免疫治疗联合使用的多次、长期放射治疗所引发的免疫反应的机制。我们用每天 3 Gy 的剂量对两种人食管癌细胞系 KYSE-450 和 OE-21 进行 5 天/周的分次照射（FIR），2 周后，我们通过 Western blot 分析和 RNA 测序确定了 I 型干扰素（IFN）和干扰素基因刺激因子（STING）途径作为通过 FIR 调节免疫反应的候选者。我们抑制了 STING、IFNAR1、STAT1 和 IFN 调节因子 1（IRF1），并研究了它们对癌细胞免疫反应和周围免疫细胞浸润的影响。我们在此揭示了由 FIR 诱导的 I 型 IFN 依赖性免疫反应和 STING、IRF1 和磷酸化 STAT1 的正反馈。敲除 STING、IFNAR1、STAT1 和 IRF1 导致免疫反应比 WT 细胞差。在 FIR 下，STING-KO KYSE-450 细胞系的 PBMC 浸润明显少于 WT 细胞系。在 STING-KO 细胞和迁移的 PBMC 分析中，我们证实了 FIR 下发生了依赖于 STING 的免疫激活。总之，我们确定了 STING-IFNAR1-STAT1-IRF1 轴调节 FIR 触发的癌细胞中的免疫反应，并且 STING 途径也有助于免疫细胞浸润癌细胞。
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