Zhao Xinrui, Hu Songling, Zeng Liang, Liu Xinglong, Song Yimeng, Zhang Yuhong, Chen Qianping, Bai Yang, Zhang Jianghong, Zhang Haowen, Pan Yan, Shao Chunlin
Institute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai 200032, China.
State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou 215123, China.
iScience. 2022 Jun 30;25(8):104690. doi: 10.1016/j.isci.2022.104690. eCollection 2022 Aug 19.
Radiotherapy combined with immune checkpoint blockade has gradually revealed the superiority in the antitumor therapy; however, the contribution of host PD-L1 remains elusive. In this study, we found that the activation of CD8 T cells was strikingly increased in both irradiated PD-L1-expressing primary tumor and distant non-irradiated syngeneic tumor in PD-L1-deficient mouse host, and thus enhanced radiation-induced antitumor abscopal effect (ATAE) by activating cGAS-STING pathway. Notably, the autophagy inhibitors distinctively promoted dsDNA aggregation in the cytoplasm and increased the release of cGAS-STING-regulated IFN-β from irradiated cells, which further activated bystander CD8 T cells to release IFN-γ and contributed to ATAE. These findings revealed a signaling cascade loop that the cytokines released from irradiated tumor recruit CD8 T cells that in turn act on the tumor cells with amplified immune responses in PD-L1-deficient host, indicating a potential sandwich therapy strategy of RT combined with PD-L1 blockage and autophagy inhibition.
放射疗法联合免疫检查点阻断在抗肿瘤治疗中逐渐显示出优势；然而，宿主程序性死亡配体1（PD-L1）的作用仍不明确。在本研究中，我们发现，在PD-L1缺陷型小鼠宿主中，照射过的表达PD-L1的原发性肿瘤和远处未照射的同基因肿瘤中，CD8 T细胞的活化均显著增加，从而通过激活环鸟苷酸-腺苷酸合成酶-干扰素基因刺激蛋白（cGAS-STING）通路增强了辐射诱导的远隔效应抗肿瘤作用（ATAE）。值得注意的是，自噬抑制剂显著促进了细胞质中双链DNA（dsDNA）的聚集，并增加了受照射细胞中cGAS-STING调节的干扰素-β（IFN-β）的释放，后者进一步激活旁观者CD8 T细胞以释放干扰素-γ（IFN-γ）并促进ATAE。这些发现揭示了一个信号级联环，即受照射肿瘤释放的细胞因子募集CD8 T细胞，而CD8 T细胞反过来作用于肿瘤细胞，在PD-L1缺陷型宿主中放大免疫反应，这表明了一种放射疗法联合PD-L1阻断和自噬抑制的潜在三明治治疗策略。
