Irradiation combined with PD-L1−/− and autophagy inhibition enhances the antitumor effect of lung cancer via cGAS-STING-mediated T cell activation
Xinrui Zhao,
Songling Hu,
Liang Zeng,
Xinglong Liu,
Yimeng Song,
Yuhong Zhang,
Qianping Chen,
Yang Bai,
Jianghong Zhang,
Haowen Zhang,
Yan Pan,
Chunlin Shao
Affiliations
Xinrui Zhao
Institute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai 200032, China
Songling Hu
Institute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai 200032, China
Liang Zeng
Institute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai 200032, China
Xinglong Liu
Institute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai 200032, China
Yimeng Song
Institute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai 200032, China
Yuhong Zhang
Institute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai 200032, China
Qianping Chen
Institute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai 200032, China
Yang Bai
Institute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai 200032, China
Jianghong Zhang
Institute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai 200032, China
Haowen Zhang
State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou 215123, China; Corresponding author
Yan Pan
Institute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai 200032, China; Corresponding author
Chunlin Shao
Institute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai 200032, China; Corresponding author
Summary: 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.
