Irradiation combined with PD-L1−/− and autophagy inhibition enhances the antitumor effect of lung cancer via cGAS-STING-mediated T cell activation
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-expre...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-08-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004222009622 |
| _version_ | 1828193794371092480 |
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| author | Xinrui Zhao Songling Hu Liang Zeng Xinglong Liu Yimeng Song Yuhong Zhang Qianping Chen Yang Bai Jianghong Zhang Haowen Zhang Yan Pan Chunlin Shao |
| author_facet | Xinrui Zhao Songling Hu Liang Zeng Xinglong Liu Yimeng Song Yuhong Zhang Qianping Chen Yang Bai Jianghong Zhang Haowen Zhang Yan Pan Chunlin Shao |
| author_sort | Xinrui Zhao |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T09:14:48Z |
| format | Article |
| id | doaj.art-4c9c19138a404144bf93bdfc09904628 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-04-12T09:14:48Z |
| publishDate | 2022-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-4c9c19138a404144bf93bdfc099046282022-12-22T03:38:53ZengElsevieriScience2589-00422022-08-01258104690Irradiation combined with PD-L1−/− and autophagy inhibition enhances the antitumor effect of lung cancer via cGAS-STING-mediated T cell activationXinrui Zhao0Songling Hu1Liang Zeng2Xinglong Liu3Yimeng Song4Yuhong Zhang5Qianping Chen6Yang Bai7Jianghong Zhang8Haowen Zhang9Yan Pan10Chunlin Shao11Institute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai 200032, ChinaInstitute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai 200032, ChinaInstitute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai 200032, ChinaInstitute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai 200032, ChinaInstitute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai 200032, ChinaInstitute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai 200032, ChinaInstitute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai 200032, ChinaInstitute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai 200032, ChinaInstitute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai 200032, ChinaState Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou 215123, China; Corresponding authorInstitute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai 200032, China; Corresponding authorInstitute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai 200032, China; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2589004222009622microenvironmentradiation biologyimmune responsecancer |
| spellingShingle | Xinrui Zhao Songling Hu Liang Zeng Xinglong Liu Yimeng Song Yuhong Zhang Qianping Chen Yang Bai Jianghong Zhang Haowen Zhang Yan Pan Chunlin Shao Irradiation combined with PD-L1−/− and autophagy inhibition enhances the antitumor effect of lung cancer via cGAS-STING-mediated T cell activation iScience microenvironment radiation biology immune response cancer |
| title | Irradiation combined with PD-L1−/− and autophagy inhibition enhances the antitumor effect of lung cancer via cGAS-STING-mediated T cell activation |
| title_full | Irradiation combined with PD-L1−/− and autophagy inhibition enhances the antitumor effect of lung cancer via cGAS-STING-mediated T cell activation |
| title_fullStr | Irradiation combined with PD-L1−/− and autophagy inhibition enhances the antitumor effect of lung cancer via cGAS-STING-mediated T cell activation |
| title_full_unstemmed | Irradiation combined with PD-L1−/− and autophagy inhibition enhances the antitumor effect of lung cancer via cGAS-STING-mediated T cell activation |
| title_short | Irradiation combined with PD-L1−/− and autophagy inhibition enhances the antitumor effect of lung cancer via cGAS-STING-mediated T cell activation |
| title_sort | irradiation combined with pd l1 and autophagy inhibition enhances the antitumor effect of lung cancer via cgas sting mediated t cell activation |
| topic | microenvironment radiation biology immune response cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2589004222009622 |
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