机构：[1]School of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou 215123, China[2]Institute of Applied Electronics, China Academy of Engineering Physics, Mianyang 621900, China[3]Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China[4]Graduate School of China Academy of Engineering Physics, Beijing 100088, China[5]Department of Oncology, Nuclear Medicine Laboratory of Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang 621000, China四川省人民医院[6]National Health Commission Key Laboratory of Nuclear Technology Medical Transformation, Mianyang Central Hospital, Mianyang 621000, China[7]Department of Radiotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China四川大学华西医院[8]Department of Interventional Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China[9]Institute of Radiation Medicine, Fudan University, Shanghai 200032, China
DNA-damaging treatments such as radiotherapy (RT) have become promising to improve the efficacy of immune checkpoint inhibitors by enhancing tumor immunogenicity. However, accompanying treatment-related detrimental events in normal tissues have posed a major obstacle to radioimmunotherapy and present new challenges to the dose delivery mode of clinical RT. In the present study, ultrahigh dose rate FLASH X-ray irradiation was applied to counteract the intestinal toxicity in the radioimmunotherapy. In the context of programmed cell death ligand-1 (PD-L1) blockade, FLASH X-ray minimized mouse enteritis by alleviating CD8+ T cell-mediated deleterious immune response compared with conventional dose rate (CONV) irradiation. Mechanistically, FLASH irradiation was less efficient than CONV X-ray in eliciting cytoplasmic double-stranded DNA (dsDNA) and in activating cyclic GMP-AMP synthase (cGAS) in the intestinal crypts, resulting in the suppression of the cascade feedback consisting of CD8+ T cell chemotaxis and gasdermin E-mediated intestinal pyroptosis in the case of PD-L1 blocking. Meanwhile, FLASH X-ray was as competent as CONV RT in boosting the antitumor immune response initiated by cGAS activation and achieved equal tumor control in metastasis burdens when combined with anti-PD-L1 administration. Together, the present study revealed an encouraging protective effect of FLASH X-ray upon the normal tissue without compromising the systemic antitumor response when combined with immunological checkpoint inhibitors, providing the rationale for testing this combination as a clinical application in radioimmunotherapy.
基金：
This work was supported by the National Natural Science Foundation of
China (Grants 82173455 and 81602793 [to H.Z.], Grant 82101848 [to W.Z.],
Grant 12005211 [to Z.Z.], Grant 11975218 [to D.W.], Grant 11805192 [to K.Z.],
Grant 31770912 [to F.L.], and Grant 81771949 [to Z.W]), the Natural Science
Key Fund for Colleges and Universities of Jiangsu Province of China (Grant
21KJA310001 [to H.Z.]), and the Opening Foundation of State Key Laboratory of
Radiation Medicine and Protection (Grant GZK1202122 [to H.Z.]).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2022]版：
大类|1 区综合性期刊
小类|1 区综合性期刊
最新[2023]版：
大类|1 区综合性期刊
小类|1 区综合性期刊
第一作者：
第一作者机构：[1]School of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou 215123, China
共同第一作者：
通讯作者：
通讯机构：[1]School of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou 215123, China[2]Institute of Applied Electronics, China Academy of Engineering Physics, Mianyang 621900, China[6]National Health Commission Key Laboratory of Nuclear Technology Medical Transformation, Mianyang Central Hospital, Mianyang 621000, China[9]Institute of Radiation Medicine, Fudan University, Shanghai 200032, China
推荐引用方式(GB/T 7714)：
Shi Xiaolin,Yang Yiwei,Zhang Wei,et al.FLASH X-ray spares intestinal crypts from pyroptosis initiated by cGAS-STING activation upon radioimmunotherapy[J].Proceedings of the National Academy of Sciences of the United States of America.2022,119(43):e2208506119.doi:10.1073/pnas.2208506119.
APA：
Shi Xiaolin,Yang Yiwei,Zhang Wei,Wang Jianxin,Xiao Dexin...&Zhang Haowen.(2022).FLASH X-ray spares intestinal crypts from pyroptosis initiated by cGAS-STING activation upon radioimmunotherapy.Proceedings of the National Academy of Sciences of the United States of America,119,(43)
MLA：
Shi Xiaolin,et al."FLASH X-ray spares intestinal crypts from pyroptosis initiated by cGAS-STING activation upon radioimmunotherapy".Proceedings of the National Academy of Sciences of the United States of America 119..43(2022):e2208506119
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