FLASH X-ray spares intestinal crypts from pyroptosis initiated by cGAS-STING activation upon radioimmunotherapy.
FLASH X-ray spares intestinal crypts from pyroptosis initiated by cGAS-STING activation upon radioimmunotherapy.
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DOI：
10.1073/pnas.2208506119
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发表时间：
2022-10-25
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
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肿瘤免疫治疗与放射治疗(RT)相结合已成为根除多种晚期肿瘤的有效手段。然而，对于可能接受放射免疫治疗的患者来说，正常组织中伴随的与治疗相关的有害事件一直是联合方案的阴暗面。本研究证实超高剂量率(110~120Gy/S)闪光X射线照射可减少肠道下垂，从而在程序性细胞死亡配体-1(PD-L1)阻断的情况下抵消常规剂量率(CONV)照射所致的肠道毒性。同时，闪光X射线联合抗PD-L1治疗，在原发灶和远端肿瘤控制方面取得了与常规放疗相当的疗效，从而拓宽了肿瘤放射免疫治疗的治疗窗口，并有可能促进这一联合方案的普及。放射治疗(RT)等DNA损伤治疗有望通过增强肿瘤的免疫原性来提高免疫检查点抑制剂的疗效。然而，正常组织中伴随的治疗相关有害事件已经成为放射免疫治疗的主要障碍，并对临床RT的剂量传递模式提出了新的挑战。本研究采用超高剂量率闪光X射线照射来对抗放射免疫治疗中的肠道毒性。在程序性细胞死亡配体-1(PD-L1)阻断的背景下，闪光X射线通过减轻CD8+T细胞介导的有害免疫反应而使小鼠肠炎最小化，与常规剂量率(Conv)照射相比。在机制上，闪光照射在激发细胞质双链DNA(DsDNA)和激活环状GMP-AMP合成酶(CGAS)方面不如普通X射线，从而在PD-L1阻断的情况下，抑制了由CD8+T细胞趋化和Gasdermin E介导的肠上皮下垂组成的级联反馈。同时，在增强cGAS激活所引发的抗肿瘤免疫反应方面，闪光X射线与常规放疗一样有效，并且与抗PD-L1联合应用，在转移负荷上达到了同等的肿瘤控制。综上所述，本研究揭示了闪光X射线对正常组织的令人鼓舞的保护作用，而不影响免疫检查点抑制剂的全身抗肿瘤反应，为测试这种组合作为放射免疫治疗的临床应用提供了理论基础。
Tumor immunotherapy synergized with radiotherapy (RT) has become promising for eradicating multiple advanced tumors. However, accompanying treatment-related detrimental events in normal tissues has been the dark side of the combination regimen, for patients potentially amenable for radioimmunotherapy. This study identifies that ultrahigh dose rate (110 to 120 Gy/s) FLASH X-ray irradiation can reduce intestinal pyroptosis and thus counteracts the intestinal toxicity induced by conventional dose rate (CONV) irradiation in the context of programmed cell death ligand-1 (PD-L1) blockade. Meanwhile, FLASH X-ray achieves comparable efficacy with CONV RT in both primary and abscopal tumor control when combined with anti–PD-L1 administration, thus widening the therapeutic window of tumor radioimmunotherapy and potentially contributing to enhancing the popularity of this combination regimen. 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.
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DOI：
10.1126/science.aaf7532
发表时间：
2016-11-11
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hu B;Jin C;Li HB;Tong J;Ouyang X;Cetinbas NM;Zhu S;Strowig T;Lam FC;Zhao C;Henao-Mejia J;Yilmaz O;Fitzgerald KA;Eisenbarth SC;Elinav E;Flavell RA
通讯作者：
Flavell RA
DOI：
10.1016/j.ijrobp.2021.03.056
发表时间：
2021-09-01
期刊：
International journal of radiation oncology, biology, physics
影响因子：
--
作者：
Cao X;Zhang R;Esipova TV;Allu SR;Ashraf R;Rahman M;Gunn JR;Bruza P;Gladstone DJ;Williams BB;Swartz HM;Hoopes PJ;Vinogradov SA;Pogue BW
通讯作者：
Pogue BW
影响因子：
64.8
作者：
Ayyaz, Arshad;Kumar, Sandeep;Gregorieff, Alex
通讯作者：
Gregorieff, Alex
影响因子：
1.7
作者：
通讯作者：
--
影响因子：
82.9
作者：
Formenti SC;Rudqvist NP;Golden E;Cooper B;Wennerberg E;Lhuillier C;Vanpouille-Box C;Friedman K;Ferrari de Andrade L;Wucherpfennig KW;Heguy A;Imai N;Gnjatic S;Emerson RO;Zhou XK;Zhang T;Chachoua A;Demaria S
通讯作者：
Demaria S