Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, China.
Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, China.
Int J Radiat Oncol Biol Phys. 2023 Aug 1;116(5):1150-1162. doi: 10.1016/j.ijrobp.2023.02.013. Epub 2023 Feb 13.
The clinical application of stereotactic body radiation therapy (SBRT) allows a high dose of radiation to be safely delivered to extracranial targets within the body; however, a high dose per fraction (hypofractionation) has opened the radiation oncology field to new questions on a variety of dose-fractionation schedules, especially the immunomodulatory effects of radiation therapy, which can change after various dose-fractionation schedules. We investigated the immunomodulatory effects of different fractionation schedules.
We established a subcutaneous tumor model in wild-type C57BL/6J mice and STING (stimulator of interferon genes)-deficient mice. We then compared the tumor control efficacy of 3 different fractionation schedules: 2 Gy × 8, 4.5 Gy × 3, and 10 Gy × 1, which are similar biologically effective doses.
We found the fractionation schedule of 10 Gy × 1 had a significantly higher antitumor effect, suggesting that a single high dose induced enhanced antitumor immunity compared with conventional fractionation (2 Gy × 8) and moderate hypofractionation (4.5 Gy × 3). However, in STING-deficient mice, differential tumor control was not observed among the 3 dose-fractionation schedules, suggesting that cGAS (cyclic GMP-AMP synthase)/STING signaling is involved in the antitumor immune effects of single high-dose schedules. Mechanistically, we found that conventional fractionation induced apoptosis; by comparison, a single high dose was more attuned to induced necroptosis, leading to the release of intracellular irradiation-induced double-stranded DNA (dsDNA) due to the loss of plasma membrane integrity, which then activated the dsDNA sensing signaling cGAS/STING in the recruited macrophage. Furthermore, iRhom2, a member of the conserved family of inhibitory rhomboid-like pseudoproteases, was upregulated in infiltrated macrophages in the single high-dose irradiation microenvironment. Therefore, iRhom2 positively regulates STING and directly promotes tumor necrosis factor α secretion. This exacerbates necroptosis of irradiated tumor cells, leading to continuous dsDNA release and enhancement of cGAS/STING signaling antitumor immunity in a positive feedback loop.
iRhom2 amplifies antitumor signaling in a positive feedback loop mediated by cGAS/STING signaling and tumor necrosis factor-driven necroptosis after single high-dose radiation.
立体定向体部放射治疗（SBRT）的临床应用可将高剂量的放射线安全地输送到体内的颅外靶区；然而，高剂量分割（超分割）使放射肿瘤学领域对各种剂量分割方案产生了新的疑问，尤其是放射治疗的免疫调节作用，这种作用在各种剂量分割方案后会发生改变。我们研究了不同分割方案的免疫调节作用。
我们在野生型 C57BL/6J 小鼠和 STING（干扰素基因刺激物）缺陷型小鼠中建立了皮下肿瘤模型。然后，我们比较了 3 种不同分割方案的肿瘤控制效果：2 Gy×8、4.5 Gy×3 和 10 Gy×1，它们具有相似的生物有效剂量。
我们发现 10 Gy×1 的分割方案具有更高的抗肿瘤效果，表明单次高剂量诱导的抗肿瘤免疫增强作用优于常规分割（2 Gy×8）和适度的超分割（4.5 Gy×3）。然而，在 STING 缺陷型小鼠中，3 种剂量分割方案之间没有观察到差异的肿瘤控制，表明 cGAS（环鸟苷酸-腺苷酸合酶）/STING 信号参与了单次高剂量方案的抗肿瘤免疫作用。从机制上讲，我们发现常规分割诱导细胞凋亡；相比之下，单次高剂量更能诱导细胞发生坏死，导致由于质膜完整性丧失而释放细胞内照射诱导的双链 DNA（dsDNA），随后激活募集的巨噬细胞中的 dsDNA 感应信号 cGAS/STING。此外，iRhom2 是保守的类菱形样假蛋白酶体家族的成员，在单次高剂量照射微环境中浸润的巨噬细胞中上调。因此，iRhom2 正向调节 STING，并直接促进肿瘤坏死因子 α 的分泌。这加剧了照射肿瘤细胞的坏死，导致 dsDNA 持续释放，并在正反馈环中增强 cGAS/STING 信号抗肿瘤免疫。
iRhom2 通过 cGAS/STING 信号和肿瘤坏死因子驱动的坏死作用放大单次高剂量照射后的正反馈环中的抗肿瘤信号。
