Strandberg Jillian, Louie Anna, Lee Seulki, Hahn Marina, Srinivasan Praveen, George Andrew, De La Cruz Arielle, Zhang Leiqing, Hernandez Borrero Liz, Huntington Kelsey E, De La Cruz Payton, Seyhan Attila A, Koffer Paul P, Wazer David E, DiPetrillo Thomas A, Graff Stephanie L, Azzoli Christopher G, Rounds Sharon I, Klein-Szanto Andres J, Tavora Fabio, Yakirevich Evgeny, Abbas Abbas E, Zhou Lanlan, El-Deiry Wafik S
Laboratory of Translational Oncology and Translational Cancer Therapeutics, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.
Biomedical Engineering Graduate Group, Brown University, Providence, Rhode Island, USA.
J Clin Invest. 2025 Jan 14;135(5):e173649. doi: 10.1172/JCI173649.
Radiotherapy can be limited by pneumonitis, which is impacted by innate immunity, including pathways regulated by TRAIL death receptor DR5. We investigated whether DR5 agonists could rescue mice from toxic effects of radiation and found that 2 different agonists, parenteral PEGylated trimeric TRAIL (TLY012) and oral TRAIL-inducing compound (TIC10/ONC201), could reduce pneumonitis, alveolar wall thickness, and oxygen desaturation. Lung protection extended to late effects of radiation including less fibrosis at 22 weeks in TLY012-rescued survivors versus unrescued surviving irradiated mice. Wild-type orthotopic breast tumor-bearing mice receiving 20 Gy thoracic radiation were protected from pneumonitis with disappearance of tumors. At the molecular level, radioprotection appeared to be due to inhibition of CCL22, a macrophage-derived chemokine previously associated with radiation pneumonitis and pulmonary fibrosis. Treatment with anti-CCL22 reduced lung injury in vivo but less so than TLY012. Pneumonitis severity was worse in female versus male mice, and this was associated with increased expression of X-linked TLR7. Irradiated mice had reduced esophagitis characterized by reduced epithelial disruption and muscularis externa thickness following treatment with the ONC201 analog ONC212. The discovery that short-term treatment with TRAIL pathway agonists effectively rescues animals from pneumonitis, dermatitis, and esophagitis following high doses of thoracic radiation exposure has important translational implications.
放射治疗可能会受到肺炎的限制，而肺炎会受到先天免疫的影响，包括由肿瘤坏死因子相关凋亡诱导配体（TRAIL）死亡受体DR5调节的信号通路。我们研究了DR5激动剂是否可以使小鼠免受辐射的毒性作用，结果发现两种不同的激动剂，即肠胃外聚乙二醇化三聚体TRAIL（TLY012）和口服TRAIL诱导化合物（TIC10/ONC201），可以减轻肺炎、肺泡壁厚度和氧饱和度下降。肺部保护作用还扩展到了辐射的晚期效应，例如与未接受救援的受辐射存活小鼠相比，接受TLY012救援的存活小鼠在22周时纤维化程度更低。接受20 Gy胸部放疗的野生型原位荷瘤小鼠免受了肺炎的影响，肿瘤也消失了。在分子水平上，放射保护作用似乎是由于抑制了CCL22，这是一种巨噬细胞衍生的趋化因子，之前与放射性肺炎和肺纤维化有关。用抗CCL22治疗可减轻体内肺损伤，但效果不如TLY012。雌性小鼠的肺炎严重程度比雄性小鼠更严重，这与X连锁的TLR7表达增加有关。在用ONC201类似物ONC212治疗后，受辐射小鼠的食管炎减轻，表现为上皮破坏和肌层厚度降低。TRAIL信号通路激动剂的短期治疗能有效使动物在高剂量胸部辐射暴露后免受肺炎、皮炎和食管炎的影响，这一发现具有重要的转化意义。
