Department of Radiology, National Taiwan University College of Medicine, Taipei, Taiwan.
National Taiwan University Cancer Center, National Taiwan University College of Medicine, Taipei, Taiwan.
Cancer Immunol Immunother. 2024 Nov 2;74(1):8. doi: 10.1007/s00262-024-03864-6.
We investigated the combined effects of ataxia telangiectasia and Rad3-related (ATR) inhibition, ablative radiotherapy, and immune checkpoint inhibitor (ICI) therapy against lung cancer. ATR inhibitor was administered combined with ablative radiotherapy to assess its radiosensitizing effect on lung cancer cells. Treatment response and survival were evaluated in vivo using A549 xenograft flank tumor and synchronous LLC lung and flank tumor mouse models. Mice received ablative radiotherapy (12 Gy/d for 2 d), ATR inhibitor, and ICI. The tumor microenvironment was assessed in irradiated flank and non-irradiated lung tumors. Programmed death-ligand 1 expression was upregulated after irradiation. ATR inhibition attenuated this upregulation. ATR inhibitor pretreatment decreased cell survival after irradiation by inhibiting DNA double-strand break repair, inducing mitotic cell death, and altering cell cycle progression. ATR inhibition enhanced radiation-induced damage-associated molecular patterns determined by high mobility group box 1 quantification and activated the cyclic GMP-AMP synthase-stimulator of interferon genes pathway. Combined ATR inhibition and ablative radiotherapy inhibited tumor growth and improved survival in mice. Adding ICI therapy further enhanced local antitumor effects, reducing the metastatic lung tumor burden and remodeling the tumor microenvironment through immunogenic cell death induction and enhanced immune cell infiltration. Triple therapy increased immune cell infiltration in distant non-irradiated lung tumors and stimulated the generation of protective T-cell immunity in splenocytes. Safety analysis showed minimal toxicity. ATR inhibition enhanced the efficacy of ablative radiotherapy and immunotherapy in lung cancer. These findings underscore the importance of combination therapies for enhancing systemic antitumor immune responses and outcomes.
我们研究了共济失调毛细血管扩张症和 Rad3 相关（ATR）抑制、消融性放疗和免疫检查点抑制剂（ICI）治疗联合对肺癌的影响。联合使用 ATR 抑制剂和消融性放疗来评估其对肺癌细胞的放射增敏作用。在 A549 异种移植 flank 肿瘤和同步 LLC 肺和 flank 肿瘤小鼠模型中评估体内治疗反应和生存情况。小鼠接受消融性放疗（12Gy/d，连续 2 天）、ATR 抑制剂和 ICI。评估照射 flank 和非照射 lung 肿瘤中的肿瘤微环境。照射后程序性死亡配体 1 表达上调。ATR 抑制通过抑制 DNA 双链断裂修复、诱导有丝分裂细胞死亡和改变细胞周期进程来减弱这种上调。ATR 抑制剂预处理通过抑制 DNA 双链断裂修复、诱导有丝分裂细胞死亡和改变细胞周期进程，降低照射后细胞的存活率。ATR 抑制增强了通过高迁移率族蛋白盒 1 定量确定的辐射诱导的损伤相关分子模式，并激活环鸟苷酸-腺苷酸合酶-干扰素基因刺激物通路。联合 ATR 抑制和消融性放疗抑制了小鼠肿瘤的生长并提高了其生存率。加入 ICI 治疗进一步增强了局部抗肿瘤作用，通过诱导免疫原性细胞死亡和增强免疫细胞浸润来减少转移性 lung 肿瘤负担和重塑肿瘤微环境。三重治疗增加了远处未照射 lung 肿瘤中的免疫细胞浸润，并刺激脾细胞中保护性 T 细胞免疫的产生。安全性分析显示毒性最小。ATR 抑制增强了消融性放疗和免疫疗法在肺癌中的疗效。这些发现强调了联合治疗对于增强全身抗肿瘤免疫反应和结果的重要性。
