Combination of ataxia telangiectasia and Rad3-related inhibition with ablative radiotherapy remodels the tumor microenvironment and enhances immunotherapy response in lung cancer.

IF 4.6 2区 医学 Q2 IMMUNOLOGY Cancer Immunology, Immunotherapy Pub Date : 2024-11-02 DOI:10.1007/s00262-024-03864-6
Jenny Ling-Yu Chen, Chun-Kai Pan, Li-Cheng Lin, Yu-Sen Huang, Tsung-Hsuan Huang, Shu-Jyuan Yang, Sung-Hsin Kuo, Yu-Li Lin
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Abstract

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.

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将共济失调毛细血管扩张症和 Rad3 相关抑制与消融放疗相结合,可重塑肿瘤微环境并增强肺癌的免疫治疗反应。
我们研究了共济失调毛细血管扩张症和Rad3相关(ATR)抑制剂、消融放疗和免疫检查点抑制剂(ICI)疗法对肺癌的联合作用。ATR 抑制剂与烧蚀放疗联合使用,以评估其对肺癌细胞的放射增敏作用。使用A549异种侧腹肿瘤和同步LLC肺部和侧腹肿瘤小鼠模型对治疗反应和存活率进行了体内评估。小鼠接受了消融放疗(12 Gy/d,2 d)、ATR抑制剂和ICI。对照射过的侧腹肿瘤和未照射过的肺部肿瘤的肿瘤微环境进行了评估。照射后,程序性死亡配体1的表达上调。ATR抑制剂减轻了这种上调。ATR抑制剂通过抑制DNA双链断裂修复、诱导有丝分裂期细胞死亡和改变细胞周期进程,降低了辐照后细胞的存活率。ATR抑制增强了高迁移率组盒1定量测定的辐射诱导损伤相关分子模式,并激活了环GMP-AMP合成酶-干扰素基因刺激器通路。联合抑制 ATR 和消融放疗可抑制肿瘤生长并提高小鼠存活率。加入 ICI 治疗可进一步增强局部抗肿瘤效果,减少转移性肺肿瘤负荷,并通过诱导免疫原性细胞死亡和增强免疫细胞浸润重塑肿瘤微环境。三联疗法增加了远处非辐照肺肿瘤的免疫细胞浸润,并刺激脾细胞产生保护性T细胞免疫。安全性分析表明毒性极小。ATR抑制增强了肺癌消融放疗和免疫疗法的疗效。这些发现强调了联合疗法对增强全身抗肿瘤免疫反应和疗效的重要性。
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来源期刊
CiteScore
10.50
自引率
1.70%
发文量
207
审稿时长
1 months
期刊介绍: Cancer Immunology, Immunotherapy has the basic aim of keeping readers informed of the latest research results in the fields of oncology and immunology. As knowledge expands, the scope of the journal has broadened to include more of the progress being made in the areas of biology concerned with biological response modifiers. This helps keep readers up to date on the latest advances in our understanding of tumor-host interactions. The journal publishes short editorials including "position papers," general reviews, original articles, and short communications, providing a forum for the most current experimental and clinical advances in tumor immunology.
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