Liu Xiang, Zhou Wangyan, Zheng Dayang, Yang Xu, Qing Yongcheng, Liao Weijun, Zeng Wei
Department of Thoracic Surgery, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China.
Department of Medical Record, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China.
Int Arch Allergy Immunol. 2025;186(4):345-357. doi: 10.1159/000540875. Epub 2024 Oct 29.
Immunotherapy has demonstrated encouraging outcomes in tackling lung adenocarcinoma (LUAD), but immune escape may bring negative impacts. Only a single study has demonstrated the function of AIM2 in LUAD and reported that NF-κB and STAT1 are the chief transcription factors, this study is designed to analyze the role of AIM2 and examine the transcription factor, BATF in LUAD immunotherapy.
Bioinformatics methods to analyze the expression and binding sites of AIM2 and BATF in LUAD, as well as the correlation between AIM2 and PD-L1. Dual-luciferase and chromatin immunoprecipitation assays were used to verify the binding of AIM2 and BATF. qRT-PCR and Western blot assayed expression of AIM2, BATF, and PD-L1 in LUAD. MTT measured cell viability, flow cytometry detected cell apoptosis, cytotoxicity assays measured the toxicity of CD8+ T cells to cancer cells, and enzyme-linked immunosorbent assay measured the expression of related cytokines. Immunohistochemistry detected the protein expression levels of AIM2, BATF, PD-L1, and CD8 in tumor tissue.
AIM2 and BATF were both highly expressed in LUAD, and there was a targeted binding relationship. BATF promoted LUAD cell proliferation and inhibited apoptosis by affecting AIM2 expression. The downregulation of AIM2 and PD-L1 expression inhibited PD-L1 and activated CD8+ T cells. The rescue experiment manifested that increased BATF weakened repression of AIM2 silencing on LUAD tumor immune escape in vitro and in vivo.
BATF promoted AIM2 expression, upregulated PD-L1, inhibited CD8+ T cell activity, and ultimately led to immune escape in LUAD. Our research uncovered an innovative outlook on the intricate regulation of immune checkpoint molecules and proposed a new approach to target the BATF/AIM2 axis in tumor immunotherapy.
免疫疗法在治疗肺腺癌（LUAD）方面已显示出令人鼓舞的结果，但免疫逃逸可能会带来负面影响。仅有一项研究证明了AIM2在LUAD中的作用，并报道NF-κB和STAT1是主要转录因子，本研究旨在分析AIM2的作用，并研究转录因子BATF在LUAD免疫治疗中的作用。
采用生物信息学方法分析AIM2和BATF在LUAD中的表达及结合位点，以及AIM2与PD-L1之间的相关性。采用双荧光素酶和染色质免疫沉淀试验验证AIM2与BATF的结合。qRT-PCR和蛋白质免疫印迹法检测LUAD中AIM2、BATF和PD-L1的表达。MTT法检测细胞活力，流式细胞术检测细胞凋亡，细胞毒性试验检测CD8+T细胞对癌细胞的毒性，酶联免疫吸附试验检测相关细胞因子的表达。免疫组织化学检测肿瘤组织中AIM2、BATF、PD-L1和CD8的蛋白表达水平。
AIM2和BATF在LUAD中均高表达，且存在靶向结合关系。BATF通过影响AIM2表达促进LUAD细胞增殖并抑制凋亡。AIM2和PD-L1表达下调可抑制PD-L1并激活CD8+T细胞。拯救实验表明，增加BATF可减弱AIM2沉默对LUAD肿瘤免疫逃逸的体外和体内抑制作用。
BATF促进AIM2表达，上调PD-L1，抑制CD8+T细胞活性，最终导致LUAD免疫逃逸。我们的研究揭示了免疫检查点分子复杂调控的新视角，并提出了在肿瘤免疫治疗中靶向BATF/AIM2轴的新方法。
