Zhu Guangsheng, Liu Jinghao, Li Yongwen, Huang Hua, Chen Chen, Wu Di, Cao Peijun, Su Lianchun, Wang Yanan, Zhang Hongbing, Liu Hongyu, Chen Jun
Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin 300052, People's Republic of China.
Tianjin Lung Cancer Institute, Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Medical University General Hospital, Tianjin 300052, People's Republic of China.
J Cancer. 2024 Mar 11;15(9):2601-2612. doi: 10.7150/jca.91955. eCollection 2024.
Lung cancer is a major cause of morbidity and mortality globally, necessitating the identification of predictive markers for effective immunotherapy. Mutations in SWI/SNF chromatin remodeling complex genes were reported sensitized human tumors to immune checkpoint inhibitors (ICIs), but the underlying mechanisms are unclear. This study aims to investigate the association between SWI/SNF gene ARID1B mutation and ICI response in non-small cell lung cancer (NSCLC) patients, to explore the functional consequences of ARID1B mutation on DNA damage response, immune microenvironment, and cGAS-STING pathway activation. TCGA LUAD, LUSC, and AACR GENIE data are analyzed to assess ARID1B mutation status in NSCLC patients. Prognostic analysis evaluates the effect of ARID1B mutation on patient outcomes. In vitro experiments carried to investigate the consequences of ARID1B knockdown on DNA damage response and repair. The immune microenvironment is assessed based on ARID1B expression, and the relationship between ARID1B and the cGAS-STING pathway is explored. ARID1B mutation frequency is 5.7% in TCGA databases and 4.4% in the AACR GENIE project. NSCLC patients with ARID1B mutation showed improved overall and progression-free survival following ICIs treatment. ARID1B knockdown in lung cancer cell lines enhances DNA damage, impairs DNA repair, alters chromatin accessibility, and activates the cGAS-STING pathway. ARID1B deficiency is associated with immune suppression, indicated by reduced immune scores, decreased immune cell infiltration, and negative correlations with immune-related cell types and functions. ARID1B mutation may predict improved response to ICIs in NSCLC patients. ARID1B mutation leads to impaired DNA damage response and repair, altered chromatin accessibility, and cGAS-STING pathway activation. These findings provide insights into ARID1B's biology and therapeutic implications in lung cancer, highlighting its potential as a target for precision medicine and immunotherapy. Further validation and clinical studies are warranted.
肺癌是全球发病和死亡的主要原因，因此需要鉴定有效的免疫治疗预测标志物。据报道，SWI/SNF染色质重塑复合基因中的突变使人类肿瘤对免疫检查点抑制剂（ICI）敏感，但其潜在机制尚不清楚。本研究旨在探讨SWI/SNF基因ARID1B突变与非小细胞肺癌（NSCLC）患者ICI反应之间的关联，以探索ARID1B突变对DNA损伤反应、免疫微环境和cGAS-STING通路激活的功能影响。分析TCGA LUAD、LUSC和AACR GENIE数据以评估NSCLC患者的ARID1B突变状态。预后分析评估ARID1B突变对患者预后的影响。进行体外实验以研究ARID1B敲低对DNA损伤反应和修复的影响。基于ARID1B表达评估免疫微环境，并探索ARID1B与cGAS-STING通路之间的关系。在TCGA数据库中，ARID1B突变频率为5.7%，在AACR GENIE项目中为4.4%。ARID1B突变的NSCLC患者在接受ICI治疗后总生存期和无进展生存期有所改善。肺癌细胞系中ARID1B敲低会增加DNA损伤、损害DNA修复、改变染色质可及性并激活cGAS-STING通路。ARID1B缺陷与免疫抑制相关，表现为免疫评分降低、免疫细胞浸润减少，以及与免疫相关细胞类型和功能呈负相关。ARID1B突变可能预示NSCLC患者对ICI的反应改善。ARID1B突变导致DNA损伤反应和修复受损、染色质可及性改变以及cGAS-STING通路激活。这些发现为ARID1B在肺癌中的生物学特性和治疗意义提供了见解，突出了其作为精准医学和免疫治疗靶点的潜力。有必要进行进一步的验证和临床研究。
