He Chao, Han Rui, Zhang Taiming, Zhong Peng, Huang Daijuan, Lu Conghua, Zhang Yimin, Li Jianghua, Deng Yuwen, He Yong
Department of Respiratory Disease, Daping Hospital, Army Medical University, Chongqing, China.
Department of Respiratory Disease, Bishan Hospital of Chongqing Medical University, Bishan Hospital of Chongqing, Chongqing, China.
Thorac Cancer. 2025 Apr;16(7):e70056. doi: 10.1111/1759-7714.70056.
Neoadjuvant chemoimmunotherapy has achieved high downstaging and pathologic response rates in nonsmall-cell lung cancer (NSCLC), but outcomes vary significantly. Early identification of beneficiaries remains a challenge.
This study analyzed baseline transcriptomic data from 24 NSCLC patients (9 major pathological response [MPR], 15 nonmajor pathological response [NMPR]) treated with neoadjuvant chemoimmunotherapy, sourced from the GEO database. Molecular analyses and immune infiltration analyses were performed using pathologic response as an endpoint. After identifying the interferon signaling subset NeoIGS, we analyzed the relationship between NeoIGS and immune scores, immune cell infiltration, and immunotherapy efficacy. A key gene in NeoIGS was screened by reveiver operating characteristic curve (ROC) analysis. Subsequently, the expression of the key gene was assessed by immunohistochemistry in 53 NSCLC patients receiving neoadjuvant chemoimmunotherapy.
Interferon signaling pathway expression and CD8+ T-cell infiltration were higher in the MPR group. NeoIGS predicted pathological response to neoadjuvant chemoimmunotherapy (AUC = 0.926) and also demonstrated predictive value in the ICIs monotherapy cohort. IPS and TIDE scores also confirmed NeoIGS's association with immunotherapy in the TCGA NSCLC dataset. Furthermore, patients with higher NeoIGS scores had more immune cell infiltration and increased expression of ICI targets. ROC analysis identified ATF3 as NeoIGS's key gene. In the clinical cohort, ATF3 outperformed PD-L1 in predicting pathologic response, with a 90.0% MPR rate in the high-expression group.
We established that a subset of interferon signaling pathways, NeoIGS, is closely associated with immunotherapy. Among them, ATF3 is the most critical gene that accurately predicts pathological remission in neoadjuvant chemoimmunotherapy.
新辅助化疗免疫疗法在非小细胞肺癌（NSCLC）中已实现较高的降期率和病理缓解率，但结果差异显著。早期识别受益患者仍然是一项挑战。
本研究分析了来自基因表达综合数据库（GEO数据库）的24例接受新辅助化疗免疫疗法的NSCLC患者（9例主要病理缓解[MPR]，15例非主要病理缓解[NMPR]）的基线转录组数据。以病理缓解为终点进行分子分析和免疫浸润分析。在鉴定出干扰素信号亚组NeoIGS后，我们分析了NeoIGS与免疫评分、免疫细胞浸润和免疫治疗疗效之间的关系。通过受试者工作特征曲线（ROC）分析筛选出NeoIGS中的关键基因。随后，通过免疫组织化学评估53例接受新辅助化疗免疫疗法的NSCLC患者中该关键基因的表达。
MPR组中干扰素信号通路表达和CD8 + T细胞浸润更高。NeoIGS可预测新辅助化疗免疫疗法的病理缓解（AUC = 0.926），并且在免疫检查点抑制剂（ICI）单药治疗队列中也显示出预测价值。免疫预后评分（IPS）和肿瘤免疫功能失调和排除（TIDE）评分也证实了NeoIGS与TCGA NSCLC数据集中免疫治疗的相关性。此外，NeoIGS评分较高的患者免疫细胞浸润更多，ICI靶点的表达增加。ROC分析确定激活转录因子3（ATF3）为NeoIGS的关键基因。在临床队列中，ATF3在预测病理缓解方面优于程序性死亡受体配体1（PD-L1），高表达组的MPR率为90.0％。
我们确定了干扰素信号通路的一个亚组NeoIGS与免疫治疗密切相关。其中，ATF3是准确预测新辅助化疗免疫疗法中病理缓解的最关键基因。
