Du Wei, Xiao Bijing, Yang Xuan, Zhan Jianhua, Sun Haishuang, Yang Yunpeng, Fang Wenfeng, Huang Yan, Sun Dongchen, Hong Shaodong, Zhang Li
State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People's Republic of China.
Department of Medical Oncology, Sun Yat-Sen University Cancer Center, No. 651 DongFeng Road E, Guangzhou, 510060, China.
Cancer Immunol Immunother. 2025 Sep 13;74(10):307. doi: 10.1007/s00262-025-04165-2.
Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality, with chemoimmunotherapy (CIT) as the first-line standard for advanced NSCLC without driver mutations. However, predictive biomarkers for CIT response are limited. Tertiary lymphoid structures (TLS) play a critical role in antitumor immunity and may serve as potential biomarkers. This study aimed to screen and validate a TLS-derived gene signature to predict responses to first-line CIT in advanced NSCLC.
Data from three randomized trials (ORIENT-11, OAK, POPLAR) and The Cancer Genome Atlas-NSCLC were analyzed. TLS scores were computed via ssGSEA based on 17 TLS-related gene signatures. Patients were stratified into TLS-high and TLS-low groups. The predictive value was assessed by survival analysis, nomograms, and receiver operating characteristic curve. Correlations with programmed cell death 1 ligand (PD-L1) and ImmuneScore were evaluated.
TLS signature 3 was identified as a predictive biomarker. In ORIENT-11, high signature 3 scores correlated with longer progression-free survival (PFS) (9.92 vs 6.77 months, p = 0.001) and overall survival (OS) (not reached vs 17.60 months, p < 0.001). Multivariate analysis confirmed signature 3 as an independent predictor for both outcomes (PFS HR = 2.14, p = 0.006; OS HR = 2.24, p = 0.002). A nomogram integrating signature 3 and clinicopathologic factors showed strong discriminative power. Signature 3 also correlated with PD-L1 expression and 'hot' immune phenotypes, enhancing prediction in PD-L1-negative subsets.
TLS signature 3 predicts CIT response independently of PD-L1, improving outcomes in PD-L1-negative patients and complementing PD-L1 testing. Integration into clinical practice may refine treatment decisions, warranting further mechanistic and clinical validation.
非小细胞肺癌（NSCLC）仍然是癌症相关死亡的主要原因，化疗免疫疗法（CIT）是无驱动基因突变的晚期NSCLC的一线标准治疗方案。然而，CIT反应的预测生物标志物有限。三级淋巴结构（TLS）在抗肿瘤免疫中起关键作用，可能作为潜在的生物标志物。本研究旨在筛选和验证一种源自TLS的基因特征，以预测晚期NSCLC患者对一线CIT的反应。
分析了来自三项随机试验（ORIENT-11、OAK、POPLAR）和癌症基因组图谱-NSCLC的数据。基于17个与TLS相关的基因特征，通过单样本基因集富集分析（ssGSEA）计算TLS评分。将患者分为TLS高分组和TLS低分组。通过生存分析、列线图和受试者工作特征曲线评估预测价值。评估了与程序性细胞死亡1配体（PD-L1）和免疫评分的相关性。
TLS特征3被确定为一种预测生物标志物。在ORIENT-11试验中，特征3高分与更长的无进展生存期（PFS）（9.92个月对6.77个月，p = 0.001）和总生存期（OS）（未达到对17.60个月，p < 0.001）相关。多变量分析证实特征3是这两个结局的独立预测因素（PFS风险比[HR] = 2.14，p = 0.006；OS HR = 2.24，p = 0.002）。整合特征3和临床病理因素的列线图显示出强大的鉴别能力。特征3还与PD-L1表达和“热”免疫表型相关，增强了对PD-L1阴性亚组的预测。
TLS特征3独立于PD-L1预测CIT反应，改善了PD-L1阴性患者的预后，并补充了PD-L1检测。将其纳入临床实践可能会优化治疗决策，值得进一步进行机制和临床验证。
