Duan Xiaohong, Sun Dawei, Liu Siyao, Su Junyan, Zhang Jiali, Liu Mengyuan, Li Ning, Qiao Ou, Liu Zichuan, Gong Yanhua
School of Disaster and Emergency Medicine, Faculty of Medicine, Tianjin University, No. 92 Weijin Road, Nankai District, Tianjin, 300072, China.
Institute of Disaster and Emergency Medicine, Faculty of Medicine, Tianjin University, Tianjin, China.
Clin Transl Oncol. 2025 Jun 28. doi: 10.1007/s12094-025-03966-2.
This study sought to identify new biomarkers by examining genomic profiling and PD-L1 expression. While the PD-L1 and tumor mutational burden (TMB) are currently the main clinically available biomarkers for predicting immunotherapy response in non-small-cell lung cancer (NSCLC), the factors that affect PD-L1 expression remain unclear.
This retrospective study included tumor and blood samples from 2750 Chinese patients with NSCLC who had successful PD-L1 assessments and targeted next-generation sequencing. Clinicopathological characteristics and genomics profile were analyzed. TMB was categorized as high (TMB-H) if there were ≥ 10 mutations per megabase. PD-L1 expression was classified into three groups: PD-L1-negative, PD-L1-low, and PD-L1-high. In addition, genomic data, and immune checkpoint inhibitor (ICI) outcomes for 197 NSCLC patients were obtained from the MSK2020 cohort.
This study included a total of 2750 NSCLC cases. Tumors with high PD-L1 expression were more commonly observed in males and exhibited a higher median TMB. Significant differences in gene mutation frequencies were observed among the different PD-L1 expression groups. Significant differences in mutation frequencies were observed in PD-L1 expression subgroups for the EGFR, TP53, LRP1B, KRAS, SPTA1, and PTPRD genes. Notably, TP53 and KRAS alterations were significantly enriched in PD-L1-high subgroup, while EGFR mutations were associated with PD-L1 negativity. Patients in the PD-L1-high group showed notably improved progression-free survival (PFS) and overall survival (OS) compared to those in the PD-L1-low and negative groups. Further analysis of the combined impact of PD-L1 expression and TMB revealed that the PD-L1-negative/TMB-low subgroup had significantly shorter PFS and OS compared to the other subgroups. This indicates that a composite biomarker combining PD-L1 expression and TMB provides superior predictive value for favorable ICI outcomes.
This study indicates that PD-L1 expression levels are significantly associated with specific genomic alterations and clinical outcomes in patients with NSCLC. Particularly in evaluating the efficacy of ICI therapy, the combined biomarker of PD-L1 and TMB shows important clinical application value.
本研究旨在通过检测基因组图谱和PD-L1表达来鉴定新的生物标志物。虽然PD-L1和肿瘤突变负荷（TMB）目前是预测非小细胞肺癌（NSCLC）免疫治疗反应的主要临床可用生物标志物，但影响PD-L1表达的因素仍不清楚。
这项回顾性研究纳入了2750例成功进行PD-L1评估并接受靶向二代测序的中国NSCLC患者的肿瘤和血液样本。分析了临床病理特征和基因组图谱。如果每兆碱基有≥10个突变，则将TMB分类为高（TMB-H）。PD-L1表达分为三组：PD-L1阴性、PD-L1低表达和PD-L1高表达。此外，从MSK2020队列中获取了197例NSCLC患者的基因组数据和免疫检查点抑制剂（ICI）治疗结果。
本研究共纳入2750例NSCLC病例。PD-L1高表达的肿瘤在男性中更常见，且中位TMB更高。在不同的PD-L1表达组中观察到基因突变频率存在显著差异。在EGFR、TP53、LRP1B、KRAS、SPTA1和PTPRD基因的PD-L1表达亚组中观察到突变频率存在显著差异。值得注意的是，TP53和KRAS改变在PD-L1高表达亚组中显著富集，而EGFR突变与PD-L1阴性相关。与PD-L1低表达和阴性组相比，PD-L1高表达组患者的无进展生存期（PFS）和总生存期（OS）显著改善。对PD-L1表达和TMB联合影响的进一步分析表明，与其他亚组相比，PD-L1阴性/TMB低亚组的PFS和OS显著缩短。这表明结合PD-L1表达和TMB的复合生物标志物对ICI治疗的良好结果具有更高的预测价值。
本研究表明，PD-L1表达水平与NSCLC患者的特定基因组改变和临床结果显著相关。特别是在评估ICI治疗的疗效时，PD-L1和TMB的联合生物标志物显示出重要的临床应用价值。
