Programmed cell death ligand (PD-L1) expression by immunohistochemistry (IHC) lacks sensitivity for pembrolizumab immunotherapy selection in non-small cell lung cancer (NSCLC), particularly for tumors with low expression. We retrospectively evaluated transcriptomic PD-L1 by mRNA next-generation sequencing (RNA-seq). In an unselected NSCLC patient cohort (n = 3168) tested during standard care (2017–2021), PD-L1 IHC and RNA-seq demonstrated moderate concordance, with 80% agreement overall. Most discordant cases were either low or negative for PD-L1 expression by IHC but high by RNA-seq. RNA-seq accurately discriminated PD-L1 IHC high from low tumors by receiver operator curve (ROC) analysis but could not distinguish PD-L1 IHC low from negative tumors. In a separate pembrolizumab monotherapy cohort (n = 102), NSCLC tumors classified as PD-L1 high versus not high by RNA-seq had significantly improved response, progression-free survival, and overall survival as an individual measure and in combination with IHC high or low status. PD-L1 IHC status (high or low) trended toward but had no significant associations with improved outcomes. Conventional PD-L1 IHC testing has inherent limitations, making it an imperfect reference standard for evaluating novel testing technologies. RNA-seq offers an objective PD-L1 measure that could represent a complementary method to IHC to improve NSCLC patient selection for immunotherapy.
在非小细胞肺癌（NSCLC）中，免疫组化检测的程序性死亡配体1（PD-L1）表达水平对帕博利珠单抗免疫治疗患者筛选的敏感性不足，尤其在低表达肿瘤中表现明显。本研究通过mRNA二代测序技术（RNA-seq）对转录组PD-L1表达进行了回顾性评估。在2017年至2021年标准诊疗期间接受检测的连续NSCLC患者队列（n=3168）中，PD-L1免疫组化与RNA-seq检测结果呈现中等程度一致性，总体符合率达80%。多数不一致病例表现为免疫组化检测PD-L1低表达或阴性，而RNA-seq检测显示高表达。通过受试者工作特征曲线分析，RNA-seq能准确区分免疫组化高表达与低表达肿瘤，但无法有效鉴别免疫组化低表达与阴性肿瘤。在独立的帕博利珠单抗单药治疗队列（n=102）中，经RNA-seq判定为PD-L1高表达的NSCLC肿瘤患者，其治疗应答率、无进展生存期和总生存期均显著改善，这一结论在单独分析及联合免疫组化高/低表达状态分析中均成立。而PD-L1免疫组化状态（高/低表达）虽呈现改善疗效的趋势，但未达到统计学显著性。传统PD-L1免疫组化检测存在固有局限性，使其作为评估新型检测技术的参考标准存在不足。RNA-seq提供了一种客观的PD-L1检测方法，可作为免疫组化的补充检测手段，优化NSCLC患者免疫治疗的筛选策略。
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