程序性细胞死亡配体1（PD-L1）表达仍然是预测免疫检查点抑制剂（ICI）反应的最广泛使用的生物标志物，但其预测能力差异很大。迫切需要确定影响PD-L1表现差异的因素。本研究利用包含1239名患者的三个独立试验的数据，根据肿瘤转录组鉴定了具有明显PD-L1预测能力区别的癌症亚型。在预测性较高（PH）组中，与三个试验中PD-L1-肿瘤相比，PD-L1+肿瘤通过ICI显示出更好的总生存期、无进展生存期和客观反应率。然而，在预测性较低（PL）组中，PD-L1-肿瘤呈相反趋势，显示出更好的结局。PH组中的PD-L1+肿瘤显示ICI优于化疗，而PL组中的PD-L1+肿瘤两种治疗方法效果相当，或者显示出偏向化疗的相反趋势。无论免疫亚型（免疫丰富或非免疫）、PD-L1调控机制（适应性或构成性）、肿瘤突变负荷或新抗原负荷如何，这种上下文相关的预测性观察都具有显著性。本研究揭示了优化PD-L1表达在临床决策和试验设计中使用的途径，但这种探索性概念应在大型试验中进一步证实。© 2023年。Nature Publishing Group UK.

Programmed cell death ligand 1 (PD-L1) expression remains the most widely used biomarker for predicting response to immune checkpoint inhibitors (ICI), but its predictiveness varies considerably. Identification of factors accounting for the varying PD-L1 performance is urgently needed. Here, using data from three independent trials comprising 1239 patients, we have identified subsets of cancer with distinct PD-L1 predictiveness based on tumor transcriptome. In the Predictiveness-High (PH) group, PD-L1+ tumors show better overall survival, progression-free survival, and objective response rate with ICI than PD-L1- tumors across three trials. However, the Predictiveness-Low (PL) group demonstrates an opposite trend towards better outcomes for PD-L1- tumors. PD-L1+ tumors from the PH group demonstrate the superiority of ICI over chemotherapy, whereas PD-L1+ tumors from the PL group show comparable efficacy between two treatments or exhibit an opposite trend favoring chemotherapy. This observation of context-dependent predictiveness remains strong regardless of immune subtype (Immune-Enriched or Non-Immune), PD-L1 regulation mechanism (adaptative or constitutive), tumor mutation burden, or neoantigen load. This work illuminates avenues for optimizing the use of PD-L1 expression in clinical decision-making and trial design, although this exploratory concept should be further confirmed in large trials.© 2023. Nature Publishing Group UK.