癌症免疫逃避对于非小细胞肺癌 (NSCLC) 至关重要，并且已成为免疫治疗的目标。高可溶性 (s)PD-L1 与晚期生存率降低和治疗失败相关。在这里，我们评估了 sPD-L1 对早期 NSCLC 中 T 细胞、无复发生存和总生存的影响。在 sPD-L1 存在的情况下进行体外 T 细胞刺激，以评估其免疫调节活性。研究了癌症基因组图谱 (TCGA) 的数据中的 PD-L1 剪接变体和参与蛋白水解切割的酶（即 ADAM10）。在治愈性手术前收集了 74 名 NSCLC（IA-IIIB 期）以及另外 73 名（对照组）患者的血浆。此后，免疫吸附测定的 sPD-L1 水平与患者结果相关。体外 sPD-L1 抑制 T 细胞的 IFN-γ 产生和增殖，并诱导表达 CD27 的终末效应 CD4 T 细胞亚型。 TCGA 的数据表明，ADAM10 mRNA 水平升高是 NSCLC 患者预后的负面预测因素。为了研究这些体外和 TCGA 结果的临床相关性，我们量化了早期 NSCLC 患者血浆中的 sPD-L1。在第一个队列中，我们发现复发性 NSCLC 患者的 sPD-L1 水平显着较高，多变量分析显示高 sPD-L1 (>1000 pg/mL) 作为生存的独立预测因子。然而，这些发现无法在两个独立的对照队列中得到验证。尽管体外和 TCGA 数据支持 sPD-L1 的抑制作用，但我们无法将其转化为临床环境。这些结果可能是由于患者数量少、患者的异质性以及缺乏标准化的 sPD-L1 ELISA 所致。我们关于 sPD-L1 在早期 NSCLC 中的价值的不确定结果需要在更大规模的（新）辅助试验中进行检测验证和进一步研究。版权所有 © 2024 作者。由 Elsevier B.V. 出版。保留所有权利。

Cancer immune evasion is critical in non-small cell lung cancer (NSCLC) and has been targeted by immunotherapy. High soluble (s)PD-L1 is associated with reduced survival and treatment failure in advanced stages. Here we evaluated the effects of sPD-L1 on T cells, relapse free survival, and overall survival in early stage NSCLC.In vitro T cell stimulation was performed in the presence of sPD-L1 to evaluate its immunomodulatory activity. Data from The Cancer Genome Atlas (TCGA) were investigated for PD-L1 splice variants and enzymes involved in proteolytic cleavage (i.e. ADAM10). Plasma from 74 NSCLC (stage IA-IIIB), as well as an additional 73 (control cohort) patients was collected prior to curative surgery. Thereafter sPD-L1 levels from an immunosorbent assay were correlated with patient outcome.In vitro sPD-L1 inhibited IFN-γ production and proliferation of T cells and induced a terminal effector CD4 T cell subtype expressing CD27. Data from the TCGA demonstrated that elevated mRNA levels of ADAM10 is a negative predictor of outcome in NSCLC patients. To investigate the clinical relevance of these in vitro and TCGA findings, we quantified sPD-L1 in the plasma of early-stage NSCLC patients. In the first cohort we found significantly higher sPD-L1 levels in relapsing NSCLC patients, with a multivariate analysis revealing high sPD-L1 (>1000 pg/mL) as an independent predictor of survival. However, these findings could not be validated in two independent control cohorts.Although in vitro and TCGA data support the suppressive effect of sPD-L1 we were unable to translate this in our clinical setting. These results may be due to the small patient number and their heterogeneity as well as the lack of a standardized sPD-L1 ELISA. Our inconclusive results regarding the value of sPD-L1 in early stage NSCLC warrant assay validation and further investigation in larger (neo-)adjuvant trials.Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.