血清PD-L1在早期非小细胞肺癌（NSCLC）中的无复发生存和总生存无关
Soluble PD-L1 shows no association to relapse and overall survival in early stage non-small cell lung cancer (NSCLC)
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影响因子:4.4
分区:医学2区 / 肿瘤学3区 呼吸系统3区
发表日期:2024 Oct
作者:
F O Mildner, M M Sykora, H Hackl, A Amann, B Zelger, S Sprung, M L Buch, F Nocera, P Moser, H Maier, F Augustin, C Manzl, F Kocher, A Pircher, J Lindenmann, I Mykoliuk, S Raftopoulou, J Kargl, D Wolf, S Sopper, G Gamerith
DOI:
10.1016/j.lungcan.2024.107955
摘要
癌症免疫逃逸在非小细胞肺癌（NSCLC）中具有关键作用，免疫疗法针对这一机制展开。高水平的可溶性（s）PD-L1与晚期患者的生存率降低和治疗失败相关。在本研究中，我们评估了sPD-L1对T细胞、无复发生存（RFS）和总生存（OS）的影响，研究对象为早期NSCLC患者。体外对T细胞进行刺激，加入sPD-L1以评估其免疫调节作用。利用癌症基因组图谱数据库（TCGA）分析PD-L1剪接变异及蛋白酶裂解相关酶（如ADAM10）表达情况。采集74例早期（IA-IIIB期）NSCLC患者及另外73例对照组患者血浆，均在根治性手术前采集。通过免疫吸附法检测血浆中sPD-L1水平，并与患者预后进行相关性分析。体外实验发现，sPD-L1抑制T细胞产生IFN-γ和增殖，并诱导表达CD27的终末效应CD4 T细胞亚型。TCGA数据显示，ADAM10 mRNA水平升高是NSCLC患者预后的负面预测因子。为验证这些体外和TCGA的发现，我们测定了早期NSCLC患者血浆中的sPD-L1水平。第一份研究中，复发患者的sPD-L1水平显著高于非复发患者，多变量分析显示sPD-L1（>1000 pg/mL）为独立的生存预测因子。然而，这些结果未能在两个独立的对照队列中得到验证。尽管体外实验和TCGA数据支持sPD-L1的免疫抑制作用，但在临床实践中未能得到证实。这可能由于患者样本量较小、异质性较大，以及缺乏标准化的sPD-L1 ELISA检测试剂盒。对于早期NSCLC中sPD-L1价值的结论性不足，提示需要进行试剂验证并在更大规模的（新辅助/辅助）临床试验中进一步研究。
Abstract
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.