可溶性PD-L1在早期非小细胞肺癌（NSCLC）中没有复发和总生存期的关联。
Soluble PD-L1 shows no association to relapse and overall survival in early stage non-small cell lung cancer (NSCLC)
影响因子:4.40000
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
摘要
癌症免疫逃避在非小细胞肺癌（NSCLC）中至关重要，并且已受到免疫疗法的靶向。高可溶性PD-L1与晚期阶段的存活率和治疗失败有关。在这里，我们评估了SPD-L1对T细胞，无复发存活的影响，并在早期NSCLC中进行了总体存活。在SPD-L1的存在下，进行了体外T细胞刺激，以评估其免疫调节活性。研究了来自癌症基因组图集（TCGA）的数据，以了解参与蛋白水解裂解的PD-L1剪接变体和酶（即ADAM10）。在治愈手术之前，收集了74个NSCLC（IA-IIIB期）的血浆以及另外73名（对照组）患者。此后，来自免疫吸附测定的SPD-L1水平与患者结局相关。在体外SPD-L1抑制了T细胞的IFN-L1产生和T细胞的增殖，并诱导了表达CD27的末端效应CD4 T细胞亚型。来自TCGA的数据表明，ADAM10的mRNA水平升高是NSCLC患者预后的负面预测指标。为了研究这些体外和TCGA发现的临床相关性，我们在早期NSCLC患者的血浆中量化了SPD-L1。在第一个队列中，我们发现复发性NSCLC患者的SPD-L1水平明显更高，多变量分析表明，作为生存的独立预测指标，高SPD-L1（> 1000 pg/ml）。但是，这些发现无法在两个独立的对照组中得到验证。尽管体外和TCGA数据支持SPD-L1的抑制作用，但我们无法在临床环境中转化这一点。这些结果可能是由于患者人数较小及其异质性以及缺乏标准化的SPD-L1 ELISA。我们关于早期NSCLC的SPD-L1价值的确定结果尚无定论，并在较大（NEO-）辅助试验中进行进一步研究。
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.