Internal Medicine V, Hematology and Oncology, Medical University Innsbruck, 6020, Innsbruck, Austria.
Internal Medicine V, Hematology and Oncology, Medical University Innsbruck, 6020, Innsbruck, Austria; Tyrolean Cancer Research Institute, 6020 Innsbruck, Austria; Department of Biosciences and Medical Biology, University of Salzburg, 5020 Salzburg, Austria.
Lung Cancer. 2024 Oct;196:107955. doi: 10.1016/j.lungcan.2024.107955. Epub 2024 Sep 16.
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.
癌症免疫逃逸在非小细胞肺癌（NSCLC）中至关重要，并已成为免疫疗法的靶点。高水平的可溶性（s）PD-L1 与晚期患者的生存时间缩短和治疗失败有关。在此，我们评估了 sPD-L1 对早期 NSCLC 中的 T 细胞、无复发生存和总生存的影响。
在存在 sPD-L1 的情况下进行体外 T 细胞刺激，以评估其免疫调节活性。研究了来自癌症基因组图谱（TCGA）的数据，以研究 PD-L1 剪接变体和参与蛋白水解切割的酶（即 ADAM10）。在根治性手术前，收集了 74 例 NSCLC（IA-IIIB 期）患者以及另外 73 例（对照队列）患者的血浆。此后，免疫吸附测定法的 sPD-L1 水平与患者的预后相关。
体外 sPD-L1 抑制 IFN-γ 的产生和 T 细胞的增殖，并诱导表达 CD27 的终末效应 CD4 T 细胞亚型。TCGA 中的数据表明，ADAM10 的 mRNA 水平升高是 NSCLC 患者预后不良的阴性预测因子。为了研究这些体外和 TCGA 发现的临床相关性，我们定量了早期 NSCLC 患者血浆中的 sPD-L1。在第一个队列中，我们发现复发 NSCLC 患者的 sPD-L1 水平显著升高，多变量分析显示高 sPD-L1（>1000 pg/mL）是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，但我们无法在临床环境中进行转化。这些结果可能是由于患者数量少且异质性以及缺乏标准化的 sPD-L1 ELISA 所致。我们关于早期 NSCLC 中 sPD-L1 价值的不确定结果需要进一步在更大的（新）辅助试验中进行验证和研究。
