Department of Surgery and Translational Medicine, Division of Pathological Anatomy, University of Florence.
Human Genetics Foundation (HuGeF), Turin.
Ann Oncol. 2014 Dec;25(12):2433-2442. doi: 10.1093/annonc/mdu452. Epub 2014 Sep 15.
Programmed cell death ligand 1 (PD-L1) is a cell surface molecule that plays a critical role in suppressing immune responses, mainly through binding of the PD-1 receptor on T lymphocytes. PD-L1 may be expressed by metastatic melanoma (MM). However, its clinical and biological significance remains unclear. Here, we investigated whether expression of PD-L1 in MM identifies a biologically more aggressive form of the disease, carrying prognostic relevance.
PD-L1 expression was analyzed by immunohistochemistry using two different antibodies in primary tumors and paired metastases from 81 melanoma patients treated at a single institution. Protein expression levels were correlated with PD-L1 mRNA, BRAF mutational status and clinical outcome. PD-L1(+) and PD-L1(-) subsets of the A375 cell line were stabilized in vitro and compared using gene expression profiling and functional assays. Results were confirmed using xenograft models.
PD-L1 membrane positivity was detected in 30/81 (37%) of patients. By multivariate analysis, Breslow thickness and PD-L1 membrane positivity were independent risk factors for melanoma-specific death {PD-L1 5% cutoff [hazard ratio (HR) 3.92, confidence interval (CI) 95% 1.61-9.55 P < 0.003], PD-L1 as continuous variable (HR 1.03, 95% CI 1.02-1.04 P < 0.002)}. PD-L1 expression defined a subset of the BRAF-mutated A375 cell line characterized by a highly invasive phenotype and by enhanced ability to grow in xenograft models.
PD-L1 is an independent prognostic marker in melanoma. If confirmed, our clinical and experimental data suggest that PD-L1(+) melanomas should be considered a disease subset with distinct genetic and morpho-phenotypic features, leading to enhanced aggressiveness and invasiveness.
程序性死亡配体 1（PD-L1）是一种细胞表面分子，在抑制免疫反应中起着关键作用，主要通过 T 淋巴细胞上的 PD-1 受体结合。PD-L1 可能在转移性黑色素瘤（MM）中表达。然而，其临床和生物学意义尚不清楚。在这里，我们研究了 MM 中 PD-L1 的表达是否确定了一种具有更强侵袭性的疾病形式，具有预后相关性。
在一家机构治疗的 81 名黑色素瘤患者的原发肿瘤和配对转移灶中，使用两种不同的抗体通过免疫组织化学分析 PD-L1 的表达。蛋白表达水平与 PD-L1mRNA、BRAF 突变状态和临床结果相关。体外稳定 A375 细胞系的 PD-L1(+)和 PD-L1(-)亚系，并通过基因表达谱和功能测定进行比较。使用异种移植模型进行验证。
在 81 名患者中的 30/81（37%）中检测到 PD-L1 膜阳性。通过多变量分析，Breslow 厚度和 PD-L1 膜阳性是黑色素瘤特异性死亡的独立危险因素{PD-L1 5%截值[危险比（HR）3.92，95%置信区间（CI）1.61-9.55 P <0.003]，PD-L1 作为连续变量（HR 1.03，95% CI 1.02-1.04 P <0.002)}。PD-L1 表达定义了 BRAF 突变的 A375 细胞系的一个亚系，其特征是侵袭性表型和在异种移植模型中生长能力增强。
PD-L1 是黑色素瘤的独立预后标志物。如果得到证实，我们的临床和实验数据表明，PD-L1(+)黑色素瘤应被视为具有独特遗传和形态表型特征的疾病亚群，导致侵袭性和侵袭性增强。
