PD-L1 marks a subset of melanomas with a shorter overall survival and distinct genetic and morphological characteristics
A partir d'échantillons de tumeurs primitives et de métastases prélevés sur des patients atteints d'un mélanome, puis menée sur une lignée cellulaire et à l'aide de xénogreffes, cette étude suggère que la surexpression de PD-L1 permet de définir une forme agressive de la maladie
Background : 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. However, its clinical and biological significance remains unclear. Here, we investigated whether expression of PD-L1 in metastatic melanoma identifies a biologically more aggressive form of the disease, carrying prognostic relevance.
Patients and Methods : 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.
Results : 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 (HR 3.92, CI 95% 1.61-9.55 p< 0.003), PD-L1 as continuous variable (HR 1.03, CI 95% 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.
Conclusions : 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.
Annals of Oncology , résumé, 2014