title: PD-L1 marks a subset of melanomas with a shorter overall survival and distinct genetic and morphological characteristics.
abstract: 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 (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.
  
  
  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 [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.
  
  
  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.
authors.affiliation: Department of Surgery and Translational Medicine, Division of Pathological Anatomy, University of Florence.
authors.forename: D
authors.initials: D
authors.lastname: Massi
authors.affiliation: Human Genetics Foundation (HuGeF), Turin.
authors.forename: D
authors.initials: D
authors.lastname: Brusa
authors.affiliation: Unit of Medical Oncology, Department of Oncology and Hematology, Papa Giovanni XXIII Hospital, Bergamo.
authors.forename: B
authors.initials: B
authors.lastname: Merelli
authors.affiliation: Human Genetics Foundation (HuGeF), Turin.
authors.forename: M
authors.initials: M
authors.lastname: Ciano
authors.affiliation: Human Genetics Foundation (HuGeF), Turin; Department of Medical Sciences, University of Turin, Turin.
authors.forename: V
authors.initials: V
authors.lastname: Audrito
authors.affiliation: Human Genetics Foundation (HuGeF), Turin; Department of Medical Sciences, University of Turin, Turin.
authors.forename: S
authors.initials: S
authors.lastname: Serra
authors.affiliation: Human Genetics Foundation (HuGeF), Turin; Department of Medical Sciences, University of Turin, Turin.
authors.forename: R
authors.initials: R
authors.lastname: Buonincontri
authors.affiliation: Department of Surgery and Translational Medicine, Division of Pathological Anatomy, University of Florence.
authors.forename: G
authors.initials: G
authors.lastname: Baroni
authors.affiliation: Unit of Clinical Pharmacology and Oncology, Department of Health Sciences, University of Florence, Firenze.
authors.forename: R
authors.initials: R
authors.lastname: Nassini
authors.affiliation: Unit of Clinical Pharmacology and Oncology, Department of Health Sciences, University of Florence, Firenze.
authors.forename: D
authors.initials: D
authors.lastname: Minocci
authors.affiliation: Division of Pathological Anatomy, Papa Giovanni XXIII Hospital, Bergamo.
authors.forename: L
authors.initials: L
authors.lastname: Cattaneo
authors.affiliation: Department of Pathology, Experimental Molecular Pathology, National Cancer Institute, Milan.
authors.forename: E
authors.initials: E
authors.lastname: Tamborini
authors.affiliation: Research Foundation, Papa Giovanni XXIII Hospital, Bergamo.
authors.forename: A
authors.initials: A
authors.lastname: Carobbio
authors.affiliation: Department of Oncology, Clinical Research Laboratory, Mario Negri Institute IRCCS, Milan, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Rulli
authors.affiliation: Human Genetics Foundation (HuGeF), Turin; Department of Medical Sciences, University of Turin, Turin.
authors.forename: S
authors.initials: S
authors.lastname: Deaglio
authors.affiliation: Unit of Medical Oncology, Department of Oncology and Hematology, Papa Giovanni XXIII Hospital, Bergamo. Electronic address: mariomandala@tin.it.
authors.forename: M
authors.initials: M
authors.lastname: Mandalà
mesh_terms: D060890:B7-H1 Antigen / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D016019:Survival Analysis
chemical_list: D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C423236:CD274 protein, human
keywords: PD-L1; metastatic melanoma; prognostic markers