PD-L1 marks a subset of melanomas with a shorter overall survival and distinct genetic and morphological characteristics

D. Massi, D. Brusa, B. Merelli, M. Ciano, V. Audrito, S. Serra, R. Buonincontri, G. Baroni, R. Nassini, D. Minocci, L. Cattaneo, E. Tamborini, A. Carobbio, E. Rulli, S. Deaglio, M. Mandalà

Research output: Contribution to journalArticlepeer-review

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.

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 [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.

Original languageEnglish
Pages (from-to)2433-2442
Number of pages10
JournalAnnals of Oncology
Volume25
Issue number12
DOIs
Publication statusPublished - Dec 1 2014

Keywords

  • metastatic melanoma
  • PD-L1
  • prognostic markers

ASJC Scopus subject areas

  • Medicine(all)

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