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Tesi etd-05222015-122908


Thesis type
Tesi di specializzazione (5 anni)
Author
NASSINI, ROMINA
URN
etd-05222015-122908
Title
Biological significance and prognostic role of PD-L1 expression in cutaneous melanoma
Struttura
RICERCA TRASLAZIONALE E DELLE NUOVE TECNOLOGIE IN MEDICINA E CHIRURGIA
Corso di studi
PATOLOGIA CLINICA
Commissione
correlatore Prof. Massi, Daniela
relatore Prof. Pompella, Alfonso
Parole chiave
  • Metastatic Melanoma
  • PD-L1
  • prognostic markers
Data inizio appello
22/06/2015;
Consultabilità
completa
Riassunto analitico
In the largest study so far reported in the literature, PD-L1 membrane expression was an independent negative prognostic factor in melanoma patients. In the present study, by multivariate analysis, Breslow thickness and PD-L1 membrane positivity were independent risk factors for melanoma-specific death.<br> This conclusion was reached upon testing PD-L1 expression in a cohort of 81 consecutive MMP treated at a single institution, and comparing two antibodies specific for PD-L1. This is the first study demonstrating the prognostic role of PD-L1 in melanoma patients by using the validated mouse monoclonal 5H1 antibody. <br> In agreement with a negative prognostic role for PD-L1, our study showed that metastatic melanoma samples express PD-L1 in significantly higher proportions than primary melanoma (40.3% vs 14%). In 17/22 patients the metastatic site resulted positive while primary melanomas were negative, suggesting that PD-L1 expression is acquired during disease progression. <br> In the second part of the work, we asked whether PD-L1 expression was simply the result of microenvironmental pressures on the tumour cell or whether it was an intrinsic feature, marking a disease subset with specific characteristics. 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.<br> Gene profiling indicated that the PD-L1+ cell subset was characterized by a unique genetic signature, with enhanced expression of genes connected to growth, activation and invasion. A functional comparison confirmed that: i) the PD-L1+ variant showed signs of increased growth and invasion in vitro, ii) these features were enhanced when using three-dimensional cultures and maintained after xenografting in immunocompromised mice.<br> From the translational standpoint, our data suggest that beside the known effects on immune response modulation, PD-L1 expression marks a subset of melanoma cells characterized by a specific gene expression profile and by increased growth and aggressiveness. Our results suggest that PD-L1 is not mechanistically responsible for the more aggressive phenotype in melanoma cells.<br> 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. <br> Future studies will tell whether PD-L1 expression is also a marker of resistance to selected therapies and whether it may be successfully exploited alone or in combination as a target for specific subsets of melanoma patients.
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