title: The status of PD-L1 and tumor-infiltrating immune cells predict resistance and poor prognosis in BRAFi-treated melanoma patients harboring mutant BRAFV600.
abstract: BACKGROUND
  BRAF inhibitors (BRAFi) improve survival in metastatic melanoma patients (MMP) but the duration of clinical benefit is limited by development of drug resistance. Here, we investigated whether the expression of programmed death-ligand 1 (PD-L1) and the density of tumor-infiltrating mononuclear cells (TIMC) predict the occurrence of resistance, hence affecting the clinical outcome in BRAFi-treated MMP.
  
  
  METHODS
  PD-L1 expression (cutoff 5%) was analyzed by immunohistochemistry with two different antibodies in BRAF(V600)-mutated formalin-fixed and paraffin-embedded samples from 80 consecutive MMP treated with BRAFi at a single institution. TIMC were evaluated by conventional hematoxylin and eosin staining.
  
  
  RESULTS
  Forty-six and 34 patients received vemurafenib and dabrafenib, respectively. Membranous expression of PD-L1 was detected in 28/80 (35%) of patients. At multivariate analysis, absence of tumoral PD-L1 staining [odd ratio (OR) 10.8, 95% confidence interval (CI) 2.7-43.3, P < 0.001] and the presence of TIMC (OR 6.5, 95% CI 1.7-24.3, P < 0.005) were associated with a better response to treatment. Median progression-free survival (PFS) and overall survival were 10 and 15 months, respectively. By multivariate assessment, PD-L1 expression [hazard ratio (HR) 4.3, 95% CI 2.1-8.7, P < 0.0001] and absence of TIMC (HR 2.5, 95% CI 1.4-4.7, P < 0.002) correlated with shorter PFS. PD-L1 overexpression (HR 6.2, 95% CI 2.8-14.2, P < 0.0001) and absence of TIMC (HR 3.1, 95% CI 1.5-6.5, P < 0.002) were independent prognostic factors for melanoma-specific survival.
  
  
  CONCLUSIONS
  Our results provide the first proof-of-principle evidence for the predictive and prognostic relevance of PD-L1 immunohistochemical expression and density of immune cell infiltration in BRAF(V600)-mutated MMP treated with BRAFi.
authors.affiliation: Division of Pathological Anatomy, Department of Surgery and Translational Medicine, University of Florence, 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: Research Foundation, Papa Giovanni XXIII Hospital, Bergamo, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Falcone
authors.affiliation: Department of Biomedicine, University Hospital of Basel, Basel, Switzerland.
authors.forename: G
authors.initials: G
authors.lastname: Xue
authors.affiliation: Department of Biomedicine, University Hospital of Basel, Basel, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Carobbio
authors.affiliation: Unit of Clinical Pharmacology and Oncology, Department of Health Sciences, University of Florence, Florence.
authors.forename: R
authors.initials: R
authors.lastname: Nassini
authors.affiliation: Division of Pathological Anatomy, Department of Surgery and Translational Medicine, University of Florence, Florence.
authors.forename: G
authors.initials: G
authors.lastname: Baroni
authors.affiliation: Experimental Molecular Pathology, Department of Pathology, National Cancer Institute, Milan.
authors.forename: E
authors.initials: E
authors.lastname: Tamborini
authors.affiliation: Division of Pathological Anatomy, Papa Giovanni XXIII Hospital, Bergamo.
authors.forename: L
authors.initials: L
authors.lastname: Cattaneo
authors.affiliation: Human Genetics Foundation (HuGeF), 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, Italy.
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: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D060890:B7-H1 Antigen / Q000096:biosynthesis*; D014408:Biomarkers, Tumor / Q000378:metabolism; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use; D007211:Indoles / Q000627:therapeutic use; D018655:Lymphocyte Count; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D008875:Middle Aged; D010091:Oximes / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D012189:Retrospective Studies; D013449:Sulfonamides / Q000627:therapeutic use; D000077484:Vemurafenib; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C423236:CD274 protein, human; D007093:Imidazoles; D007211:Indoles; D010091:Oximes; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C561627:dabrafenib
keywords: BRAF inhibitors; PD-L1; immune cell infiltration; melanoma; prognosis; resistance