Baseline β-catenin, programmed death-ligand 1 expression and tumour-infiltrating lymphocytes predict response and poor prognosis in BRAF inhibitor-treated melanoma patients

Daniela Massi, Emanuela Romano, Eliana Rulli, Barbara Merelli, Romina Nassini, Francesco De Logu, Ivan Bieche, Gianna Baroni, Laura Cattaneo, Gongda Xue, Mario Mandalà

Research output: Contribution to journalArticle

Abstract

Background The activation of oncogenic Wnt/β-catenin pathway in melanoma contributes to a lack of T-cell infiltration. Whether baseline β-catenin expression in the context of tumour-infiltrating lymphocytes (TILs) and programmed death ligand-1 (PD-L1) overexpression correlates with prognosis of metastatic melanoma patients (MMPs) treated with mitogen-activated protein kinase, MAPK inhibitor (MAPKi) monotherapy, however, has not been fully clarified. Patients and methods Sixty-four pre-treatment formalin-fixed and paraffin embedded melanoma samples from MMP treated with a BRAF inhibitor (n = 39) or BRAF and MEK inhibitors (n = 25) were assessed for presence of β-catenin, PD-L1, cluster of differentiation (CD)8, CD103 and forkhead box protein P3 (FOXP3) expression by immunohistochemistry, and results were correlated with clinical outcome. Quantitative assessment of mRNA transcripts associated with Wnt/β-catenin pathway and immune response was performed in 51 patients. Results We found an inverse correlation between tumoural β-catenin expression and the level of CD8, CD103 or forkhead box protein P3 (FOXP3) positivity in the tumour microenvironment (TME). By multivariate analysis, PD-L1 <5% (odds ratio, OR 0.12, 95% confidence interval, CI 0.03–0.53, p = 0.005) and the presence of CD8+ T cells (OR 18.27, 95%CI 2.54–131.52, p = 0.004) were significantly associated with a higher probability of response to MAPKi monotherapy. Responding patients showed a significantly increased expression of mRNA transcripts associated with adaptive immunity and antigen presentation. By multivariate analysis, progression-free survival (PFS) (hazards ratio (HR) = 0.25 95%CI 0.10–0.61, p = 0.002) and overall survival (OS) (HR = 0.24 95%CI 0.09–0.67, p = 0.006) were longer in patients with high density of CD8+ T cells and β-catenin <10% than those without CD8+ T cells infiltration and β-catenin ≥10%. Conclusion Our findings provide evidence that in the context of MAPKi monotherapy, immune subsets in the (TME) and gene signature predict prognosis in MMPs.

Original languageEnglish
Pages (from-to)70-81
Number of pages12
JournalEuropean Journal of Cancer
Volume78
DOIs
Publication statusPublished - Jun 1 2017

Keywords

  • BRAF inhibitors
  • Melanoma
  • prognosis
  • T lymphocytes
  • β-catenin

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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