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

16 Citations (Scopus)

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

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Tumor-Infiltrating Lymphocytes
Catenins
Melanoma
Ligands
Forkhead Transcription Factors
T-Lymphocytes
Wnt Signaling Pathway
Tumor Microenvironment
Multivariate Analysis
Messenger RNA
Mitogen-Activated Protein Kinase Kinases
Antigen Presentation
Adaptive Immunity
Protein Kinase Inhibitors
Mitogen-Activated Protein Kinases
Paraffin
Formaldehyde
Disease-Free Survival
Immunohistochemistry
Odds Ratio

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Baseline β-catenin, programmed death-ligand 1 expression and tumour-infiltrating lymphocytes predict response and poor prognosis in BRAF inhibitor-treated melanoma patients. / Massi, Daniela; Romano, Emanuela; Rulli, Eliana; Merelli, Barbara; Nassini, Romina; De Logu, Francesco; Bieche, Ivan; Baroni, Gianna; Cattaneo, Laura; Xue, Gongda; Mandalà, Mario.

In: European Journal of Cancer, Vol. 78, 01.06.2017, p. 70-81.

Research output: Contribution to journalArticle

Massi, Daniela ; Romano, Emanuela ; Rulli, Eliana ; Merelli, Barbara ; Nassini, Romina ; De Logu, Francesco ; Bieche, Ivan ; Baroni, Gianna ; Cattaneo, Laura ; Xue, Gongda ; Mandalà, Mario. / Baseline β-catenin, programmed death-ligand 1 expression and tumour-infiltrating lymphocytes predict response and poor prognosis in BRAF inhibitor-treated melanoma patients. In: European Journal of Cancer. 2017 ; Vol. 78. pp. 70-81.
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title = "Baseline β-catenin, programmed death-ligand 1 expression and tumour-infiltrating lymphocytes predict response and poor prognosis in BRAF inhibitor-treated melanoma patients",
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.",
keywords = "BRAF inhibitors, Melanoma, prognosis, T lymphocytes, β-catenin",
author = "Daniela Massi and Emanuela Romano and Eliana Rulli and Barbara Merelli and Romina Nassini and {De Logu}, Francesco and Ivan Bieche and Gianna Baroni and Laura Cattaneo and Gongda Xue and Mario Mandal{\`a}",
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TY - JOUR

T1 - Baseline β-catenin, programmed death-ligand 1 expression and tumour-infiltrating lymphocytes predict response and poor prognosis in BRAF inhibitor-treated melanoma patients

AU - Massi, Daniela

AU - Romano, Emanuela

AU - Rulli, Eliana

AU - Merelli, Barbara

AU - Nassini, Romina

AU - De Logu, Francesco

AU - Bieche, Ivan

AU - Baroni, Gianna

AU - Cattaneo, Laura

AU - Xue, Gongda

AU - Mandalà, Mario

PY - 2017/6/1

Y1 - 2017/6/1

N2 - 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.

AB - 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.

KW - BRAF inhibitors

KW - Melanoma

KW - prognosis

KW - T lymphocytes

KW - β-catenin

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U2 - 10.1016/j.ejca.2017.03.012

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C2 - 28412591

AN - SCOPUS:85017437018

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JO - European Journal of Cancer

JF - European Journal of Cancer

SN - 0959-8049

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