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 language | English |
|---|---|
| Pages (from-to) | 70-81 |
| Number of pages | 12 |
| Journal | European Journal of Cancer |
| Volume | 78 |
| DOIs | |
| Publication status | Published - Jun 1 2017 |
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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 journal › Article
}
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
UR - http://www.scopus.com/inward/record.url?scp=85017437018&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85017437018&partnerID=8YFLogxK
U2 - 10.1016/j.ejca.2017.03.012
DO - 10.1016/j.ejca.2017.03.012
M3 - Article
C2 - 28412591
AN - SCOPUS:85017437018
VL - 78
SP - 70
EP - 81
JO - European Journal of Cancer
JF - European Journal of Cancer
SN - 0959-8049
ER -