The density and spatial tissue distribution of CD8+ and CD163+ immune cells predict response and outcome in melanoma patients receiving MAPK inhibitors

Italian Melanoma Intergroup

Research output: Contribution to journalArticle

Abstract

BACKGROUND: Clinical response to MAPK inhibitors in metastatic melanoma patients is heterogeneous for reasons still needing to be elucidated. As the patient immune activity contributes to treatment clinical benefit, the pre-existing level of immunity at tumor site may provide biomarkers of disease outcome to therapy. Here we investigated whether assessing the density and spatial tissue distribution of key immune cells in the tumor microenvironment could identify patients predisposed to respond to MAPK inhibitors. METHODS: Pretreatment tumor biopsies from a total of 213 patients (158 for the training set and 55 for the validation set) treated with BRAF or BRAF/MEK inhibitors within the Italian Melanoma Intergroup were stained with selected immune markers (CD8, CD163, β-catenin, PD-L1, PD-L2). Results, obtained by blinded immunohistochemical scoring and digital image analysis, were correlated with clinical response and outcome by multivariate logistic models on response to treatment and clinical outcome, adjusted for American Joint Committee on Cancer stage, performance status, lactate dehydrogenase and treatment received. RESULTS: Patients with high intratumoral, but not peritumoral, CD8+ T cells and concomitantly low CD163+ myeloid cells displayed higher probability of response (OR 9.91, 95% CI 2.23-44.0, p = 0.003) and longer overall survival (HR 0.34, 95% CI 0.16-0.72, p = 0.005) compared to those with intratumoral low CD8+ T cells and high CD163+ myeloid cells. The latter phenotype was instead associated with a shorter progression free survival (p = 0.010). In contrast, PD-L1 and PD-L2 did not correlate with clinical outcome while tumor β-catenin overexpression showed association with lower probability of response (OR 0.48, 95% CI 0.21-1.06, p = 0.068). CONCLUSIONS: Analysis of the spatially constrained distribution of CD8+ and CD163+ cells, representative of the opposite circuits of antitumor vs protumor immunity, respectively, may assist in identifying melanoma patients with improved response and better outcome upon treatment with MAPK inhibitors. These data underline the role of endogenous immune microenvironment in predisposing metastatic melanoma patients to benefit from therapies targeting driver-oncogenic pathways.

Original languageEnglish
Number of pages1
JournalJournal for ImmunoTherapy of Cancer
Volume7
Issue number1
DOIs
Publication statusPublished - Nov 15 2019

Fingerprint

Tissue Distribution
Melanoma
Catenins
Myeloid Cells
Immunity
Neoplasms
Biomarkers
T-Lymphocytes
Tumor Microenvironment
Mitogen-Activated Protein Kinase Kinases
Therapeutics
L-Lactate Dehydrogenase
Disease-Free Survival
Logistic Models
Phenotype
Biopsy
Survival

Keywords

  • Melanoma prognosis
  • Microenvironment
  • Myeloid cells
  • T lymphocytes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

Cite this

@article{ae0c7402701f457f8d399f9a5ad1e3e8,
title = "The density and spatial tissue distribution of CD8+ and CD163+ immune cells predict response and outcome in melanoma patients receiving MAPK inhibitors",
abstract = "BACKGROUND: Clinical response to MAPK inhibitors in metastatic melanoma patients is heterogeneous for reasons still needing to be elucidated. As the patient immune activity contributes to treatment clinical benefit, the pre-existing level of immunity at tumor site may provide biomarkers of disease outcome to therapy. Here we investigated whether assessing the density and spatial tissue distribution of key immune cells in the tumor microenvironment could identify patients predisposed to respond to MAPK inhibitors. METHODS: Pretreatment tumor biopsies from a total of 213 patients (158 for the training set and 55 for the validation set) treated with BRAF or BRAF/MEK inhibitors within the Italian Melanoma Intergroup were stained with selected immune markers (CD8, CD163, β-catenin, PD-L1, PD-L2). Results, obtained by blinded immunohistochemical scoring and digital image analysis, were correlated with clinical response and outcome by multivariate logistic models on response to treatment and clinical outcome, adjusted for American Joint Committee on Cancer stage, performance status, lactate dehydrogenase and treatment received. RESULTS: Patients with high intratumoral, but not peritumoral, CD8+ T cells and concomitantly low CD163+ myeloid cells displayed higher probability of response (OR 9.91, 95{\%} CI 2.23-44.0, p = 0.003) and longer overall survival (HR 0.34, 95{\%} CI 0.16-0.72, p = 0.005) compared to those with intratumoral low CD8+ T cells and high CD163+ myeloid cells. The latter phenotype was instead associated with a shorter progression free survival (p = 0.010). In contrast, PD-L1 and PD-L2 did not correlate with clinical outcome while tumor β-catenin overexpression showed association with lower probability of response (OR 0.48, 95{\%} CI 0.21-1.06, p = 0.068). CONCLUSIONS: Analysis of the spatially constrained distribution of CD8+ and CD163+ cells, representative of the opposite circuits of antitumor vs protumor immunity, respectively, may assist in identifying melanoma patients with improved response and better outcome upon treatment with MAPK inhibitors. These data underline the role of endogenous immune microenvironment in predisposing metastatic melanoma patients to benefit from therapies targeting driver-oncogenic pathways.",
keywords = "Melanoma prognosis, Microenvironment, Myeloid cells, T lymphocytes",
author = "{Italian Melanoma Intergroup} and Daniela Massi and Eliana Rulli and Mara Cossa and Barbara Valeri and Monica Rodolfo and Barbara Merelli and {De Logu}, Francesco and Romina Nassini and {Del Vecchio}, Michele and {Di Guardo}, Lorenza and {De Penni}, Roberta and Michele Guida and Sileni, {Vanna Chiarion} and {Di Giacomo}, {Anna Maria} and Marco Tucci and Marcella Occelli and Francesca Portelli and Viviana Vallacchi and Francesca Consoli and Pietro Quaglino and Paola Queirolo and Gianna Baroni and Fabrizio Carnevale-Schianca and Laura Cattaneo and Alessandro Minisini and Giuseppe Palmieri and Licia Rivoltini and Mario Mandal{\`a}",
year = "2019",
month = "11",
day = "15",
doi = "10.1186/s40425-019-0797-4",
language = "English",
volume = "7",
journal = "Journal for ImmunoTherapy of Cancer",
issn = "2051-1426",
publisher = "BioMed Central",
number = "1",

}

TY - JOUR

T1 - The density and spatial tissue distribution of CD8+ and CD163+ immune cells predict response and outcome in melanoma patients receiving MAPK inhibitors

AU - Italian Melanoma Intergroup

AU - Massi, Daniela

AU - Rulli, Eliana

AU - Cossa, Mara

AU - Valeri, Barbara

AU - Rodolfo, Monica

AU - Merelli, Barbara

AU - De Logu, Francesco

AU - Nassini, Romina

AU - Del Vecchio, Michele

AU - Di Guardo, Lorenza

AU - De Penni, Roberta

AU - Guida, Michele

AU - Sileni, Vanna Chiarion

AU - Di Giacomo, Anna Maria

AU - Tucci, Marco

AU - Occelli, Marcella

AU - Portelli, Francesca

AU - Vallacchi, Viviana

AU - Consoli, Francesca

AU - Quaglino, Pietro

AU - Queirolo, Paola

AU - Baroni, Gianna

AU - Carnevale-Schianca, Fabrizio

AU - Cattaneo, Laura

AU - Minisini, Alessandro

AU - Palmieri, Giuseppe

AU - Rivoltini, Licia

AU - Mandalà, Mario

PY - 2019/11/15

Y1 - 2019/11/15

N2 - BACKGROUND: Clinical response to MAPK inhibitors in metastatic melanoma patients is heterogeneous for reasons still needing to be elucidated. As the patient immune activity contributes to treatment clinical benefit, the pre-existing level of immunity at tumor site may provide biomarkers of disease outcome to therapy. Here we investigated whether assessing the density and spatial tissue distribution of key immune cells in the tumor microenvironment could identify patients predisposed to respond to MAPK inhibitors. METHODS: Pretreatment tumor biopsies from a total of 213 patients (158 for the training set and 55 for the validation set) treated with BRAF or BRAF/MEK inhibitors within the Italian Melanoma Intergroup were stained with selected immune markers (CD8, CD163, β-catenin, PD-L1, PD-L2). Results, obtained by blinded immunohistochemical scoring and digital image analysis, were correlated with clinical response and outcome by multivariate logistic models on response to treatment and clinical outcome, adjusted for American Joint Committee on Cancer stage, performance status, lactate dehydrogenase and treatment received. RESULTS: Patients with high intratumoral, but not peritumoral, CD8+ T cells and concomitantly low CD163+ myeloid cells displayed higher probability of response (OR 9.91, 95% CI 2.23-44.0, p = 0.003) and longer overall survival (HR 0.34, 95% CI 0.16-0.72, p = 0.005) compared to those with intratumoral low CD8+ T cells and high CD163+ myeloid cells. The latter phenotype was instead associated with a shorter progression free survival (p = 0.010). In contrast, PD-L1 and PD-L2 did not correlate with clinical outcome while tumor β-catenin overexpression showed association with lower probability of response (OR 0.48, 95% CI 0.21-1.06, p = 0.068). CONCLUSIONS: Analysis of the spatially constrained distribution of CD8+ and CD163+ cells, representative of the opposite circuits of antitumor vs protumor immunity, respectively, may assist in identifying melanoma patients with improved response and better outcome upon treatment with MAPK inhibitors. These data underline the role of endogenous immune microenvironment in predisposing metastatic melanoma patients to benefit from therapies targeting driver-oncogenic pathways.

AB - BACKGROUND: Clinical response to MAPK inhibitors in metastatic melanoma patients is heterogeneous for reasons still needing to be elucidated. As the patient immune activity contributes to treatment clinical benefit, the pre-existing level of immunity at tumor site may provide biomarkers of disease outcome to therapy. Here we investigated whether assessing the density and spatial tissue distribution of key immune cells in the tumor microenvironment could identify patients predisposed to respond to MAPK inhibitors. METHODS: Pretreatment tumor biopsies from a total of 213 patients (158 for the training set and 55 for the validation set) treated with BRAF or BRAF/MEK inhibitors within the Italian Melanoma Intergroup were stained with selected immune markers (CD8, CD163, β-catenin, PD-L1, PD-L2). Results, obtained by blinded immunohistochemical scoring and digital image analysis, were correlated with clinical response and outcome by multivariate logistic models on response to treatment and clinical outcome, adjusted for American Joint Committee on Cancer stage, performance status, lactate dehydrogenase and treatment received. RESULTS: Patients with high intratumoral, but not peritumoral, CD8+ T cells and concomitantly low CD163+ myeloid cells displayed higher probability of response (OR 9.91, 95% CI 2.23-44.0, p = 0.003) and longer overall survival (HR 0.34, 95% CI 0.16-0.72, p = 0.005) compared to those with intratumoral low CD8+ T cells and high CD163+ myeloid cells. The latter phenotype was instead associated with a shorter progression free survival (p = 0.010). In contrast, PD-L1 and PD-L2 did not correlate with clinical outcome while tumor β-catenin overexpression showed association with lower probability of response (OR 0.48, 95% CI 0.21-1.06, p = 0.068). CONCLUSIONS: Analysis of the spatially constrained distribution of CD8+ and CD163+ cells, representative of the opposite circuits of antitumor vs protumor immunity, respectively, may assist in identifying melanoma patients with improved response and better outcome upon treatment with MAPK inhibitors. These data underline the role of endogenous immune microenvironment in predisposing metastatic melanoma patients to benefit from therapies targeting driver-oncogenic pathways.

KW - Melanoma prognosis

KW - Microenvironment

KW - Myeloid cells

KW - T lymphocytes

UR - http://www.scopus.com/inward/record.url?scp=85075088750&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85075088750&partnerID=8YFLogxK

U2 - 10.1186/s40425-019-0797-4

DO - 10.1186/s40425-019-0797-4

M3 - Article

C2 - 31730502

AN - SCOPUS:85075088750

VL - 7

JO - Journal for ImmunoTherapy of Cancer

JF - Journal for ImmunoTherapy of Cancer

SN - 2051-1426

IS - 1

ER -