Clinical Significance of Tumor-Associated Inflammatory Cells in Metastatic Neuroblastoma

Children diagnosed at age ≥ 18 months with metastatic MYCN-nonamplified neuroblastoma (NBL-NA) are at high risk for disease relapse, whereas those diagnosed at age < 18 months are nearly always cured. In this study, we investigated the hypothesis that expression of genes related to tumor-associat...

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Published in:	Journal of clinical oncology Vol. 30; no. 28; pp. 3525 - 3532
Main Authors:	ASGHARZADEH, Shahab, SALO, Jill A, WAKAMATSU, Peter, VILLABLANCA, Judith G, KREISSMAN, Susan G, MATTHAY, Katherine K, SHIMADA, Hiroyuki, LONDON, Wendy B, SPOSTO, Richard, SEEGER, Robert C, JI, Lingyun, OBERTHUER, André, FISCHER, Matthias, BERTHOLD, Frank, HADJIDANIEL, Michael, LIU, Cathy Wei-Yao, METELITSA, Leonid S, PIQUE-REGI, Roger
Format:	Journal Article
Language:	English
Published:	Alexandria, VA American Society of Clinical Oncology 01-10-2012
Subjects:	Antigens, CD - analysis Antigens, Differentiation, Myelomonocytic - analysis Biological and medical sciences Calcium-Binding Proteins - analysis Child, Preschool Disease Progression Disease-Free Survival DNA-Binding Proteins - analysis Gene Amplification Humans Infant Inflammation - genetics Macrophages - immunology Macrophages - pathology Medical sciences N-Myc Proto-Oncogene Protein Neoplasm Metastasis Neuroblastoma - genetics Neuroblastoma - pathology Neurology Nuclear Proteins - genetics Oncogene Proteins - genetics ORIGINAL REPORTS Prognosis Receptor, trkB - analysis Receptors, Cell Surface - analysis Receptors, Interleukin-6 - analysis Trans-Activators - analysis Tumors Tumors of the nervous system. Phacomatoses Nervous system diseases Cancerology Advanced stage Inflammation Malignant tumor Inflammatory cell Metastasis Neuroblastoma Autonomic neuropathy Tumor cell Cancer
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Summary:	Children diagnosed at age ≥ 18 months with metastatic MYCN-nonamplified neuroblastoma (NBL-NA) are at high risk for disease relapse, whereas those diagnosed at age < 18 months are nearly always cured. In this study, we investigated the hypothesis that expression of genes related to tumor-associated inflammatory cells correlates with the observed differences in survival by age at diagnosis and contributes to a prognostic signature. Tumor-associated macrophages (TAMs) in localized and metastatic neuroblastomas (n = 71) were assessed by immunohistochemistry. Expression of 44 genes representing tumor and inflammatory cells was quantified in 133 metastatic NBL-NAs to assess age-dependent expression and to develop a logistic regression model to provide low- and high-risk scores for predicting progression-free survival (PFS). Tumors from high-risk patients enrolled onto two additional studies (n = 91) served as independent validation cohorts. Metastatic neuroblastomas had higher infiltration of TAMs than locoregional tumors, and metastatic tumors diagnosed in patients at age ≥ 18 months had higher expression of inflammation-related genes than those in patients diagnosed at age < 18 months. Expression of genes representing TAMs (CD33/CD16/IL6R/IL10/FCGR3) contributed to 25% of the accuracy of a novel 14-gene tumor classification score. PFS at 5 years for children diagnosed at age ≥ 18 months with NBL-NA with a low- versus high-risk score was 47% versus 12%, 57% versus 8%, and 50% versus 20% in three independent clinical trials, respectively. These data suggest that interactions between tumor and inflammatory cells may contribute to the clinical metastatic neuroblastoma phenotype, improve prognostication, and reveal novel therapeutic targets.
ISSN:	0732-183X 1527-7755
DOI:	10.1200/JCO.2011.40.9169