title: Clinical significance of tumor-associated inflammatory cells in metastatic neuroblastoma.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA. sasgharzadeh@chla.usc.edu
authors.forename: Shahab
authors.initials: S
authors.lastname: Asgharzadeh
authors.forename: Jill A
authors.initials: JA
authors.lastname: Salo
authors.forename: Lingyun
authors.initials: L
authors.lastname: Ji
authors.forename: André
authors.initials: A
authors.lastname: Oberthuer
authors.forename: Matthias
authors.initials: M
authors.lastname: Fischer
authors.forename: Frank
authors.initials: F
authors.lastname: Berthold
authors.forename: Michael
authors.initials: M
authors.lastname: Hadjidaniel
authors.forename: Cathy Wei-Yao
authors.initials: CW
authors.lastname: Liu
authors.forename: Leonid S
authors.initials: LS
authors.lastname: Metelitsa
authors.forename: Roger
authors.initials: R
authors.lastname: Pique-Regi
authors.forename: Peter
authors.initials: P
authors.lastname: Wakamatsu
authors.forename: Judith G
authors.initials: JG
authors.lastname: Villablanca
authors.forename: Susan G
authors.initials: SG
authors.lastname: Kreissman
authors.forename: Katherine K
authors.initials: KK
authors.lastname: Matthay
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Shimada
authors.forename: Wendy B
authors.initials: WB
authors.lastname: London
authors.forename: Richard
authors.initials: R
authors.lastname: Sposto
authors.forename: Robert C
authors.initials: RC
authors.lastname: Seeger
mesh_terms: D015703:Antigens, CD / Q000032:analysis; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D002135:Calcium-Binding Proteins / Q000032:analysis; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000032:analysis; D018450:Disease Progression; D018572:Disease-Free Survival; D005784:Gene Amplification; D006801:Humans; D007223:Infant; D007249:Inflammation / Q000235:genetics; D008264:Macrophages / Q000276:immunology / Q000473:pathology*; D008840:Microfilament Proteins; D000071447:N-Myc Proto-Oncogene Protein; D009362:Neoplasm Metastasis; D009447:Neuroblastoma / Q000235:genetics / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics; D015513:Oncogene Proteins / Q000235:genetics; D011379:Prognosis; D020813:Receptor, trkB / Q000032:analysis; D011956:Receptors, Cell Surface / Q000032:analysis; D019947:Receptors, Interleukin-6 / Q000032:analysis; D015534:Trans-Activators / Q000032:analysis; D000098902:CD163 Antigen
chemical_list: C112986:AIF1 protein, human; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; C487554:CAMTA1 protein, human; D000098902:CD163 Antigen; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; C508603:IL6R protein, human; C459801:MYCN protein, human; D008840:Microfilament Proteins; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D011956:Receptors, Cell Surface; D019947:Receptors, Interleukin-6; D015534:Trans-Activators; D020813:Receptor, trkB