title: Immunosurveillance and survivin-specific T-cell immunity in children with high-risk neuroblastoma.
abstract: OBJECTIVE
  Tumor immunosurveillance influences oncogenesis and tumor growth, but it remains controversial whether clinical failure of immunosurveillance is a result of lymphocyte dysfunction or tumor escape. In this study, our goal was to characterize the physiology of tumor immunosurveillance in children with high-risk neuroblastoma (HR-NBL).
  
  
  METHODS
  Immunohistopathologic studies were carried out on 26 tumor samples from a cohort of HR-NBL patients diagnosed at Children's Hospital of Philadelphia for the 2-year period from May 2003 to May 2005. Blood from nine HLA-A2+ patients in this cohort was analyzed for T cells specific for the antiapoptotic protein survivin.
  
  
  RESULTS
  Survivin protein was expressed by 26 of 26 tumors. In HLA-A2+ patients, circulating cytotoxic T lymphocytes (CTLs) specific for survivin were detected by peptide/major histocompatibility complex tetramer analysis in the blood of eight of nine children with HR-NBL at the time of diagnosis. Rather than being selectively rendered anergic in vivo, circulating survivin-specific CTLs were highly functional as shown by cytotoxicity and interferon gamma enzyme-linked immunospot assays in six of nine patients. Survivin-specific CD107a mobilization by T cells was found in five of five patients. By immunohistochemistry, tumor-infiltrating T cells were few or absent in 26 of 26 tumors.
  
  
  CONCLUSIONS
  Children with HR-NBL harbor robust cellular immune responses to the universal tumor antigen survivin at the time of diagnosis, but intratumoral T cells are strikingly rare, suggesting a failure of cellular immunosurveillance. Efforts to develop novel therapies that increase T-cell trafficking into tumor nests are warranted.
authors.affiliation: Abramson Family Cancer Research Institute, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Coughlin
authors.forename: Mark D
authors.initials: MD
authors.lastname: Fleming
authors.forename: Richard G
authors.initials: RG
authors.lastname: Carroll
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Pawel
authors.forename: Michael D
authors.initials: MD
authors.lastname: Hogarty
authors.forename: Xiaochuan
authors.initials: X
authors.lastname: Shan
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Vance
authors.forename: Jarish N
authors.initials: JN
authors.lastname: Cohen
authors.forename: Sonya
authors.initials: S
authors.lastname: Jairaj
authors.forename: Elaina M
authors.initials: EM
authors.lastname: Lord
authors.forename: Michael H
authors.initials: MH
authors.lastname: Wexler
authors.forename: Gwenn-aël H
authors.initials: GA
authors.lastname: Danet-Desnoyers
authors.forename: Jack L
authors.initials: JL
authors.lastname: Pinkus
authors.forename: Geraldine S
authors.initials: GS
authors.lastname: Pinkus
authors.forename: John M
authors.initials: JM
authors.lastname: Maris
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Grupp
authors.forename: Robert H
authors.initials: RH
authors.lastname: Vonderheide
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007157:Immunologic Surveillance; D007223:Infant; D051034:Inhibitor of Apoptosis Proteins; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D009447:Neuroblastoma / Q000276:immunology*; D012307:Risk Factors; D000077022:Survivin
chemical_list: C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin