title: Interferon-gamma-dependent infiltration of human T cells into neuroblastoma tumors in vivo.
abstract: OBJECTIVE
  To investigate the impact of interferon-gamma-mediated upregulation of major histocompatibility complex class I expression on tumor-specific T-cell cytotoxicity and T-cell trafficking into neuroblastoma tumors in vivo.
  
  
  METHODS
  Restoration of major histocompatibility complex class I expression by interferon-gamma treatment enhances killing of neuroblastoma cells. To understand the potential of this approach in vivo, we developed a novel model of neuroblastoma in which NOD/scid/IL2R gamma(null) immunodeficient mice are engrafted with both human T cells and tumor cells.
  
  
  RESULTS
  Here, we show enhanced killing of neuroblastoma cells by patient-derived, tumor-specific T cells in vitro. In addition, interferon-gamma treatment in vivo induces efficient upregulation of major histocompatibility complex class I expression on neuroblastoma tumor cells, and this is accompanied by significantly enhanced infiltration of T cells into the tumor. In a pilot clinical trial in patients with high-risk neuroblastoma, we similarly observed augmented T-cell trafficking into neuroblastoma nests in tumor biopsy specimens obtained from patients after 5 days of systemic interferon-gamma therapy.
  
  
  CONCLUSIONS
  Interferon-gamma overcomes critical obstacles to the killing of human neuroblastoma cells by specific T cells. Together, these findings provide a rationale for the further testing of interferon-gamma as an approach for improving the efficacy of T cell-based therapies for neuroblastoma and other major histocompatibility complex class I-deficient malignancies. In addition, we describe a model that may expedite the preclinical screening of approaches aimed at augmenting T-cell trafficking into human tumors.
authors.affiliation: Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: Gregor S D
authors.initials: GS
authors.lastname: Reid
authors.forename: Xiaochuan
authors.initials: X
authors.lastname: Shan
authors.forename: Christina M
authors.initials: CM
authors.lastname: Coughlin
authors.forename: Wiem
authors.initials: W
authors.lastname: Lassoued
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Pawel
authors.forename: Leonard H
authors.initials: LH
authors.lastname: Wexler
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Thiele
authors.forename: Maria
authors.initials: M
authors.lastname: Tsokos
authors.forename: Jack L
authors.initials: JL
authors.lastname: Pinkus
authors.forename: Geraldine S
authors.initials: GS
authors.lastname: Pinkus
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Grupp
authors.forename: Robert H
authors.initials: RH
authors.lastname: Vonderheide
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009447:Neuroblastoma / Q000276:immunology*; D010865:Pilot Projects; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D015854:Up-Regulation
chemical_list: D015395:Histocompatibility Antigens Class I; D007371:Interferon-gamma