title: Characterization of MHC Class I and β-2-Microglobulin Expression in Pediatric Solid Malignancies to Guide Selection of Immune-Based Therapeutic Trials.
abstract: BACKGROUND
  Over 10,000 US children are diagnosed with cancer yearly. Though outcomes have improved by optimizing conventional therapies, recent immunotherapeutic successes in adult cancers are emerging. Cytotoxic T lymphocytes (CTLs) are the primary executioners of adaptive antitumor immunity and require antigenic presentation in the context of major histocompatibility complex (MHC) class I and the associated β-2-microglobulin (B2M). Loss of MHC I expression is a common immune escape mechanism in adult malignancies, but pediatric cancers have not been thoroughly characterized. The essential nature of MHC I expression in CTL-mediated cell death may dictate the success of immunotherapies, which rely on eliciting an adaptive response.
  
  
  METHODS
  We queried pediatric tumor microarray databases for MHC I and B2M gene expression. We detected MHC I in pediatric tumor cell lines by flow cytometry and characterized MHC I and B2M expression in patient samples by immunohistochemistry. To determine whether therapeutic approaches might enhance MHC I expression in selected models in vitro, we tested effects of exposure to IFN-γ and histone deacetylase inhibitors.
  
  
  RESULTS
  Pediatric tumors overall, as well as samples within select individual tumor subtypes, exhibit wide ranges of MHC I and B2M gene and protein expression. For most cell lines tested, MHC I was inducible in vitro.
  
  
  CONCLUSIONS
  MHC I and B2M expression vary among pediatric tumor types and should be evaluated as potential biomarkers, which might identify patients most likely to benefit from MHC I dependent immunotherapies. Modulation of MHC I expression may be a promising mechanism for enhancing MHC I dependent immunotherapeutic efficacy.
authors.affiliation: Division of Hematology/Oncology/Blood and Marrow Transplant, Nationwide Children's Hospital, Columbus, Ohio.|Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Kellie B
authors.initials: KB
authors.lastname: Haworth
authors.affiliation: Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio.|Department of Pathology, The Ohio State University College of Medicine, Columbus, Ohio.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Arnold
authors.affiliation: Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio.|Department of Pathology, The Ohio State University College of Medicine, Columbus, Ohio.|Division of Anatomy, The Ohio State University, Columbus, Ohio.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Pierson
authors.affiliation: Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.|Medical Scientist Training Program, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio.|Immunobiology Graduate Training Program, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Leddon
authors.affiliation: Greehey Children's Cancer Research Institute, University of Texas Health Science Center, San Antonio, Texas.
authors.forename: Dias K
authors.initials: DK
authors.lastname: Kurmashev
authors.affiliation: Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Hayley M
authors.initials: HM
authors.lastname: Swain
authors.affiliation: Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Hutzen
authors.affiliation: Division of Hematology/Oncology/Blood and Marrow Transplant, Nationwide Children's Hospital, Columbus, Ohio.|Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Roberts
authors.affiliation: Division of Hematology/Oncology/Blood and Marrow Transplant, Nationwide Children's Hospital, Columbus, Ohio.|Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Cripe
mesh_terms: D045744:Cell Line, Tumor; D002648:Child; D002986:Clinical Trials as Topic / Q000379:methods*; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000032:analysis / Q000096:biosynthesis*; D006801:Humans; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods*; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy; D020411:Oligonucleotide Array Sequence Analysis; D018579:Patient Selection; D046888:Tissue Array Analysis; D001613:beta 2-Microglobulin / Q000032:analysis / Q000096:biosynthesis*
chemical_list: D015395:Histocompatibility Antigens Class I; D001613:beta 2-Microglobulin
keywords: MHC class I; immunophenotype; immunotherapy; pediatric oncology; solid tumors; tumor biology