title: Upregulation of HLA Expression in Primary Uveal Melanoma by Infiltrating Leukocytes.
abstract: BACKGROUND
  Uveal melanoma (UM) with an inflammatory phenotype, characterized by infiltrating leukocytes and increased human leukocyte antigen (HLA) expression, carry an increased risk of death due to metastases. These tumors should be ideal for T-cell based therapies, yet it is not clear why prognostically-infaust tumors have a high HLA expression. We set out to determine whether the level of HLA molecules in UM is associated with other genetic factors, HLA transcriptional regulators, or microenvironmental factors.
  
  
  METHODS
  28 enucleated UM were used to study HLA class I and II expression, and several regulators of HLA by immunohistochemistry, PCR microarray, qPCR and chromosome SNP-array. Fresh tumor samples of eight primary UM and four metastases were compared to their corresponding xenograft in SCID mice, using a PCR microarray and SNP array.
  
  
  RESULTS
  Increased expression levels of HLA class I and II showed no dosage effect of chromosome 6p, but, as expected, were associated with monosomy of chromosome 3. Increased HLA class I and II protein levels were positively associated with their gene expression and with raised levels of the peptide-loading gene TAP1, and HLA transcriptional regulators IRF1, IRF8, CIITA, and NLRC5, revealing a higher transcriptional activity in prognostically-bad tumors. Implantation of fresh human tumor samples into SCID mice led to a loss of infiltrating leukocytes, and to a decreased expression of HLA class I and II genes, and their regulators.
  
  
  CONCLUSIONS
  Our data provides evidence for a proper functioning HLA regulatory system in UM, offering a target for T-cell based therapies.
authors.affiliation: Department of Ophthalmology, LUMC, Leiden, the Netherlands.
authors.forename: T Huibertus
authors.initials: TH
authors.lastname: van Essen
authors.affiliation: Department of Medical Statistics, LUMC, Leiden, the Netherlands.
authors.forename: Sake I
authors.initials: SI
authors.lastname: van Pelt
authors.affiliation: Department of Ophthalmology, LUMC, Leiden, the Netherlands.
authors.forename: Inge H G
authors.initials: IH
authors.lastname: Bronkhorst
authors.affiliation: Department of Ophthalmology, LUMC, Leiden, the Netherlands.
authors.forename: Mieke
authors.initials: M
authors.lastname: Versluis
authors.affiliation: Laboratory of Preclinical Investigation, Translational Research Department, Institut Curie, Paris, France.
authors.forename: Fariba
authors.initials: F
authors.lastname: Némati
authors.affiliation: Laboratory of Preclinical Investigation, Translational Research Department, Institut Curie, Paris, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Laurent
authors.affiliation: Department of Ophthalmology, LUMC, Leiden, the Netherlands.
authors.forename: Gregorius P M
authors.initials: GP
authors.lastname: Luyten
authors.affiliation: Department of Clinical Oncology, LUMC, Leiden, the Netherlands.
authors.forename: Thorbald
authors.initials: T
authors.lastname: van Hall
authors.affiliation: Department of Immunohematology and Blood Transfusion, LUMC, Leiden, the Netherlands.|Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: van den Elsen
authors.affiliation: Department of Ophthalmology, LUMC, Leiden, the Netherlands.
authors.forename: Pieter A
authors.initials: PA
authors.lastname: van der Velden
authors.affiliation: Laboratory of Preclinical Investigation, Translational Research Department, Institut Curie, Paris, France.|Department of Clinical Hematology, Institut Curie, Paris France.
authors.forename: Didier
authors.initials: D
authors.lastname: Decaudin
authors.affiliation: Department of Ophthalmology, LUMC, Leiden, the Netherlands.
authors.forename: Martine J
authors.initials: MJ
authors.lastname: Jager
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002893:Chromosomes, Human, Pair 3; D002896:Chromosomes, Human, Pair 6; D005260:Female; D006680:HLA Antigens / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D014183:Transplantation, Heterologous; D015854:Up-Regulation; D014604:Uveal Neoplasms / Q000378:metabolism / Q000473:pathology*; D000098943:Uveal Melanoma
chemical_list: D006680:HLA Antigens; D010455:Peptides