title: Evidence for natural killer cell-mediated protection from metastasis formation in uveal melanoma patients.
abstract: OBJECTIVE
  In uveal melanoma, low human leukocyte antigen (HLA) class I expression on primary tumors is associated with a decreased risk of metastasis. Consequently, it has been suggested that natural killer (NK) cells, which detect decreased expression of HLA class I, are involved in the immune control of metastases. In this study, three novel lines of evidence were identified that support a role for NK cells.
  
  
  METHODS
  Uveal melanoma cell lines were used to determine the expression of NK cell receptor ligands (MICA, MICB, ULBP1-3, CD112, CD155, and HLA class I) and to examine sensitivity to lysis by human NK cell lines. Because interactions between polymorphic killer immunoglobulin receptors (KIRs) and HLA regulate NK cell function, KIR and HLA genotyping was performed on 154 patients with uveal melanoma and 222 healthy control subjects.
  
  
  RESULTS
  First, all 11 uveal melanoma cell lines tested expressed ligands for activating as well as inhibitory NK cell receptors. Second, such cell lines were lysed efficiently by human NK cells in vitro. Finally, the HLA-C genotype was related to the risk of metastasis-related death in patients with uveal melanoma: The patients carrying HLA-C alleles encoding ligands for KIR2DL1 and KIR2DL2/3 (HLA-C group 1/group 2 heterozygous patients), both inhibitory NK receptors, had a longer metastasis-free survival than did those carrying HLA-C ligands for either KIR2DL1 (HLA-C group 2 homozygotes) or KIR2DL2/3 (HLA-C group 1 homozygotes).
  
  
  CONCLUSIONS
  Together, the data support a role for NK cells in the prevention of uveal melanoma metastases.
authors.affiliation: Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Willem
authors.initials: W
authors.lastname: Maat
authors.forename: Arno R
authors.initials: AR
authors.lastname: van der Slik
authors.forename: Dirk H J
authors.initials: DH
authors.lastname: Verhoeven
authors.forename: Behrooz Z
authors.initials: BZ
authors.lastname: Alizadeh
authors.forename: Long V
authors.initials: LV
authors.lastname: Ly
authors.forename: Willem
authors.initials: W
authors.lastname: Verduijn
authors.forename: Gregorius P M
authors.initials: GP
authors.lastname: Luyten
authors.forename: Arend
authors.initials: A
authors.lastname: Mulder
authors.forename: Thorbald
authors.initials: T
authors.lastname: van Hall
authors.forename: Frits
authors.initials: F
authors.lastname: Koning
authors.forename: Martine J
authors.initials: MJ
authors.lastname: Jager
authors.forename: Jeroen
authors.initials: J
authors.lastname: van Bergen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D005434:Flow Cytometry; D005838:Genotype; D015236:HLA-C Antigens / Q000235:genetics; D006801:Humans; D007694:Killer Cells, Natural / Q000502:physiology*; D008024:Ligands; D008113:Liver Neoplasms / Q000235:genetics / Q000276:immunology / Q000517:prevention & control* / Q000556:secondary; D008213:Lymphocyte Activation; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000276:immunology / Q000517:prevention & control* / Q000556:secondary; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D054342:Receptors, KIR2DL1 / Q000235:genetics; D054343:Receptors, KIR2DL2 / Q000235:genetics; D054344:Receptors, KIR2DL3 / Q000235:genetics; D055607:Receptors, Natural Killer Cell / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014604:Uveal Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*
chemical_list: D015236:HLA-C Antigens; C093100:KIR2DL1 protein, human; C515077:KIR2DL2 protein, human; C515078:KIR2DL3 protein, human; D008024:Ligands; D054342:Receptors, KIR2DL1; D054343:Receptors, KIR2DL2; D054344:Receptors, KIR2DL3; D055607:Receptors, Natural Killer Cell