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Originally published In Press as doi:10.1167/iovs.08-2733 on February 21, 2009
 (Investigative Ophthalmology and Visual Science. 2009;50:2888-2895.)
© 2009 by The Association for Research in Vision and Ophthalmology, Inc.
doi:10.1167/iovs.08-2733
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Evidence for Natural Killer Cell–Mediated Protection from Metastasis Formation in Uveal Melanoma Patients

Willem Maat,1 Arno R. van der Slik,2,3 Dirk H. J. Verhoeven,2,4 Behrooz Z. Alizadeh,2,5 Long V. Ly,1 Willem Verduijn,3 Gregorius P. M. Luyten,1 Arend Mulder,3 Thorbald van Hall,6 Frits Koning,3 Martine J. Jager,1,7 and Jeroen van Bergen3,7

1From the Departments of Ophthalmology, 3Immunohaematology and Blood Transfusion, 4Paediatrics, and 6Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands; and the 5Complex Genetics Section, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.

PURPOSE. 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.






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