Evidence for natural killer cell-mediated protection from metastasis formation in uveal melanoma patients.
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.
Maat
Willem
W
Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands.
van der Slik
Arno R
AR
Verhoeven
Dirk H J
DH
Alizadeh
Behrooz Z
BZ
Ly
Long V
LV
Verduijn
Willem
W
Luyten
Gregorius P M
GP
Mulder
Arend
A
van Hall
Thorbald
T
Koning
Frits
F
Jager
Martine J
MJ
van Bergen
Jeroen
J
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*
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