High frequency of allele-specific down-regulation of HLA class I expression in uveal melanoma cell lines.
Uveal melanoma is the most common primary intra-ocular tumor in adults and has a high mortality rate due to liver metastases, for which no effective treatment is available. To investigate whether immunotherapy might be feasible in uveal melanoma, the HLA class I surface expression of 6 uveal melanoma cell lines was analyzed by flow cytometry using a broad panel of allele-specific monoclonal antibodies. To up-regulate HLA expression, cells were also cultured with IFN-alpha or -gamma. In general, expression of HLA-A alleles was high (except for cell line EOM-3) and could be further up-regulated by both IFN-alpha and -gamma. In cell line EOM-3, IFN-gamma treatment resulted in significant HLA-A expression while IFN-alpha treatment did not. Expression of HLA-B alleles was low or even negative. Variable effects were observed after IFN treatment. In 3 cell lines, expression of some HLA-B alleles could not be induced by IFN-alpha or -gamma: HLA-B44 in cell line 92-1, HLA-B15 in cell line OCM-1 and HLA-B5 in cell line MEL-202. The other B alleles of these cell lines showed enhanced expression levels upon IFN stimulation. In OMM-1 cells, IFN-alpha and -gamma increased the expression of HLA-A but did not induce expression of the 2 B alleles, indicating an HLA-B locus-specific loss. We thus found a high frequency of allele-specific and locus-specific down-regulation of HLA expression in uveal melanoma cell lines. Some of these defects were not restored by IFN-alpha or -gamma treatment. The lack of HLA expression may explain why uveal melanoma cells escape immune surveillance by cytotoxic T cells and complicate the development of immunotherapy in uveal melanoma.
Hurks
H M
HM
Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands. Mhurks@div3.azl.nl
Metzelaar-Blok
J A
JA
Mulder
A
A
Claas
F H
FH
Jager
M J
MJ
D000328:Adult; D000483:Alleles; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000276:immunology*; D005805:Genes, MHC Class I; D006580:Genetic Carrier Screening; D005819:Genetic Markers; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D008545:Melanoma / Q000235:genetics* / Q000276:immunology*; D011994:Recombinant Proteins; D014407:Tumor Cells, Cultured; D014604:Uveal Neoplasms / Q000235:genetics* / Q000276:immunology*
D005819:Genetic Markers; D015395:Histocompatibility Antigens Class I; D007370:Interferon Type I; D011994:Recombinant Proteins; D007371:Interferon-gamma