Loss of single HLA class I allospecificities in melanoma cells due to selective genomic abbreviations.
Details
Serval ID
serval:BIB_29C634232235
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Loss of single HLA class I allospecificities in melanoma cells due to selective genomic abbreviations.
Journal
International Journal of Cancer
ISSN
0020-7136
Publication state
Published
Issued date
2002
Peer-reviewed
Oui
Volume
99
Number
1
Pages
82-87
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Abstract
Expression of human leucocyte antigen (HLA) Class I molecules is essential for the recognition of malignant melanoma (MM) cells by CD8(+) T lymphocytes. A complete or partial loss of HLA Class I molecules is a potent strategy for MM cells to escape from immunosurveillance. In 2 out of 55 melanoma cell cultures we identified a complete phenotypic loss of HLA allospecificities. Both patients have been treated unsuccessfully with HLA-A2 peptides. To identify the reasons underlying the loss of single HLA-A allospecificities, we searched for genomic alterations at the locus for HLA Class I alpha-chain on chromosome 6 in melanoma cell cultures established from 2 selected patients with MM in advanced stage. This deficiency was associated with alterations of HLA-A2 gene sequences as determined by polymerase chain reaction-sequence specific primers (PCR-SSP). Karyotyping revealed a chromosomal loss in Patient 1, whereas melanoma cell cultures established from Patient 2 displayed 2 copies of chromosome 6. Loss of heterozygosity (LOH) using markers located around position 6p21 was detected in both cases. By applying group-specific primer-mixes spanning the 5'-flanking region of the HLA-A2 gene locus the relevant region was amplified by PCR and subsequent sequencing allowed alignment with the known HLA Class I reference sequences. Functional assays using HLA-A2-restricted cytotoxic T-cell clones were performed in HLA-A2 deficient MM cultures and revealed a drastically reduced susceptibility to CTL lysis in HLA-A2 negative cells. We could document the occurrence of selective HLA-A2 deficiencies in cultured advanced-stage melanoma metastases and identify their molecular causes as genomic alterations within the HLA-A gene locus.
Keywords
Alleles, Antigens, Neoplasm/genetics, Chromosomes, Human, Pair 6/genetics, Flow Cytometry, Genes, MHC Class I/genetics, HLA-A2 Antigen/genetics, Humans, Karyotyping, Loss of Heterozygosity, Melanoma/genetics, Melanoma/immunology, Middle Aged, Polymerase Chain Reaction, Polymorphism, Single-Stranded Conformational, Sequence Analysis, DNA, Skin Neoplasms/genetics, Skin Neoplasms/immunology, T-Lymphocytes, Cytotoxic/immunology, Tumor Cells, Cultured
Pubmed
Web of science
Create date
28/01/2008 11:28
Last modification date
20/08/2019 13:09