Show simple item record

dc.contributor.authorBrady, C S
dc.contributor.authorBartholomew, J S
dc.contributor.authorBurt, Deborah J
dc.contributor.authorDuggan-Keen, Margaret F
dc.contributor.authorGlenville, S
dc.contributor.authorTelford, Nicholas
dc.contributor.authorLittle, A M
dc.contributor.authorDavidson, J A
dc.contributor.authorJimenez, P
dc.contributor.authorRuiz-Cabello, F
dc.contributor.authorGarrido, F
dc.contributor.authorStern, Peter L
dc.date.accessioned2009-11-23T12:00:07Z
dc.date.available2009-11-23T12:00:07Z
dc.date.issued2000-05
dc.identifier.citationMultiple mechanisms underlie HLA dysregulation in cervical cancer. 2000, 55 (5):401-11 Tissue Antigensen
dc.identifier.issn0001-2815
dc.identifier.pmid10885560
dc.identifier.doi10.1034/j.1399-0039.2000.550502.x
dc.identifier.urihttp://hdl.handle.net/10541/86668
dc.description.abstractThe consistent dysregulation of HLA expression in cervical neoplasia is likely to influence the natural history of the disease and prospects for cell-mediated vaccine therapies. We have studied the underlying mechanisms in eight new cervical cancer cell lines derived from primary tumour biopsies. At least five independent mechanisms leading to changes in HLA expression were seen: HLA class I allelic transcription but no protein; abnormal HLA class I allelic transcription; no HLA-B locus transcription; loss of heterozygosity (LOH); no gammaIFN-mediated upregulation of HLA class I expression, and/or no interferon-gamma (gammaIFN)-mediated HLA class II induction. These were evident in different combinations in 7/8 cell lines showing that multiple, mostly irreversible mechanisms not overridden by gammaIFN, are responsible for HLA dysregulation in cervical neoplasia. Point mutations were responsible for lack of HLA-A2 expression in two cases. In cell line 808, the mutation encodes a stop codon in exon 3; in cell line 778, mutation of the first intron acceptor site leads to use of an alternative AG site in exon 2, resulting in a frameshift and a stop codon after the translation of only 38 amino acids. Tumour cells showing specific HLA class I loss may have selective advantage in the face of tumour-specific cytotoxic T cells (CTL). Such immune escape mechanisms present a major obstacle for the success of CTL-mediated therapies in cervical cancer.
dc.language.isoenen
dc.subjectCultured Tumour Cellsen
dc.subjectTumour Virus Infectionsen
dc.subjectUterine Cervical Canceren
dc.subject.meshATP-Binding Cassette Transporters
dc.subject.meshAlleles
dc.subject.meshBiopsy
dc.subject.meshCarcinoma, Squamous Cell
dc.subject.meshDNA Primers
dc.subject.meshFemale
dc.subject.meshGene Expression Regulation, Neoplastic
dc.subject.meshGene Expression Regulation, Viral
dc.subject.meshGenotype
dc.subject.meshHistocompatibility Antigens Class I
dc.subject.meshHistocompatibility Testing
dc.subject.meshHumans
dc.subject.meshOncogene Proteins, Viral
dc.subject.meshPapillomaviridae
dc.subject.meshPapillomavirus Infections
dc.subject.meshPhenotype
dc.subject.meshReceptors, Interferon
dc.subject.meshReverse Transcriptase Polymerase Chain Reaction
dc.subject.meshSequence Analysis, DNA
dc.subject.meshT-Lymphocytes, Cytotoxic
dc.subject.meshTranscription, Genetic
dc.subject.meshTumor Cells, Cultured
dc.subject.meshTumor Virus Infections
dc.subject.meshUterine Cervical Neoplasms
dc.titleMultiple mechanisms underlie HLA dysregulation in cervical cancer.en
dc.typeArticleen
dc.contributor.departmentCRC Immunology Group, Paterson Institute for Cancer Research, Manchester, United Kingdom.en
dc.identifier.journalTissue Antigensen
html.description.abstractThe consistent dysregulation of HLA expression in cervical neoplasia is likely to influence the natural history of the disease and prospects for cell-mediated vaccine therapies. We have studied the underlying mechanisms in eight new cervical cancer cell lines derived from primary tumour biopsies. At least five independent mechanisms leading to changes in HLA expression were seen: HLA class I allelic transcription but no protein; abnormal HLA class I allelic transcription; no HLA-B locus transcription; loss of heterozygosity (LOH); no gammaIFN-mediated upregulation of HLA class I expression, and/or no interferon-gamma (gammaIFN)-mediated HLA class II induction. These were evident in different combinations in 7/8 cell lines showing that multiple, mostly irreversible mechanisms not overridden by gammaIFN, are responsible for HLA dysregulation in cervical neoplasia. Point mutations were responsible for lack of HLA-A2 expression in two cases. In cell line 808, the mutation encodes a stop codon in exon 3; in cell line 778, mutation of the first intron acceptor site leads to use of an alternative AG site in exon 2, resulting in a frameshift and a stop codon after the translation of only 38 amino acids. Tumour cells showing specific HLA class I loss may have selective advantage in the face of tumour-specific cytotoxic T cells (CTL). Such immune escape mechanisms present a major obstacle for the success of CTL-mediated therapies in cervical cancer.


This item appears in the following Collection(s)

Show simple item record