title: Multiple mechanisms underlie HLA dysregulation in cervical cancer.
abstract: The 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.
authors.affiliation: CRC Immunology Group, Paterson Institute for Cancer Research, Manchester, United Kingdom.
authors.forename: C S
authors.initials: CS
authors.lastname: Brady
authors.forename: J S
authors.initials: JS
authors.lastname: Bartholomew
authors.forename: D J
authors.initials: DJ
authors.lastname: Burt
authors.forename: M F
authors.initials: MF
authors.lastname: Duggan-Keen
authors.forename: S
authors.initials: S
authors.lastname: Glenville
authors.forename: N
authors.initials: N
authors.lastname: Telford
authors.forename: A M
authors.initials: AM
authors.lastname: Little
authors.forename: J A
authors.initials: JA
authors.lastname: Davidson
authors.forename: P
authors.initials: P
authors.lastname: Jimenez
authors.forename: F
authors.initials: F
authors.lastname: Ruiz-Cabello
authors.forename: F
authors.initials: F
authors.lastname: Garrido
authors.forename: P L
authors.initials: PL
authors.lastname: Stern
mesh_terms: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000276:immunology; D000483:Alleles; D001706:Biopsy; D002294:Carcinoma, Squamous Cell / Q000276:immunology* / Q000473:pathology / Q000821:virology; D017931:DNA Primers; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D015967:Gene Expression Regulation, Viral / Q000276:immunology; D005838:Genotype; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology*; D006650:Histocompatibility Testing; D006801:Humans; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000276:immunology*; D027383:Papillomaviridae / Q000235:genetics / Q000276:immunology; D030361:Papillomavirus Infections / Q000235:genetics / Q000276:immunology; D010641:Phenotype; D017471:Receptors, Interferon / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014158:Transcription, Genetic / Q000276:immunology; D014407:Tumor Cells, Cultured; D014412:Tumor Virus Infections / Q000235:genetics / Q000276:immunology; D002583:Uterine Cervical Neoplasms / Q000276:immunology* / Q000473:pathology / Q000821:virology; D000096743:Interferon gamma Receptor
chemical_list: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D017931:DNA Primers; D015395:Histocompatibility Antigens Class I; D009856:Oncogene Proteins, Viral; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor; C073119:TAP1 protein, human