Multiple mechanisms underlie HLA dysregulation in cervical cancer

• Published in: Tissue antigens Vol. 55; no. 5; pp. 401 - 411
• Main Authors: Brady, C.S., Bartholomew, J.S., Burt, D.J., Duggan-Keen, M.F., Glenville, S., Telford, N., Little, A-M., Davidson, J.A., Jimenez, P., Ruiz-Cabello, F., Garrido, F., Stern, P.L.
• Format: Journal Article
• Language: English
• Published: Copenhagen Munksgaard International Publishers 01-05-2000
• Subjects: Alleles; ATP Binding Cassette Transporter, Subfamily B, Member 2; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - immunology; Biopsy; Carcinoma, Squamous Cell - immunology; Carcinoma, Squamous Cell - pathology; Carcinoma, Squamous Cell - virology; cervical cancer; DNA Primers; Female; g-Interferon; Gene Expression Regulation, Neoplastic - immunology; Gene Expression Regulation, Viral - immunology; Genotype; histocompatibility antigen HLA; Histocompatibility Antigens Class I - genetics; Histocompatibility Antigens Class I - immunology; Histocompatibility Testing; HLA; HPV vaccines; human papillomavirus; Humans; Interferon gamma Receptor; mutation; Oncogene Proteins, Viral - genetics; Oncogene Proteins, Viral - immunology; Papillomaviridae - genetics; Papillomaviridae - immunology; Papillomavirus Infections - genetics; Papillomavirus Infections - immunology; Phenotype; Receptors, Interferon - immunology; Reverse Transcriptase Polymerase Chain Reaction; Sequence Analysis, DNA; T-Lymphocytes, Cytotoxic - immunology; Transcription, Genetic - immunology; Tumor Cells, Cultured; Tumor Virus Infections - genetics; Tumor Virus Infections - immunology; tumour immunotherapy; Uterine Cervical Neoplasms - immunology; Uterine Cervical Neoplasms - pathology; Uterine Cervical Neoplasms - virology
• ISSN: 0001-2815; 1399-0039
• DOI: 10.1034/j.1399-0039.2000.550502.x

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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 γIFN‐mediated upregulation of HLA class I expression, and/or no interferon‐gamma (γIFN)‐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 γIFN, 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.