Multiple mechanisms underlie HLA dysregulation in cervical cancer

The consistent dysregulation of HLA expression in cervical neoplasia is lik ely to influence the natural history of the disease and prospects for cell- mediated vaccine therapies. We have studied the underlying mechanisms in ei ght new cervical cancer cell lines derived from primary tumour biopsies. At least five independent mechanisms leading to changes in HLA expression wer e seen: HLA class I allelic transcription but no protein; abnormal HLA clas s I allelic transcription; no HLA-B locus transcription; loss of heterozygo sity (LOH); no gamma IFN-mediated upregulation of HLA class I expression, a nd/or no interferon-gamma (gamma IFN)-mediated HLA class II induction. Thes e were evident in different combinations in 7/8 cell lines showing that mul tiple, mostly irreversible mechanisms not overridden by gamma IFN, are resp onsible for HLA dysregulation in cervical neoplasia. Point mutations were r esponsible for lack of HLA-A2 expression in two cases. In cell line 808, th e mutation encodes a stop codon in exon 3; in cell line 778, mutation of th e 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 onl y 38 amino acids. Tumour cells showing specific HLA class I loss may have s elective advantage in the face of tumour-specific cytotoxic T cells (CTL). Such immune escape mechanisms present a major obstacle for the success of C TL-mediated therapies in cervical cancer.