title: Frequent loss of HLA-A2 expression in metastasizing ovarian carcinomas associated with genomic haplotype loss and HLA-A2-restricted HER-2/neu-specific immunity.
abstract: Defective expression of HLA class I molecules is common in tumor cells and may allow escape from CTL-mediated immunity. We here investigate alterations in expression of HLA class I and their underlying molecular mechanisms in ovarian cancer patients. The HLA class I and HLA-A2 expression levels on noncultured tumor cells of 12 patients diagnosed with ovarian carcinoma were investigated by flow cytometry. Molecular analyses of antigen-processing machinery (APM) components were done in metastatic cancer cells, and the HLA genotype was determined in both these and the primary tumor. HER-2/neu-specific immunity was evaluated by enzyme-linked immunospot assays. The metastatic tumor cells from all patients expressed low levels of HLA class I surface antigens. In six of nine HLA-A2+ patients, HLA-A2 expression was heterogeneous with a subpopulation of tumor cells exhibiting decreased or absent HLA-A2 expression. One patient-derived tumor cell line completely lacked HLA-A2 but exhibited constitutive expression of APM components and high HLA class I expression that was further inducible by IFN-gamma treatment. Genotyping showed a haplotype loss in the metastatic tumor cells, whereas tumor tissue microdissected from the primary tumor exhibited an intact HLA gene complex. Interestingly, HLA-A2-restricted HER-2/neu-specific T-cell responses were evident among the lymphocytes of this patient. Abnormalities in HLA class I antigen expression are common features during the progression of ovarian cancer, and haplotype loss was, for the first time, described as an underlying mechanism.
authors.affiliation: Department of Oncology and Pathology, Immune and Gene Therapy Laboratory, Cancer Center Karolinska, Karolinska Institutet, Karolinska University Hospital, Sweden. hakan.norell@cck.ki.se
authors.forename: Håkan
authors.initials: H
authors.lastname: Norell
authors.forename: Mattias
authors.initials: M
authors.lastname: Carlsten
authors.forename: Tomas
authors.initials: T
authors.lastname: Ohlum
authors.forename: Karl-Johan
authors.initials: KJ
authors.lastname: Malmberg
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Masucci
authors.forename: Kjell
authors.initials: K
authors.lastname: Schedvins
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Altermann
authors.forename: Diana
authors.initials: D
authors.lastname: Handke
authors.forename: Derek
authors.initials: D
authors.lastname: Atkins
authors.forename: Barbara
authors.initials: B
authors.lastname: Seliger
authors.forename: Rolf
authors.initials: R
authors.lastname: Kiessling
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D005434:Flow Cytometry; D015789:HLA-A2 Antigen / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D006239:Haplotypes / Q000276:immunology; D006801:Humans; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010051:Ovarian Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D015789:HLA-A2 Antigen; D018719:Erb-b2 Receptor Tyrosine Kinases