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.

Primary Human Tumor Cells Expressing CD155 Impair Tumor Targeting by Down-Regulating DNAM-1 on NK Cells

“…We recently demonstrated that the DNAM-1/CD155 interaction is crucial for recognition and killing of freshly isolated human ovarian carcinoma cells by resting allogeneic NK cells (15). Since the ovarian carcinoma cells constitutively express CD155 in combination with reduced levels of HLA class I molecules (15,22,23), autologous NK cells could theoretically target this tumor type. However, early studies suggest that the function of NK cells in patients with ovarian carcinoma is suppressed by an as yet unclear mechanism (24,25).…”

Cytotoxic T cells and Cancer Therapy

“…Even though CTL transfer facilitates a potent means to combat tumorgrowth, some adverse conditions still pertain and most prevalent among them is the emergence of antigenic variants. This is more reflected in human cases of tumours than with mouse syngeneic tumormodels (Norell et al, 2006).…”

The link between MHC class I abnormalities of tumors, oncogenes, tumor suppressor genes, and transcription factors

“…Correlations between MHC class I APM abnormalities and the clinical outcome of patients have not only been described for melanoma, but also for other malignancies including RCC, prostate, cervical, ovarian, and head and neck squamous cell carcinoma (Atkins et al, 2004;Ferris et al, 2006;Kageshita et al, 1999;Mehta et al, 2008;Meissner et al, 2005;Vitale et al, 1998). In prostate cancer, down-regulation of MHC class I molecules did correlate with higher progression rates and early tumor recurrence, which can be further accompanied with reduced or even loss of TAP1 and ERAP1 expression levels (Norell et al, 2006;Seliger et al, 2010). Thus, the characterization of the molecular mechanisms resulting in the down-regulation of APM components in human and murine tumors, as well as in oncogene-transformed cells of distinct origin, is currently still of great interest.…”