Alterations in classical and nonclassical HLA expression in recurrent and progressive HPV-induced usual vulvar intraepithelial neoplasia and implications for immunotherapy
| Autor: | E M G, van Esch, B, Tummers, V, Baartmans, E M, Osse, N, Ter Haar, M D, Trietsch, B W J, Hellebrekers, C A G, Holleboom, H T C, Nagel, L T, Tan, G J, Fleuren, M I E, van Poelgeest, S H, van der Burg, E S, Jordanova |
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| Rok vydání: | 2013 |
| Předmět: |
Adult
Aged 80 and over Keratinocytes Adolescent Genotype Vulvar Neoplasms Carcinoma Papillomavirus Infections Down-Regulation Loss of Heterozygosity Middle Aged Cohort Studies Gene Expression Regulation Neoplastic Interferon-gamma Gene Expression Regulation HLA Antigens Recurrence Case-Control Studies Humans Female Immunotherapy Aged |
| Zdroj: | International journal of cancer. 135(4) |
| ISSN: | 1097-0215 |
| Popis: | Immunotherapy of usual vulvar intraepithelial neoplasia (uVIN) is promising; however, many patients still fail to show clinical responses, which could be explained by an immune escape through alterations in human leukocyte antigen (HLA) expression. Therefore, we analyzed a cohort of patients with a primary (n = 43) and subsequent recurrent uVIN lesion (n = 20), vaccine-treated uVIN patients (n = 12), patients with human papillomavirus (HPV)-induced vulvar carcinoma (n = 21) and healthy controls (n = 26) for the expression of classical HLA-class I/II and nonclassical HLA-E/-G and MHC class I chain-related molecule A (MICA). HLA-class I was downregulated in 70% of uVIN patients, including patients with a clinical response to immunotherapy. Downregulation of HLA-class I is probably reversible, as only 15% of the uVIN cases displayed loss of heterozygosity (LOH) and HLA-class I could be upregulated in uVIN keratinocyte cultures by interferon γ. HLA-class I downregulation is more frequently associated with LOH in vulvar carcinomas (25-55.5%). HLA-class II was found to be focally expressed in 65% of uVIN patients. Of the nonclassical molecules, MICA was downregulated in 80% of uVIN whereas HLA-E and -G were expressed in a minority of cases. Their expression was more prominent in vulvar carcinoma. No differences were found between the alterations observed in paired primary and recurrent uVIN. Importantly, downregulation of HLA-B/C in primary uVIN lesions was associated with the development of recurrences and progression to cancer. We conclude that downregulation of HLA is frequently observed in premalignant HPV-induced lesions, including clinical responders to immunotherapy, and is associated with worse clinical outcome. However, in the majority of cases downregulation may still be reversible. |
| Databáze: | OpenAIRE |
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