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 5 43) and subsequent recurrent uVIN lesion (n 5 20), vaccinetreated uVIN patients (n 5 12), patients with human papillomavirus (HPV)-induced vulvar carcinoma (n 5 21) and healthy controls (n 5 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 c. 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.Usual vulvar intraepithelial neoplasia (uVIN) is a chronic premalignant skin condition with an increasing incidence mainly in young women, which is caused by a persistent high-risk human papillomavirus (HPV) infection in more than 90% of cases.1,2 uVIN causes complaints of severe and long-lasting pruritis, pain and sexual dysfunction and has a malignant potential of 3-4% in treated and of 9% in untreated patients.1,3 Because conventional treatments for uVIN are characterized by high recurrence rates of 20-40% and psychosexual problems, there is a need for alternative therapies. [4][5][6] Failure of the immune system to induce a strong and effective immune response to HPV is known to cause
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