title: Alterations in classical and nonclassical HLA expression in recurrent and progressive HPV-induced usual vulvar intraepithelial neoplasia and implications for immunotherapy.
abstract: 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.
authors.affiliation: Department of Gynaecology, Leiden University Medical Center, Leiden, The Netherlands; Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: E M G
authors.initials: EM
authors.lastname: van Esch
authors.forename: B
authors.initials: B
authors.lastname: Tummers
authors.forename: V
authors.initials: V
authors.lastname: Baartmans
authors.forename: E M
authors.initials: EM
authors.lastname: Osse
authors.forename: N
authors.initials: N
authors.lastname: Ter Haar
authors.forename: M D
authors.initials: MD
authors.lastname: Trietsch
authors.forename: B W J
authors.initials: BW
authors.lastname: Hellebrekers
authors.forename: C A G
authors.initials: CA
authors.lastname: Holleboom
authors.forename: H T C
authors.initials: HT
authors.lastname: Nagel
authors.forename: L T
authors.initials: LT
authors.lastname: Tan
authors.forename: G J
authors.initials: GJ
authors.lastname: Fleuren
authors.forename: M I E
authors.initials: MI
authors.lastname: van Poelgeest
authors.forename: S H
authors.initials: SH
authors.lastname: van der Burg
authors.forename: E S
authors.initials: ES
authors.lastname: Jordanova
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002277:Carcinoma / Q000276:immunology* / Q000628:therapy / Q000821:virology; D016022:Case-Control Studies; D015331:Cohort Studies; D015536:Down-Regulation; D005260:Female; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D006680:HLA Antigens / Q000378:metabolism*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000821:virology; D019656:Loss of Heterozygosity; D008875:Middle Aged; D030361:Papillomavirus Infections / Q000276:immunology* / Q000628:therapy; D012008:Recurrence; D014846:Vulvar Neoplasms / Q000276:immunology* / Q000628:therapy / Q000821:virology
chemical_list: D006680:HLA Antigens; D007371:Interferon-gamma
keywords: HLA expression; immunotherapy; microenvironment; uVIN; vulvar carcinoma