Alterations in classical and nonclassical HLA expression in recurrent and progressive HPV‐induced usual vulvar intraepithelial neoplasia and implications for immunotherapy

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...

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Bibliographic Details
Published in:	International journal of cancer Vol. 135; no. 4; pp. 830 - 842
Main Authors:	van Esch, E.M.G., Tummers, B., Baartmans, V., Osse, E.M., ter Haar, N., Trietsch, M.D., Hellebrekers, B.W.J., Holleboom, C.A.G., Nagel, H.T.C., Tan, L.T., Fleuren, G.J., van Poelgeest, M.I.E., van der Burg, S.H., Jordanova, E.S.
Format:	Journal Article
Language:	English
Published:	Hoboken, NJ Wiley-Blackwell 15-08-2014 Wiley Subscription Services, Inc
Subjects:	Adolescent Adult Aged Aged, 80 and over Biological and medical sciences Cancer Carcinoma - immunology Carcinoma - therapy Carcinoma - virology Case-Control Studies Cohort Studies Down-Regulation Female Female genital diseases Gene Expression Regulation Gene Expression Regulation, Neoplastic Genital cancers Genotype Gynecology. Andrology. Obstetrics HLA Antigens - metabolism HLA expression Human papillomavirus Humans Immunotherapy Immunotherapy - methods Interferon-gamma - metabolism Keratinocytes - cytology Keratinocytes - drug effects Keratinocytes - virology Loss of Heterozygosity Medical research Medical sciences microenvironment Middle Aged Papillomavirus Infections - immunology Papillomavirus Infections - therapy Recurrence Tumors uVIN vulvar carcinoma Vulvar Neoplasms - immunology Vulvar Neoplasms - therapy Vulvar Neoplasms - virology Vulvar intraepithelial neoplasia vulvar carcinoma HLA-System Relapse Premalignant lesion Major histocompatibility system HLA expression Papovaviridae Vulva carcinoma Microenvironment Female genital diseases Papillomavirus Virus uVIN Human papillomavirus Cancerology Treatment Immunotherapy Vulvar diseases Class I histocompatibility antigen microenvironment immunotherapy
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Summary:	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. What's new? Premalignant HPV‐induced neoplasias of the vulva often display downregulation of HLA‐class I but this is not genetically imprinted, can be restored upon stimulation with IFNγ, and does not bear impact on the clinical response to therapeutic vaccination. Vulvar carcinomas more often display gene loss‐associated HLA‐class I downregulation and upregulated expression of the immune inhibitory molecules HLA‐E and ‐G, suggesting that immunotherapy may achieve its best success at the premalignant stage.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1
ISSN:	0020-7136 1097-0215
DOI:	10.1002/ijc.28713