{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T06:41:07Z","timestamp":1789540867869,"version":"build-2803163510"},"reference-count":50,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2014,9,15]],"date-time":"2014-09-15T00:00:00Z","timestamp":1410739200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Intl Journal of Cancer"],"published-print":{"date-parts":[[2015,2,15]]},"abstract":"<jats:p>Human papillomavirus\u2010induced usual\u2010type vulvar intraepithelial neoplasia (uVIN) are infiltrated by immune cells but apparently not cleared. A potential explanation for this is an impaired T cell effector function by an immunesuppressive milieu, coinfiltrating regulatory T cells or the expression of coinhibitory molecules. Here, the role of these potential inhibitory mechanisms was evaluated by a detailed immunohistochemical analysis of T cell infiltration in the context of FoxP3, Tbet, indoleamine 2,3\u2010dioxygenase, programmed cell death 1, T cell immunoglobulin mucin 3 (TIM3), natural killer cell lectin\u2010like receptor A (NKG2A) and galectins\u20101, \u22123 and \u22129. Paraffin\u2010embedded tissues of primary uVIN lesions (n\u2009=\u200943), recurrent uVIN lesions (n\u2009=\u200920), vulvar carcinoma (n\u2009=\u200921) and healthy vulvar tissue (n\u2009=\u200926) were studied. We show that the vulva constitutes an area intensely surveyed by CD8+, CD4+, Tbet+ and regulatory T cell populations, parts of which express the examined coinhibitory molecules. In uVIN especially, the number of regulatory T cells and TIM3+ T cells increased. The expression of the coinhibitory markers TIM3 and NKG2A probably reflected a higher degree of T cell activation as a dense infiltration with stromal CD8+TIM3+ T cells and CD3+NKG2A+ T cells was related to the absence of recurrences and\/or a prolonged recurrence\u2010free survival. A dense coinfiltrate with regulatory T cells was negatively associated with the time to recurrence, most dominantly when the stromal CD8+TIM3+ infiltration was limited. This notion was sustained in vulvar carcinoma's where the numbers of regulatory T cells progressively increased to outnumber coinfiltrating CD8+TIM3+ T cells and CD3+NKG2A+ T cells.<\/jats:p>","DOI":"10.1002\/ijc.29174","type":"journal-article","created":{"date-parts":[[2014,9,15]],"date-time":"2014-09-15T07:06:07Z","timestamp":1410764767000},"source":"Crossref","is-referenced-by-count":22,"title":["Expression of coinhibitory receptors on T cells in the microenvironment of usual vulvar intraepithelial neoplasia is related to proinflammatory effector T cells and an increased recurrence\u2010free survival"],"prefix":"10.1002","volume":"136","author":[{"given":"Edith M.G.","family":"van Esch","sequence":"first","affiliation":[{"name":"Department of Gynaecology Leiden University Medical Center Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariette I.E.","family":"van Poelgeest","sequence":"additional","affiliation":[{"name":"Department of Gynaecology Leiden University Medical Center Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Kouwenberg","sequence":"additional","affiliation":[{"name":"Department of Gynaecology Leiden University Medical Center Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. 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