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-free survival

Edith M.G. Van Esch, Mariette I.E. Van Poelgeest, Simone Kouwenberg, E. Michelle Osse, J. Baptist M.Z. Trimbos, Gert Jan Fleuren, Ekaterina S. Jordanova, Sjoerd H. Van Der Burg*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Human papillomavirus-induced usual-type 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-dioxygenase, programmed cell death 1, T cell immunoglobulin mucin 3 (TIM3), natural killer cell lectin-like receptor A (NKG2A) and galectins-1, -3 and -9. Paraffin-embedded tissues of primary uVIN lesions (n=43), recurrent uVIN lesions (n=20), vulvar carcinoma (n=21) and healthy vulvar tissue (n=26) 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-free 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.

Original languageEnglish
Pages (from-to)E95-E106
JournalInternational Journal of Cancer
Issue number4
Publication statusPublished - 1 Jan 2016

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