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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
Author(s) -
van Esch Edith M.G.,
van Poelgeest Mariette I.E.,
Kouwenberg Simone,
Osse E. Michelle,
Trimbos J. Baptist M.Z.,
Fleuren Gert Jan,
Jordanova Ekaterina S.,
van der Burg Sjoerd H.
Publication year - 2014
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.29174
Subject(s) - foxp3 , cd8 , stromal cell , biology , cytotoxic t cell , immunology , proinflammatory cytokine , t cell , cancer research , immune system , inflammation , in vitro , biochemistry
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.