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-free survival.
abstract: 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.
authors.affiliation: Department of Gynaecology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Edith M G
authors.initials: EM
authors.lastname: van Esch
authors.forename: Mariette I E
authors.initials: MI
authors.lastname: van Poelgeest
authors.forename: Simone
authors.initials: S
authors.lastname: Kouwenberg
authors.forename: E Michelle
authors.initials: EM
authors.lastname: Osse
authors.forename: J Baptist M Z
authors.initials: JB
authors.lastname: Trimbos
authors.forename: Gert Jan
authors.initials: GJ
authors.lastname: Fleuren
authors.forename: Ekaterina S
authors.initials: ES
authors.lastname: Jordanova
authors.forename: Sjoerd H
authors.initials: SH
authors.lastname: van der Burg
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002278:Carcinoma in Situ / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D016022:Case-Control Studies; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D018572:Disease-Free Survival; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D037483:Galectin 1 / Q000378:metabolism; D037161:Galectins / Q000378:metabolism; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D053208:Kaplan-Meier Estimate; D008565:Membrane Proteins / Q000378:metabolism*; D008875:Middle Aged; D055654:NK Cell Lectin-Like Receptor Subfamily C / Q000378:metabolism*; D009364:Neoplasm Recurrence, Local / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D030361:Papillomavirus Infections / Q000276:immunology / Q000378:metabolism*; D016016:Proportional Hazards Models; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D059016:Tumor Microenvironment / Q000276:immunology; D014846:Vulvar Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D055815:Young Adult
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D037483:Galectin 1; D037161:Galectins; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; C445499:LGALS1 protein, human; C105032:LGALS9 protein, human; D008565:Membrane Proteins; D055654:NK Cell Lectin-Like Receptor Subfamily C
keywords: HPV; TIM3; coinhibitory receptors; immunotherapy; usual VIN