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

Int J Cancer. 2015 Feb 15;136(4):E95-106. doi: 10.1002/ijc.29174. Epub 2014 Sep 15.


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.

Keywords: HPV; TIM3; coinhibitory receptors; immunotherapy; usual VIN.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Carcinoma in Situ / immunology
  • Carcinoma in Situ / metabolism*
  • Carcinoma in Situ / virology
  • Case-Control Studies
  • Chemotaxis, Leukocyte / immunology
  • Disease-Free Survival
  • Female
  • Forkhead Transcription Factors / metabolism
  • Galectin 1 / metabolism
  • Galectins / metabolism
  • Hepatitis A Virus Cellular Receptor 2
  • Humans
  • Kaplan-Meier Estimate
  • Membrane Proteins / metabolism*
  • Middle Aged
  • NK Cell Lectin-Like Receptor Subfamily C / metabolism*
  • Neoplasm Recurrence, Local / immunology
  • Neoplasm Recurrence, Local / metabolism*
  • Neoplasm Recurrence, Local / virology
  • Papillomavirus Infections / immunology
  • Papillomavirus Infections / metabolism*
  • Proportional Hazards Models
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • Tumor Microenvironment / immunology
  • Vulvar Neoplasms / immunology
  • Vulvar Neoplasms / metabolism*
  • Vulvar Neoplasms / virology
  • Young Adult


  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Galectin 1
  • Galectins
  • HAVCR2 protein, human
  • Hepatitis A Virus Cellular Receptor 2
  • LGALS1 protein, human
  • LGALS9 protein, human
  • Membrane Proteins
  • NK Cell Lectin-Like Receptor Subfamily C