Characterising the local immune responses in cervical intraepithelial neoplasia: a cross-sectional and longitudinal analysis

Immunological competence influences the progression of cervical intraepithelial neoplasia (CIN) to invasive cancer. Information on the local immunological changes during the natural course of CIN is central for the development of new therapies. This study defines the populations of tissue-infiltrating immune cells in a cross-sectional cohort of different grades of CIN and also in a longitudinal cohort of regressing, persistent and progressing low-grade (LG)-CIN. A cohort of 125 women with LG cytological atypia was recruited, of which 64/125 (51%) women with LG-CIN were followed prospectively for 1 year. Paraffin-embedded entry and exit cervical biopsies were used for immunohistochemistry analysis (CD4, CD8, CD56, FOXP3, CD1a and granzyme B). At recruitment, 74/125 (59%), 39/125 (31%) and 12/125 (10%) women referred with LG smears had histologically proven LG-CIN, high-grade (HG) and normal biopsies, respectively. Seventeen of 64 (24.6%) women with LG-CIN progressed to HG-CIN within 1 year. In both LG-CIN and HG-CIN, the predominant intraepithelial cell population were cytotoxic T cells, while CD4+ and FOXP3+ T cells predominated the stromal compartment. Women with LG-CIN who later on regressed displayed a significantly higher number of cytotoxic (granzyme B+) cells in their entry samples. In addition, the ratio between CD8+ cells and granzyme B+ cells was close to 1, suggesting that all infiltrating CD8+ T cells were highly active. In contrast, this ratio was three-fold lower in women, in whom the lesions persisted or progressed. This study suggests that the early infiltration of lesions by highly cytotoxic effector cells protects against progression.