Loss of ICOSL expression in the progression to cervical carcinoma

Human papillomavirus (HPV)-related lesions contain types with benign outcomes and those with a risk of progression to cancer. We addressed the role of immune surveillance in 76 cervical biopsies (normal = 23, HPV+ benign = 16, HPV+ precancer = 37) by studying the infiltration of cytotoxic T cells and the expression of the immune modulators PDL1, ICOSL, and miR-155, and compared the data to 101 cervical squamous cell carcinomas. In the normal cervix, ICOSL expression was restricted to the endocervical epithelia, whereas neither miR-155 nor PDL1 was detected. MiR-155 was up-regulated in both the benign (88%) and precancerous (92%) HPV squamous intraepithelial lesions (SIL) and co-localized to cells in the upper part of the lesion, that is, the area with productive viral infection. Both PDL1 (95%) and ICOSL (89%) were only evident in the precancerous SIL, and each localized to squamous cells in the basal aspect that lacked replicating virus. In both microinvasive and invasive cervical squamous cell cancer, miR-155 expression remained high (83%), as did PDL1 expression (80%), but ICOSL detection was reduced to 17%. Infiltration by CD8+ T cells was intense in the invasive lesions, and these cells were mostly inactive as determined by the lack of granzyme B co-localization. It is concluded that miR-155 expression is a marker of HPV infection in both benign and precancerous lesions, whereas approximately 10% of the latter lesions that progress to cancer gain PDL1 and lose ICOSL expression, which are important factors in avoiding immune surveillance.