Infiltrating CD4 and CD8 lymphocytes in HPV infected uterine cervical milieu

Tumor infiltrating lymphocytes (TILs) have been extensively described in anti-tumor immunity, but their functional alterations in the immunoediting processes during neoplastic progression in the uterine cervix are still not clear. Our aim was to gain insight into cervical tissue T cell populations, determine if there are any differences in the localization and quantity distribution of T lymphocytes, and to evaluate their role in disease regression or progression in the cervical neoplastic milieu.

Serial section analysis of immunohistochemically stained CD4 and CD8 lymphocytes was performed on a total number of 72 samples, categorized into four cohorts: 23 HPV non-infected (HPV-) normal cervix, 20 HPV infected (HPV+) normal cervix, 17 HPV+ low grade cervical intraepithelial neoplasia (CIN), and 12 HPV+ high grade CIN.

Low infiltrating lymphocytes (ILs) in normal cervix and high ILs in CIN were observed, while the trend of ILs increased with increasing grade of CIN, which was statistically significant (P<0.0001). Quantitative and localization analysis between the subsets of T cells showed that, in the epithelial layer, infiltrating CD8+ lymphocytes (CD8+_ILs) were significantly higher than CD4+_ILs in HPV+ normal cervix, while the trend decreased with increasing grade of CIN (P=0.011). Whereas, in the stromal layer, CD4+_ILs were predominant in all study groups and no statistical difference was found between these groups. However, tumor infiltrating CD8+ lymphocytes (CD8+_TILs) were noted to be significantly higher than CD4+_TILs in severe dysplastic cases.

T cell infiltrates were predominant as the grade of the lesion progressed into more advanced lesions, which likely represent the lesions that have persisted over time. The variation in the infiltration rate and the location of CD4+_ILs and CD8_ILs may suggest the efficacious role of CD8 T cells in eliminating HPV infected cervical epithelial cells and also provides insight into the complex role of TILs in facilitating and mediating sustained anti-tumor responses, hence preventing tumor outgrowth.