Regulatory T cells in a spectrum of HPV-induced cervical lesions: cervicitis, cervical intraepithelial neoplasia and squamous cell carcinoma

Abstract

Problem: Thriving of tumors amidst rich immune infiltrates is an unexplained paradox.

Method of study: Immune markers on lymphocytic infiltrates in HPV-positive cervicitis, cervical intraepithelial neoplasia III (CIN III), squamous cell carcinoma (SCC) and normal cervices were characterized immunohistochemically. Regulatory T cells were enumerated and phenotypically characterized using antibodies to FOXP3.

Results: SCCs had higher numbers of CD4 and CD8 cells; infiltrates expressed more CD25, TGFbeta, and IL10 but had significantly lower IL2 compared with cervicitis and CIN III. Expression of CD25 and IL2 correlated well in cervicitis and CIN III but not in SCC. FOXP3 expression was also higher and ratios of CD4/FOXP3 and CD8/FOXP3 were lower in SCC. A fraction of cervicitis, CIN I, CIN II and CIN III had natural (n) regulatory T cells (Tregs); their lesional distribution was predominantly intraepithelial in cervicitis, while in CIN they were also present in the stroma. The proportion of FOXP3(+) CD25(+); FOXP3(+) CD25(-) and TGFbeta(+) CD25(+) in invasive tumors was 17; 19 and 22 respectively.

Conclusion: Cervical tumors are marked by the presence of an immunoregulatory environment, and harbor equal proportions of 'inactive' n Tregs; activated n Tregs; and Tregs operating via TGFbeta. nTregs in cervicitis and CIN may be a potential marker of persistence.