Frequencies and role of regulatory T cells in patients with (pre)malignant cervical neoplasia

Abstract

Oncogenic human papillomavirus (HPV)-infection is crucial for developing cervical cancer and its precursor lesions [cervical intraepithelial neoplasia (CIN)]. Regulatory T cells (T_regs) might be involved in the failure of the immune system to control the development of HPV-induced cancer. We investigated frequencies, phenotype and activity of T_regs in patients with cervical neoplasia. CIN and cervical cancer patients showed increased CD4⁺/CD25^high T cell frequencies in peripheral blood and CD4⁺ T cell fraction. These CD4⁺/CD25^high T cells represent T_regs as demonstrated by their low proliferation rate, low interferon (IFN)-γ/interleukin (IL)-10 ratio, high expression of CD45RO, GITR, CTLA-4, forkhead box P3 (FoxP3) and low CD45RA expression. Moreover, in HPV16⁺ cervical cancer patients, in-vitro depletion of CD25⁺ T cells resulted in increased IFN-γ T cell responses against HPV16 E6- and E7 peptides. Thus, increased frequencies of T_regs in cervical cancer patients may indeed suppress HPV-specific immunity. Longitudinal analysis of CD4⁺/CD25^high T cell frequencies in patients showed a modest decline 1 year after curative surgery or chemoradiation. This study demonstrates increased frequencies and suppressive activity of T_regs in cervical cancer. These results imply that T_regs may suppress the immune control of cervical neoplasia and furthermore that suppression of immunity by T_regs will be another hurdle to overcome in therapeutic immunization strategies against cervical neoplasia.