Cervical intraepithelial neoplasia (CIN) and cervical carcinoma harbour highly increased numbers of Foxp3+ CD4+ CD25+ regulatory T-cells

Abstract

Active immune suppression by tumors and premalignant lesions supports malignant growth and limits the effect of immune based therapies. Reduction of MHC-mediated antigen presentation or release of immunosuppressive cytokines are common immune escape strategies in cancer, in addition there is a rapidly growing body of evidence that utilization of regulatory T-cells for inactivation of tumor specific cytotoxic T-cells is an accessory widespread and important key mechanism for active immune suppression by cancer. During the last two years several relevant preclinical studies have been published, which show that inactivation of regulatory T-cells substantially enhance the efficacy of immune based therapies. Since there is only limited information about the presence of regulatory T-cells in cervical cancer and its precursors we have compared the amount of Foxp3+ T-cells in cervical cancer, melanoma, colon cancer and lung cancer by immunohistochemistry. We could demonstrate that among these tumors cervical carcinoma harbour the highest numbers of regulatory T-cells. Lymphocyte infiltration is predominantly confined to tumor stroma, where the amount of regulatory T-cells reaches up to 10–20% of all CD3+ lymphocytes. Increased amounts of regulatory T-cells can also be detected in the stroma of cervical neoplastic lesions (CIN). In a mouse model for cervical cancer (TC1 tumors) we demonstrated that inactivation of regulatory T-cells by specific antibodies during the effector phase after therapeutic vaccination (with an HPV E6/E7 specific adenoviral vector) enhances the therapeutic effect of the viral vaccine. These findings suggest that future protocols for immune therapy of cervical cancer and cervical neoplasia should integrate measures for inactivation of regulatory T-cells to improve the cytotoxic strength of tumor specific CD8+ T-cells.