In VivoExpression of Immunosuppressive Cytokines in Human Papillomavirus-Transformed Cervical Cancer Cells

Abstract

Genital human Papillomavirus infection is common and only a minor fraction of infected subjects develop progressing cervical epithelial lesions or cancer. Bypassing local immune responses is important for the development of cervical cancer. In this work we determined the cytokine pattern in samples from patients with cervical cancer. Thus, we examined the local mRNA expression profile of helper T cell type 1 (Th1), Th2, and Th3 cytokines in HPV-positive cervical cancer biopsies by reverse transcription-polymerase chain reaction. Our data indicate that 80% of the tumors expressed low levels of CD4 mRNA, with all of them expressing higher CD8 mRNA levels. Most tumors expressed interleukin (IL)-4 and IL-10 mRNAs and, most importantly, all of them expressed transforming growth factor (TGF)-beta1 and interferon gamma mRNA. None of the tumors studied expressed IL-12, IL-6, or tumor necrosis factor (TNF) mRNA. Immunohistochemical analysis identified IL-10 only in tumor cells and koilocytic cells, but not in tumor-infiltrating lymphocytes, suggesting that IL-10-producing cells are those transformed by HPV. We found a correlation between immunostaining for IL-10 protein and the level of IL-10 mRNA expression. Moreover, supernatants from HPV-transformed cell cultures contained IL-10 and TGF- beta1. Our findings indicate a predominant expression of immunosuppressive cytokines, which might help downregulate tumor-specific immune responses in the microenvironment of the tumor. This information may be useful for cervical cancer immunotherapies or for therapeutic vaccine design against Human Papillomavirus.

M2 Macrophages Induced by Prostaglandin E2 and IL-6 from Cervical Carcinoma Are Switched to Activated M1 Macrophages by CD4+ Th1 Cells

“…Factors secreted by tumor cells that have been implicated in the prevention or modulation of DC differentiation and/or function are VEGF, macrophage colony-stimulating factor (M-CSF), TGF (TGF-b1), IL-10, IL-6, and prostanoids (e.g., PGE 2 ) (12). CxCas are known also to secrete immunomodulatory compounds, but their effect on APCs is yet unknown (15)(16)(17)(18)(19).…”

IL-10 expression is regulated by HPV E2 protein in cervical cancer cells

“…Previously, we demonstrated that HPV infection induces il-10 expression in patients with cervical cancer (26). in addition, an HPV e2 recognition site in the position from -2,203 to -2,191 nt in the human il-10 promoter has been reported (18).…”

“…in other cases, il-10 is produced by activated cells involved in the host antitumor response; thus il-10 may be an indicator of a potent inflammatory response rather than immunosuppression. in particular, it has been found that il-10 is highly expressed locally in biopsies from patients with premalignant lesions and cervical cancer, and may induce a local immunosuppressive state (5,26,29,30). Thus, elucidating the mechanisms of il-10 gene expression during cervical cancer development may aid in the understanding of il-10 function in the context of the antitumor immune response.…”

“…Thus, our findings suggest that an event that occurs during HPV infection and may influence cervical cancer development consists of the induction of il-10 gene expression by HPV e2 protein expression. This event represents an escape mechanism of antitumor immune repsonse, as il-10 overexpression may generate an immunosuppression state in the tumor microenvironment (6,26).…”

A therapeutic perspective of cytokines in tumor management

“…These pro-tumor immune activities are mediated by molecules like cytokines, chemokines, myeloid suppressor cells, and Treg or regulatory T-cells [17] . Tumor derived cytokine and chemokine signals neutralize the immune effector cells, which may be mediated by NF-κB pathway [18,19] . Surface antigens in tumor cells are tumor specific, and this characteristic has been targeted effectively at clinical level by tumor antigen specific monoclonal antibodies like rituximab, trastuzumab and cetuximab [20] .…”