In vivo expression 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.