Retinoids and interferons are important regulators of human epithelial cell differentiation and have been successfully used in the clinical treatment of HPV-involved cervical cancer. In this study, 2 HPV-positive human cervical-carcinoma cell lines were analyzed for their surface expression of MHC-Class-I, MHC-Class-II and ICAM-1 surface antigens before and after exposure to all-trans retinoic acid, interferon-gamma and the combination of the 2 compounds. In addition, the effects on HLA-Class-I-mRNA expression were evaluated after such treatments. Both cell lines expressed MHC-Class-I molecules, and their levels were markedly up-regulated after exposure to IFN-gamma. Similarly, MHC-Class-II and ICAM-1 antigens were either induced or significantly up-regulated by IFN-gamma. Exposure to all-trans retinoic acid was also able to significantly increase the expression of MHC-Class-I and ICAM-I antigens as compared with untreated tumor cells. However, unlike IFN-gamma, retinoids were not able to induce the expression of HLA-Class-II surface antigens. Exposure to the combination of IFN-gamma plus retinoic acid significantly up-regulated (in an additive manner) HLA-Class-I and ICAM-1 molecules as compared with the levels obtainable after exposure to IFN-gamma alone. Finally, Northern-blot analysis of HLA-Class-I-mRNA expression confirmed that the activity of both of these biologic response modifiers was at transcriptional level. These data indicate that the combination of these modalities could induce an additive effect on the expression of immunologically important surface antigens on human cervical-cancer cells. These findings, together with the known anti-proliferative effects mediated by retinoids and IFN-gamma on tumor cells, further support the combination of these agents in the treatment of pre-invasive and invasive human cervical cancer.
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