Effects of retinoic acid combined with interferon-γ on the expression of a tumor rejection antigen (heat shdck protein gp96) in human cervical cancer

Retinoids and interferons are important regulators of human epithelial cell differentiation and have been used successfully in the clinical treatment of HPV-involved cervical cancer. Hsp-gp96 molecules recently have been implicated in the presentation pathways of tumor and viral antigens and have resulted in an effective protein vaccine in several tumor animal models. In this study, we analyzed at the transcriptional (northern blot) and post- transcriptional levels (western blot) the effects of retinoic acid and interferon-γ alone or in combination on the expression of the tumor rejection antigen heat shock protein-gp96 molecules (Hsp-gp96) in two human cervical carcinoma cell lines (SiHa and HT-3). Exposure to retinoic acid or IFN-γ was able to upregulate the expression of Hsp-gp96 molecules in both cervical cell lines studied. Exposure to the combination of IFN-γ plus retinoic acid significantly upregulated (in an additive manner) Hsp-gp96 molecules when compared to the levels obtained after exposure to IFN-γ or retinoic acid alone. Northern blot analysis of mRNA for Hsp-gp96 molecule confirmed that the activity of both of these biologic response modifiers was at the transcriptional level. Taken together, these data indicate that the combination of these modalities could induce a previously unrecognized additive effect on the expression of another immunologically important antigen, the Hspgp96 tumor rejection antigen, in human cervical cancer cells. These findings extend previous reports on the effects of retinoids and IFN- γ on tumor cells and provide further support for the combined use of these powerful biologic response modifiers in the adjuvant treatment of cervical cancer.