IFN-gamma- Mediated Upmodulation of MHC Class I Expression Activates Tumor-Specific Immune Response in a Mouse Model of Prostate Cancer

The mouse prostatic adenocarcinoma tumorigenic cell lines TRAMP-C1 and TRAMP-C2 represent a suitable animal model to study the role of major histocompatibility class-I (MHC-I) molecules expression in protection against tumor development and progression in vivo. In these cell lines, MHC-I expression decreases after time of in vitro cell culture, but it can be restored by treatment with IFN-γ. We have transduced TRAMP-C2 cells with the cDNA of the co-stimulatory molecule B7-1. TRAMP-C2/B7 transfectants showed impaired growth in vivo, but they did not elicit a protective response against TRAMP-C2 parental tumor, unless after treatment with IFN-γ prior to injection. IFN-γ is an inducer of some components of the MHC-I antigen processing and presentation machinery (APM). IFN-γ is also an antagonist of the immunosuppressant activity of TGF-β, largely produced by TRAMP-C2. Thus, immunization with TRAMP-C2/B7 conferred protection against TRAMP-C2-derived tumors in function of the IFN-γ-mediated fine-tuned modulation of either APM expression or TGF-β signaling. To explore possible clinical traslation of these results we attempted to deliver IFN-γ to TRAMP-C2 tumor growth site by means of genetically engineered mesenchymal stem cells (MSCs) secreting IFN-γ. This approach produced results matching those obtained with IFN-γ-treated TRAMP-C2 cells.