IFN-g- MEDIATED UPMODULATION OF MHC CLASS I EXPRESSION ACTIVATES TUMOR-SPECIFIC IMMUNE RESPONSE IN A MOUSE MODEL OF PROSTATE CANCER
M. Martini1 , M. G. Testi, 1 M. Pasetto1, M. C. Picchio1, G. Innamorati1, M. Mazzocco1, S. Ugel2,S.
Cingarlini3, V. Bronte2, P. Zanovello2, M. Krampera3, F. Mosna3, T. Cestari1, A.P. Riviera1, N.
Brutti1, O. Barbieri4, L. Matera5, G. Tridente1, M. Colombatti, 1 S. Sartoris1
1University of Verona, Dept. Pathology, Section Immunology, Verona, Italy, 2University of
Padova, Dept. Oncology and Surgical Sciences, Section Oncology, Padova, Italy, 3University of
Verona, Dept. Clinical and Experimental Medicine, Section Hematology, Verona, Italy.
4University of Genova, Dept. Oncology, Biology and Genetics, Genova, Italy, 5University of
Torino, Dept. Internal Medicine, Torino, Italy.
The mouse prostatic adenocarcinoma tumorigenic cell line TRAMP-C2 represents 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-g. 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-g prior to injection. IFN-g antagonyzes the immunosuppressant activity of TGF-b, largely produced by TRAMP-C2. Immunization with TRAMP-C2/B7 conferred protection against TRAMP-C2-derived tumors in function of the IFN-g-mediated fine-tuned modulation of either APM expression or TGF-b signaling. To explore possible clinical traslation of these results we attempted to deliver IFN-g to TRAMP-C2 tumor growth site by means of genetically engineered mesenchymal stem cells (MSCs) secreting IFN-g. This approach produced results matching those obtained with IFN-g-treated TRAMP-C2 cells.
