IFN-gamma- Mediated Upmodulation of MHC Class I Expression Associated to a B7-1-Expressing Tumor Cell Vaccine Activates Tumor-Specific Immune Response in a Mouse Model of Prostate Cancer.

Prostatic adenocarcinoma (PCa) carries out a mechanism of immune evasion based on the progressive donwnmodulation of the MHC class I (MHC-I) genes and the lack of the expression of MHC class II genes. The mouse PCa cell lines TRAMP-C1 and TRAMP-C2, derived from the TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP), which develops in C57BL/6 male mice transgenic for the SV40 large tumor antigen coding region under the transcriptional control of the prostate-specific rat probasin promoter, represent a suitable animal model to study the influence of MHC-I molecules on protection against tumor development and progression in vivo. In these cell lines, in fact, MHC-I expression decreases after in vitro passaging, a phenotype closely resembling that described in human PCa. TRAMP-C1 and -C2 are tumorigenic when injected in syngeneic C57BL/6 mice. In this study we have analyzed the effect of transfection of TRAMP-C2 with the cDNA of the costimulatory molecule B7-1 (TRAMP-C2/B7 transfectants) on tumor growth in vivo and on tumor-specific immune response. TRAMP-C2/B7 showed impaired growth in vivo, although it did not elicit a protective response against the B7-1 negative TRAMP-C2 parental tumor. Upon increasing MHC-I expression in TRAMP-C2 and TRAMP-C2/B7 cells with IFN-g prior to injection in syngeneic animals, protection against TRAMP-C2 tumor growth rised (tumor incidence: 44%), as well as tumor-specific cytotoxicity of spleen-derived cells. IFN-a increased MHC-I expression in TRAMP-C2 and TRAMP-C2/B7 as well, but it did not inhibit tumor growth (tumor incidence: 100%). Western blot analysis showed that both interferons enhanced TAP-1, TAP-2, LMP-2 and LMP-7 expression, but IFN-g was quantitatively more efficient than IFN-a. These results suggest that IFN-g plays a fundamental role in TRAMP-C2 immunogenicity, by inducing TAP-1, TAP-2, LMP-2 and LMP-7 enough to provide correct production and transport of immunogenic peptides from cytosol to endoplasmic reticulum to be assembled to MHC-I molecules.