ABSTRACT
De novo expression of B7-1 impaired tumorigenicity of TRAMP-C2 mouse prostate adenocarcinoma (TRAMP-C2/B7), but it did not elicit a protective response against TRAMP-C2 parental tumor, unless after in vitro treatment with IFN-gamma. TRAMP-C2 cells secrete TGF-beta and show low MHC-I expression. Treatment with IFN-gamma increased MHC-I expression by induction of some APM components and antagonizing the immunosuppressant activity of TGF-beta. Thus, immunization with TRAMP-C2/B7 conferred protection against TRAMP-C2-derived tumors in function of the IFN-gamma-mediated fine-tuned modulation of either APM expression or TGF-beta signaling. To explore possible clinical translation, we delivered IFN-gamma to TRAMP-C2 tumor site by means of genetically engineered MSCs secreting IFN-gamma.
Subject(s)
Adenocarcinoma/immunology , Histocompatibility Antigens Class I/immunology , Interferon-gamma/immunology , Prostatic Neoplasms/immunology , Adenocarcinoma/genetics , Animals , B7-1 Antigen/genetics , B7-1 Antigen/immunology , Cell Line, Tumor , Gene Expression Regulation, Neoplastic , Genes, MHC Class I , Histocompatibility Antigens Class I/genetics , Male , Mesenchymal Stem Cells/immunology , Mice , Mice, Inbred C57BL , Neoplasms, Experimental/genetics , Neoplasms, Experimental/immunology , Prostatic Neoplasms/genetics , Spleen/cytology , Spleen/immunology , Transfection , Transforming Growth Factor beta/immunology , Up-RegulationABSTRACT
We show here that human and mouse mesenchymal stem cells (MSCs) can be obtained not only from bone marrow (BM), but also from adult spleen and thymus. In vitro, both human and mouse spleen- and thymus-derived MSCs exhibit immunophenotypic characteristics and differentiation potential completely comparable to BM-MSCs. In addition, they can inhibit immune responses mediated by activated T lymphocytes with efficiency comparable to BM-MSCs. In vivo, mouse MSCs from BM, spleen, and thymus, if injected together with a genetically modified tumor cell vaccine, can equally prevent the onset of an anti-tumor memory immune response, thus leading to tumor growth in normally resistant mice. Our data suggest that not only do spleen and thymus have a stem cell reservoir to build up their stromal architecture, but also contain microenviromental immunoregulatory cells with the same properties of BM-MSCs.