B7-1, IFN gamma and anti-CTLA-4 co-operate to prevent T-cell tolerization during immunotherapy against a murine T-lymphoma.
We previously reported on a murine T lymphoma cell line, BW-Sp3, with inherent immunogenicity. BW-Sp3 tumors can elicit an anti-tumor CD8(+) CTL response capable of mediating a regression of subcutaneous tumors. However, this immune response is inadequate to eliminate cancer cells completely in a significant percentage of the recipients, resulting in progressing tumors. In this tumor model, tumor progression correlated with a tolerization of tumor-reactive T cells and cellular immunotherapy of tumor bearing animals, with or without B7-mediated costimulation, even increased tumor progression (Raes et al, 1998). In the present study, we investigated whether the co-expression of IFN gamma, together with B7-1, could have beneficial effects on immunotherapy. Although immunotherapy with IFN gamma and B7-1 single transfectants tended to tolerize anti-tumor T-cells and consequently increased tumor growth, the B7-1/IFN gamma double transfectants resulted in a more beneficial outcome. This phenomenon correlated with an increased CTL-inducing potential of the double transfectants. Secondly, we wondered whether CTLA-4 signalling was involved in the down-regulation of the anti-tumor response. Indeed, when immunotherapy was provided along with anti-CTLA-4, the protection by B71/IFN gamma double transfectants was further improved and the tumor-promoting effect of BW-Sp3(B7-1) was compensated for. Our results indicate that B7-1, IFN gamma and the blockade of CTLA-4 cooperate to tilt the balance in favour of tumor elimination, while either factor alone fails to do so or even promotes tumor growth.
Department of Cellular Immunology, Flanders Interuniversity Institute For Biotechnology, Vrije Universiteit Brussel, Sint-Genesius-Rode, Belgium. jvangind@vub.ac.be
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Van Ginderachter
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Liu
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Geldhof
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Brijs
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Thielemans
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De Baetselier
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Raes
D000069594:Abatacept; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology* / Q000502:physiology; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology*; D060908:CTLA-4 Antigen; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology; D005260:Female; D007108:Immune Tolerance / Q000276:immunology; D018796:Immunoconjugates; D016233:Immunotherapy, Active / Q000379:methods*; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology*; D016399:Lymphoma, T-Cell / Q000276:immunology* / Q000628:therapy; D051379:Mice; D008806:Mice, Inbred AKR; D009368:Neoplasm Transplantation; D015398:Signal Transduction / Q000502:physiology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014162:Transfection; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D060908:CTLA-4 Antigen; D019496:Cancer Vaccines; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D000069594:Abatacept; D007371:Interferon-gamma