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.
Van Ginderachter
J A
JA
Department of Cellular Immunology, Flanders Interuniversity Institute For Biotechnology, Vrije Universiteit Brussel, Sint-Genesius-Rode, Belgium. jvangind@vub.ac.be
Liu
Y
Y
Geldhof
A B
AB
Brijs
L
L
Thielemans
K
K
De Baetselier
P
P
Raes
G
G
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