Active antitumor immunotherapy, with or without B7-mediated costimulation, increases tumor progression in an immunogenic murine T cell lymphoma model.
BW-Sp3 is a BW-5147-derived T cell lymphoma with limited immunogenicity since, despite regression of the majority of subcutaneous tumors, an important fraction of the animals will die from metastases. In the present study, the BW-Sp3 cells were transfected with genes encoding B7-1 or B7-2, known to be involved in the induction of T cell responses. The resulting transfectants exhibited a reduced tumorigenicity and did not cause mortality in the syngeneic recipients. Furthermore, immunization with the B7-1 or B7-2 transfectants resulted in an increased generation of cytotoxic T lymphocytes (CTL) that lysed both the transfectants and the wild-type BW-Sp3 cells. Since the B7 transfectants were completely rejected in syngeneic recipients and induced potent CTL recognizing the wild-type BW-Sp3 cells, these engineered cells were considered as candidates for immunotherapy. Vaccinations with the B7-1 or B7-2 transfectants could completely protect the animals from metastatic disease when subsequently challenged with wild-type BW-Sp3 cells. Furthermore, immunization with the B7 transfectants could prolong the survival time of mice that had been challenged intravenously with BW-Sp3 cells. Surprisingly, however, when these transfectants, as well as the wild-type BW-Sp3 cells, were used for vaccination of tumor-bearing animals, the presence of the subcutaneous BW-Sp3 tumors clearly interfered with the outcome of immunotherapy, resulting in increased malignancy, as reflected by a higher incidence of progressing tumors and a reduced survival rate. Possible implications for immunotherapy in humans are discussed.
Raes
G
G
Laboratory of Cellular Immunology, Flanders Interuniversity Institute of Biotechnology, Free University of Brussels, Sint-Genesius-Rode, Belgium.
Van Ginderachter
J
J
Liu
Y Q
YQ
Brys
L
L
Thielemans
K
K
De Baetselier
P
P
Geldhof
A
A
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology*; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology*; D051940:B7-2 Antigen; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D018450:Disease Progression; D005260:Female; D016233:Immunotherapy, Active; D016399:Lymphoma, T-Cell / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008815:Mice, Inbred Strains; D009362:Neoplasm Metastasis; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014162:Transfection
D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D019496:Cancer Vaccines; C497965:Cd86 protein, mouse; D008562:Membrane Glycoproteins