Intrinsic and extrinsic manipulation of B7/CTLA-4 interaction for induction of anti-tumor immunity against osteosarcoma cells.
BACKGROUND
B7 family members play a central costimulatory role in T cell activation. We identified B7-1a, an alternatively spliced form of B7-1. The therapeutic efficacy of B7-1a-expressing tumor vaccine remains uncertain.


METHODS
The murine osteosarcoma cell line, LM8, was engineered to express equivalent levels of B7-1 (B7-1-LM8) and B7-1a (B7-1a-LM8). The therapeutic efficacy of B7-transfected cells and anti-CTLA-4 blocking mAb was evaluated by the mixing experiments on the primary tumor, pulmonary metastasis and survival time.


RESULTS
(i) a mixture of B7-1-LM8 or B7-1a-LM8 cells inhibited growth of the subcutaneous LM8 tumors and augmented the therapeutic effects of anti-CTLA-4 mAb and (ii) a combination of B7-1a-LM8 cells and anti-CTLA-4 mAb most significantly eradicated pulmonary metastasis and prolonged the survival time of mice.


CONCLUSIONS
These findings suggest that intrinsic (lack of IgC-like domain in B7-1a) and extrinsic (anti-CTLA-4 mAb) manipulations of B7/CTLA-4 interaction synergistically improve the therapeutic efficacy of B7-based osteosarcoma vaccines.
Nagamori
Masashi
M
Department of Orthopaedic Surgery, Sapporo Medical University School of Medicine, South 1, West 16, Chuo-ku, Sapporo, 060-8543 Japan.
Kawaguchi
Satoshi
S
Murakami
Masaaki
M
Wada
Takuro
T
Nagoya
Satoshi
S
Yamashita
Toshihiko
T
Inobe
Manabu
M
Uede
Toshimitsu
T
D000069594:Abatacept; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology*; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology*; D001859:Bone Neoplasms / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D060908:CTLA-4 Antigen; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D018796:Immunoconjugates; D007167:Immunotherapy / Q000379:methods*; D008175:Lung Neoplasms / Q000276:immunology / Q000517:prevention & control / Q000556:secondary; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D012516:Osteosarcoma / Q000235:genetics / Q000276:immunology* / Q000556:secondary / Q000628:therapy; D014162:Transfection
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