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.

MATERIALS AND 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.

CONCLUSION

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.