The anti-tumor activity of anti-CTLA-4 is mediated through its induction of IFN gamma

The T-cell-specific receptor, CTLA-4, has been demonstrated to be a potent negative regulator of lymphocyte activation, the functional significance of which has been demonstrated in murine tumor models using blocking antibodi es. However, the mechanism(s) involved in enhancing tumor regression has no t been identified. In this study, we determined whether IFN gamma, was play ing a role in this activity. In vitro, anti-CTLA-4 enhanced IFN gamma produ ction by lymph node cells obtained from tumor-bearing mice (351 pg/ml vs 77 pg/ mi). Additionally, fibrosarcoma-challenged animals treated with anti-C TLA-4 had elevated levels of the IFN-inducible enzyme 2-5-OAS in draining l ymph nodes (850 pM vs 260 pM for controls) and an increased amount of IFN g amma in tumor lysates (at day 7, 620 pg/ 100 mug vs 160 pg/100 mug in contr ols). The importance of IFN gamma was demonstrated by the ability of neutra lizing antibodies to completely abrogate the anti-tumor effects of anti-CTL A-4. Moreover, fibrosarcoma cells were shown to be exquisitely sensitive to IFN gamma -mediated class I upregulation and histological examination of t umors from anti-CTLA-4-treated mice revealed a trend toward increased tumor cell apoptosis and decreased angiogenesis. These studies have demonstrated that one mechanism for the anti-tumor effects of anti-CTLA-4 relates to it s ability to augment IFN gamma production, resulting in an increased expres sion of class I on the tumor, enhanced apoptosis, and a decrease in blood v essel growth.