Abstract
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 antibodies. However, the mechanism(s) involved in enhancing tumor regression has not been identified. In this study, we determined whether IFNγ was playing a role in this activity. In vitro, anti-CTLA-4 enhanced IFNγ production by lymph node cells obtained from tumor-bearing mice (351 pg/ml vs 77 pg/ml). Additionally, fibrosarcoma-challenged animals treated with anti-CTLA-4 had elevated levels of the IFN-inducible enzyme 2-5-OAS in draining lymph nodes (850 pM vs 260 pM for controls) and an increased amount of IFNγ in tumor lysates (at day 7, 620 pg/100 μg vs 160 pg/100 μg in controls). The importance of IFNγ was demonstrated by the ability of neutralizing antibodies to completely abrogate the anti-tumor effects of anti-CTLA-4. Moreover, fibrosarcoma cells were shown to be exquisitely sensitive to IFNγ-mediated class I upregulation and histological examination of tumors 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 its ability to augment IFNγ production, resulting in an increased expression of class I on the tumor, enhanced apoptosis, and a decrease in blood vessel growth.
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Received: 17 November 2000 / Accepted: 26 January 2001
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Paradis, T., Floyd, E., Burkwit, J. et al. The anti-tumor activity of anti-CTLA-4 is mediated through its induction of IFNγ. Cancer Immunol Immunother 50, 125–133 (2001). https://doi.org/10.1007/s002620100181
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DOI: https://doi.org/10.1007/s002620100181