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Angiostatin enhances B7.1-mediated cancer immunotherapy independently of effects on vascular endothelial growth factor expression

Cancer Gene Therapy volume 8, pages 719–727 (2001)Cite this article

Abstract

Tumors must develop an adequate vascular network to meet their increasing demands for nutrition and oxygen. Angiostatin, a multiple kringle (1–4)–containing fragment of plasminogen, is an effective natural inhibitor of tumor angiogenesis. Here we show that gene transfer of angiostatin into small (0.1 cm in diameter) solid EL-4 lymphomas established in syngeneic C57BL/6 mice led to reduced tumor angiogenesis and weak inhibition of tumor growth. In contrast, when angiostatin gene therapy was preceded by in situ gene transfer of the T-cell costimulator B7.1, large (0.4 cm in diameter) tumors were rapidly and completely eradicated, whereas B7.1 and angiostatin monotherapies were ineffective. Combined gene transfer of B7.1 and angiostatin generated potent systemic antitumor immunity that was effective in eradicating a systemic challenge of 107 EL-4 cells. Gene transfer of angiostatin expression plasmids led to overexpression of angiostatin in tumors, increased apoptosis of tumor cells, and decreased density of tumor blood vessels, which may allow the immune system to overcome tumor immune resistance. The latter effects were not the result of a decrease in vascular endothelial growth factor expression, as tumoral vascular endothelial growth factor expression increased slightly after angiostatin gene transfer, presumably in response to increasing hypoxia. These results suggest that combining immunogene therapy with a vascular attack by angiostatin is a particularly effective approach for eliciting antitumor immunity. Cancer Gene Therapy (2001) 8, 719–727

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Acknowledgements

This work was supported, in part, by grants from the World Health Organization, the Wellcome Trust, the Royal Society of New Zealand, the Cancer Society of New Zealand, the Health Research Council of New Zealand, the Lottery Grants Board of New Zealand, and the Maurice and Phyllis Paykel Trust.

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Authors and Affiliations

  1. Division of Molecular Medicine, School of Medicine and Health Science, University of Auckland, Auckland, New Zealand

    Xueying Sun, Jagat R Kanwar, Euphemia Leung, Klaus Lehnert, Dongmao Wang & Geoffrey W Krissansen

  2. Department of Surgery, Qilu Hospital, Shandong University, Jinan, Shandong Province, China

    Xueying Sun

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  1. Xueying Sun
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  2. Jagat R Kanwar
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Correspondence to Geoffrey W Krissansen.

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Sun, X., Kanwar, J., Leung, E. et al. Angiostatin enhances B7.1-mediated cancer immunotherapy independently of effects on vascular endothelial growth factor expression. Cancer Gene Ther 8, 719–727 (2001). https://doi.org/10.1038/sj.cgt.7700370

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