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Gene transfer of antisense hypoxia inducible factor-1 α enhances the therapeutic efficacy of cancer immunotherapy

Gene Therapy volume 8, pages 638–645 (2001)Cite this article

Abstract

Solid tumors meet their demands for nascent blood vessels and increased glycolysis, to combat hypoxia, by activating multiple genes involved in angiogenesis and glucose metabolism. Hypoxia inducible factor-1 (HIF-1) is a constitutively expressed basic helix–loop–helix transcription factor, formed by the assembly of HIF-1α and HIF-1β (Arnt), that is stablized in response to hypoxia, and rapidly degraded under normoxic conditions. It activates the transcription of genes important for maintaining oxygen homeostasis. Here, we demonstrate that engineered down-regulation of HIF-1α by intratumoral gene transfer of an antisense HIF-1α plasmid leads to the down-regulation of VEGF, and decreased tumor microvessel density. Antisense HIF-1α monotherapy resulted in the complete and permanent rejection of small (0.1 cm in diameter) EL-4 tumors, which is unusual for an anti-angiogenic agent where transient suppression of tumor growth is the norm. It induced NK cell-dependent rejection of tumors, but failed to stimulate systemic T cell-mediated anti-tumor immunity, and synergized with B7–1-mediated immunotherapy to cause the NK cell and CD8 T cell-dependent rejection of larger EL-4 tumors (0.4 cm in diameter) that were refractory to monotherapies. Mice cured of their tumors by combination therapy resisted a rechallenge with parental tumor cells, indicating systemic antitumor immunity had been achieved. In summary, whilst intensive investigations are in progress to target the many HIF-1 effectors, the results herein indicate that blocking hypoxia-inducible pathways and enhancing NK-mediated antitumor immunity by targeting HIF-1 itself may be advantageous, especially when combined with cancer immunotherapy.

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Acknowledgements

This work was supported in part by grants from the World Health Organization, the Royal Society of New Zealand, the Wellcome Trust (UK), 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. We thank Ms Joanna Stewart (Community Health Department, University of Auckland) for help with statistical analyses.

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Authors and Affiliations

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

    X Sun, J R Kanwar, E Leung, K Lehnert, D Wang & G W Krissansen

  2. Department of Surgery, Affiliated Hospital of Shandong Medical University, Jinan, Shandong Province, P.R. China

    X Sun

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Sun, X., Kanwar, J., Leung, E. et al. Gene transfer of antisense hypoxia inducible factor-1 α enhances the therapeutic efficacy of cancer immunotherapy. Gene Ther 8, 638–645 (2001). https://doi.org/10.1038/sj.gt.3301388

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