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Requirements for ICAM-1 immunogene therapy of lymphoma

Cancer Gene Therapy volume 10, pages 468–476 (2003)Cite this article

Abstract

Intercellular cell adhesion molecule-1 (ICAM-1) is a cell-surface glycoprotein capable of eliciting bidirectional signals that activate signalling pathways in leukocytes, endothelial, and smooth muscle cells. Gene transfer of xenogeneic ICAM-1 into EL-4 lymphomas causes complete tumor rejection; however, it is unknown whether the mechanism responsible involves the “foreignness” of the ICAM-1 transgene, bidirectional signalling events, ICAM-1-receptor interaction, or a combination of the latter. To begin to address this question, we constructed four different therapeutic expression vectors encoding full-length ICAM-1, and forms in which the N-terminal ligand-binding domains and cytoplasmic tail had been deleted. Mouse EL-4 tumors (0.5 cm in diameter), which actively suppress the immune response, were significantly inhibited in their growth following injection of expression plasmids encoding either full-length xenogenic (human) ICAM-1, or a functional cytoplasmic domain-deficient form that retains ligand-binding activity. Efficacy of ICAM-1-mediated antitumor immunity was significantly augmented by administration of the antivascular drug 5,6-dimethylxanthenone-4-acetic acid (DMXAA), which suppressed blood supply to the tumor, leading to enhanced leukocyte infiltration, and complete tumor eradication in a gene dosage and CD8+ T cell and NK cell-dependent fashion. Generation of potent cytotoxic T cell (CTL)-mediated antitumor immunity was reflected by ICAM-1-facilitated apoptosis of tumor cells in situ. In contrast, nonfunctional ICAM-1 lacking the N-terminal ligand-binding Ig domain failed to generate antitumor immunity, even in the presence of DMXAA. These studies demonstrate that ICAM-1-stimulated antitumor immunity can overcome tumor-mediated immunosuppression, particularly when employed in combination with an attack on the tumor vasculature. The ligand-binding domain of ICAM-1 is essential for generating antitumor immunity, whereas the cytoplasmic domain and bidirectional activation of tumor signalling pathways are not essential.

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Acknowledgements

We are grateful to Professors Bill Denny and Bruce Baguley (Auckland Cancer Society Research Centre) for supplying the DMXAA. This work was supported by grants from the Royal Society of New Zealand, the Cancer Society of New Zealand, the Health Research Council of New Zealand, the Wellcome Trust, the Lottery Grants Board of New Zealand, and the Maurice and Phyllis Paykel Trust. GWK was supported by a James Cook Research Fellowship funded by the Royal Society of New Zealand.

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Authors and Affiliations

  1. Department of Molecular Medicine & Pathology, Faculty of Medicine and Health Science, University of Auckland, Auckland, New Zealand

    Jagat R Kanwar, Randy W Berg, Yi Yang, Rupinder K Kanwar, Xueying Sun & Geoffrey W Krissansen

  2. Auckland Cancer Society Research Centre, Faculty of Medicine and Health Science, University of Auckland, Auckland, New Zealand

    Lai Ming Ching

  3. Department of Surgery, Qilu Hospital of Shandong University, Jinan, People's Republic of China

    Xueying Sun

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  1. Jagat R Kanwar
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Correspondence to Geoffrey W Krissansen.

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Kanwar, J., Berg, R., Yang, Y. et al. Requirements for ICAM-1 immunogene therapy of lymphoma. Cancer Gene Ther 10, 468–476 (2003). https://doi.org/10.1038/sj.cgt.7700590

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