Requirements for ICAM-1 immunogene therapy of lymphoma.

Kanwar, Jagat R., Berg, Randy W., Yang, Yi, Kanwar, Rupinder K., Ching, Lai Ming, Sun, Xueying and Krissansen, Geoffrey W. 2003, Requirements for ICAM-1 immunogene therapy of lymphoma., Cancer gene therapy, vol. 10, no. 6, pp. 468-476.


Title Requirements for ICAM-1 immunogene therapy of lymphoma.
Formatted title

Author(s) Kanwar, Jagat R.
Berg, Randy W.
Yang, Yi
Kanwar, Rupinder K.
Ching, Lai Ming
Sun, Xueying
Krissansen, Geoffrey W.
Journal name Cancer gene therapy
Volume number 10
Issue number 6
Start page 468
End page 476
Publisher Nature Publishing Group
Place of publication London, England
Publication date 2003-06
ISSN 0929-1903
1476-5500
Summary 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.
Language eng
Field of Research 111204 Cancer Therapy (excl Chemotherapy and Radiation Therapy)
111203 Cancer Genetics
HERDC Research category C1.1 Refereed article in a scholarly journal
Copyright notice ©2003, Nature Publishing Group
Persistent URL http://hdl.handle.net/10536/DRO/DU:30026565

Document type: Journal Article
Collection: Institute for Technology Research and Innovation
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Created: Thu, 01 Apr 2010, 10:49:34 EST by Rupinder Kanwar

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