Requirements for ICAM-1 immunogene therapy of lymphoma.
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.
Kanwar
Jagat R
JR
Department of Molecular Medicine & Pathology, Faculty of Medicine and Health Science, University of Auckland, Auckland, New Zealand.
Berg
Randy W
RW
Yang
Yi
Y
Kanwar
Rupinder K
RK
Ching
Lai Ming
LM
Sun
Xueying
X
Krissansen
Geoffrey W
GW
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D019556:COS Cells; D002448:Cell Adhesion; D003593:Cytoplasm / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D005434:Flow Cytometry; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics*; D007694:Killer Cells, Natural / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D008223:Lymphoma / Q000628:therapy*; D051379:Mice; D009154:Mutation; D009369:Neoplasms / Q000098:blood supply; D010957:Plasmids / Q000378:metabolism; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D019076:Transgenes; D044004:Xanthones / Q000737:chemistry
D018076:DNA, Complementary; D044004:Xanthones; C066668:vadimezan; D018799:Intercellular Adhesion Molecule-1