Alpha(v)beta(3) integrin-mediated adenoviral transfer of interleukin-12 at the periphery of hepatic colon cancer metastases induces VCAM-1 expression and T-cell recruitment.
We previously reported that systemic injection of recombinant adenovirus resulted in a rim of gene transduction around experimental liver tumor nodules. This zone of higher infection is dependent on the alpha(v)beta(3) integrin, acting as an adenovirus internalization receptor, which is overexpressed in tissues surrounding liver metastases. When a recombinant adenovirus encoding interleukin-12 (AdCMVIL-12) is given into a subcutaneous tumor nodule in mice also bearing concomitant liver tumors, a fraction of AdCMVIL-12 reaches the systemic circulation and infects liver tissue, especially at the malignant/healthy tissue interface. As a result of the expression at this location of the interleukin-12 transgenes, VCAM-1 is induced on vessel cells and mediates the recruitment of adoptively transferred anti-tumor cytolytic T-lymphocytes. These studies provide mechanistic explanations for the potent therapeutic synergy observed between interleukin-12 gene transfer and adoptive T-cell therapy.
Mazzolini
G
G
Gene Therapy Unit, University of Navarra School of Medicine, C/Irunlarrea, I 31008 Pamplona, Spain.
Narvaiza
I
I
Bustos
M
M
Duarte
M
M
Tirapu
I
I
Bilbao
R
R
Qian
C
C
Prieto
J
J
Melero
I
I
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D002448:Cell Adhesion; D002465:Cell Movement; D002469:Cell Separation; D003110:Colonic Neoplasms / Q000473:pathology* / Q000628:therapy*; D004727:Endothelium / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D005697:Galactosides / Q000378:metabolism; D007150:Immunohistochemistry; D007211:Indoles / Q000378:metabolism; D018664:Interleukin-12 / Q000235:genetics*; D008113:Liver Neoplasms / Q000556:secondary* / Q000628:therapy*; D008214:Lymphocytes / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D009362:Neoplasm Metastasis; D019030:Receptors, Vitronectin / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism; D019076:Transgenes; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis*
D000911:Antibodies, Monoclonal; D005697:Galactosides; D007211:Indoles; D019030:Receptors, Vitronectin; D019010:Vascular Cell Adhesion Molecule-1; D018664:Interleukin-12; C044888:5-bromo-4-chloro-3-indolyl beta-galactoside