Comparative analysis of antitumor activity of CD40L, RANKL, and 4-1BBL in vivo following intratumoral administration of viral vectors or transduced dendritic cells.
The tumor necrosis factor (TNF) family comprises a group of ligands that regulate cell proliferation, differentiation, activation, maturation and apoptosis through interaction with the corresponding TNF receptor family members. In this study, we have evaluated whether adenovirus-mediated intratumoral gene transfer of CD40L, RANKL, or 4-1BBL elicits an immune response to established murine MC38 and TS/A tumors. Intratumoral administration of the recombinant adenoviral vectors expressing CD40L, RANKL or 4-1BBL 7 days post-tumor cell inoculation resulted in significant inhibition of MC38 tumor growth for all three ligands when compared with control groups treated with either saline or control adenovirus. However, intratumoral injection of Ad-4-1BBL or Ad-CD40L resulted in a significantly stronger inhibition of TS/A tumor progression than did Ad-RANKL treatment. We also demonstrated that intratumoral administration of dendritic cells (DC) transduced with adenoviral vectors encoding the TNF-related ligands resulted in a significant inhibition of MC38 tumor growth as compared with control groups treated with Ad-LacZ-transduced DC or saline-treated DC. In addition, DC overexpressing CD40L secreted considerably more IL-12 and expressed higher levels of the co-stimulatory molecules, CD80, CD86 and CD40, than did DC overexpressing LacZ, 4-1BBL or RANKL. We have also demonstrated that DC/CD40L, DC/4-1BBL, and DC/RANKL survived significantly longer than control DC or DC infected with the LacZ vector. Taken together, these results demonstrate that adenoviral gene transfer of CD40L, RANKL or 4-1BBL elicit a significant antitumor effect in two different tumor models, with CD40L gene transfer inducing the strongest antitumor effect.
Yurkovetsky
Zoya R
ZR
Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Shurin
Galina V
GV
Barry
Denise A
DA
Schuh
Andre C
AC
Shurin
Michael R
MR
Robbins
Paul D
PD
D053330:4-1BB Ligand; D000818:Animals; D023201:CD40 Ligand / Q000235:genetics / Q000627:therapeutic use*; D002352:Carrier Proteins / Q000235:genetics / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D003713:Dendritic Cells / Q000502:physiology / Q000637:transplantation; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D008562:Membrane Glycoproteins / Q000235:genetics / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000188:drug therapy*; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D014161:Transduction, Genetic; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000627:therapeutic use*
D053330:4-1BB Ligand; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; C505975:Tnfsf9 protein, mouse; D048069:Tumor Necrosis Factors; D023201:CD40 Ligand