Local AdCD40L gene therapy is effective for disseminated murine experimental cancer by breaking T-cell tolerance and inducing tumor cell growth inhibition.
CD40 ligand (CD40L) is one of the most potent stimulators of Th1-type immunity through its maturation of dendritic cells that, in turn, stimulate effector cells such as T cells and NK cells. Lately, CD40-mediated cell growth inhibition and apoptosis have been in focus for the development of novel cancer treatment regiments, including recombinant soluble CD40L or CD40-stimulating antibodies. In this study, intravesical CD40L gene transfer through adenoviral vectors (AdCD40L) was used to treat an aggressive model of disseminated bladder cancer (MB49/C57BL/6). Three weekly AdCD40L vector instillations increased overall survival of tumor-bearing mice (mean 18.5 d, control mice 13 d). Furthermore, bladder tumors were eradicated (2 of 10) simultaneously as lung metastases (6 of 10) were cleared. FoxP3 levels were similar in the tumors of AdCD40L-treated mice and control mice but the tumor-infiltrating effector T cells in AdCD40L-treated mice were cytotoxic (CD107a+) in contrast to those in control-treated tumors. Furthermore, AdCD40L gene therapy could induce cell growth inhibition and cell death in the MB49 tumor cells in vitro and in vivo. However, this effect was not potent enough to cure growing tumors in immunodeficient mice. In conclusion, AdCD40L gene therapy is potent for disseminated cancer both by activation of T cells and controlling tumor cell growth and viability.
Lindqvist
Camilla
C
Clinical Immunology Division, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden.
Sandin
Linda C
LC
Fransson
Moa
M
Loskog
Angelica
A
D000256:Adenoviridae; D000818:Animals; D017209:Apoptosis; D023201:CD40 Ligand / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D048708:Cell Growth Processes; D003602:Cytotoxicity, Immunologic; D015316:Genetic Therapy; D005822:Genetic Vectors; D008175:Lung Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000556:secondary / Q000628:therapy; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D052118:Lysosomal-Associated Membrane Protein 1 / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D047368:Tumor Burden; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000473:pathology / Q000628:therapy
D052118:Lysosomal-Associated Membrane Protein 1; D023201:CD40 Ligand