CD4+ T helper cell-independent antitumor response mediated by murine IFN-beta gene delivery in immunocompetent mice.
Previously, we provided evidence that adenovirus-mediated interferon-beta (IFN-beta) gene therapy inhibits tumor formation and causes dramatic regression of established tumors in immunodeficient mice. We suggested that local IFN-beta gene therapy with adenoviral vectors could be an effective treatment for cancer. In this report, the actions of murine IFN-beta (MuIFN-beta) gene delivery on both subcutaneous and metastatic tumors were evaluated in syngeneic immunocompetent mice. We found that the antitumor response mediated by MuIFN-beta gene delivery relied on CD8(+) T cells but was completely independent of CD4(+) T cells. In fact, depletion of CD4(+) T cells appeared to enhance the effect on tumor inhibition and animal survival induced by adenovirus-MuIFN-beta gene delivery. Therefore, adenovirus-MuIFN-beta gene therapy can bypass CD4(+) T helper (Th) cells and activate an effective CD8(+) T cell-dependent antitumor immunity in immunocompetent mice. Furthermore, we found that depletion of macrophages but not natural killer (NK) cells suppressed the antitumor response induced by MuIFN-beta gene therapy. These data, together with our previous results, suggest that in the clinical setting, local adenovirus-mediated IFN-beta gene therapy may lead to an efficient and long-lasting eradication of tumors by a direct antitumor effect and via activation of the innate and the adoptive immune systems.
Brown
Jennifer L
JL
Biogen, Inc., Cambridge, MA 02142, USA.
Barsoum
James
J
Qin
Xiao-Qiang
XQ
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015496:CD4-Positive T-Lymphocytes; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D016899:Interferon-beta / Q000008:administration & dosage / Q000235:genetics* / Q000627:therapeutic use*; D008212:Lymphocyte Depletion; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D009374:Neoplasms, Experimental / Q000235:genetics / Q000628:therapy*; D016019:Survival Analysis
D016899:Interferon-beta