Antitumor mechanism of intratumoral injection with IL-12-expressing adenoviral vector against IL-12-unresponsive tumor.
Interleukin-12 (IL-12) has potent antitumor activities through the activation of natural killer cells and cytotoxic T lymphocytes. Some tumors, however, are resistant to IL-12; for example, in murine Meth-A fibrosarcoma, an IL-12-unresponsive tumor model, tumors do not regress following IL-12 administration due to the fact that few T cells migrate to tumor sites. Transduction of IL-12 genes into preexisting Meth-A tumors using RGD fiber-mutant adenoviral vectors (AdRGD), however, enhances tumor infiltration by T cells, thereby inducing tumor regression due to enhanced tumor infiltration by T cells. Here, we demonstrated the mechanism underlying the anti-tumor effect induced by intratumoral injection of AdRGD encoding IL-12 (AdRGD-IL12). The anti-tumor activity of the IL-12 treatment was T cell-dependent, requiring mainly CD8(+) cytotoxic T lymphocytes in the effector phase, as confirmed by analysis using BALB/c nude mice and an in vivo depletion assay. Additionally, intratumoral injection of AdRGD-IL12 promoted cellular immunity, as determined by the frequency of interferon-gamma-positive cells in regional lymph nodes, and changed the tumor microenvironment to an immunologic activation state with enhanced expression of lymphocyte activation markers and cell adhesion molecules. The present data provide evidence that the antitumor effect of IL-12 gene transduction in a local tumor site is dependent on induced alterations of the tumor microenvironment and systemic immunity.
Department of Biotechnology and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
Naoko
N
Kanagawa
Jian-Qing
JQ
Gao
Yoshiaki
Y
Motomura
Tatsuya
T
Yanagawa
Yohei
Y
Mukai
Yasuo
Y
Yoshioka
Naoki
N
Okada
Shinsaku
S
Nakagawa
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D007267:Injections; D018664:Interleukin-12 / Q000235:genetics*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014161:Transduction, Genetic / Q000379:methods
D018664:Interleukin-12