Intratumoral delivery of IL-18 naked DNA induces T-cell activation and Th1 response in a mouse hepatic cancer model.
BACKGROUND
The novel cytokine, interleukin (IL)-18, is a strong interferon-gamma inducer and costimulatory factor in Th1 cell activation. IL-18 triggers IFN-gamma production and enhances cytolytic activity in both T and NK cells. However, the exact mechanism of antitumor action of IL-18 remains to be clarified. To determine the effects of IL-18 plasmid DNA on hepatic cancer in mice, CT26 murine colon adenocarcinoma cells were established in mouse liver.


METHODS
Plasmid vectors encoding IL-18 were transferred directly into the liver 7 days after tumor injection to restrict IL-18 expression within the tumor site. The IL-18 protein level was increased in the liver 4 days after plasmid injection, and a marked antitumoral effect was observed at day 7. Antitumor effects were evaluated by measuring tumor regression, immune cell population, and IFN-gamma production.


RESULTS
The IL-18 plasmid controlled the growth of hepatic tumors and proliferation of splenic immune cells. Moreover, treatment of CT26 tumors with the IL-18 plasmid significantly enhanced the population of the effector T and NK cells in the spleen and peripheral blood. In spleen, the population of CD4+CD62Low cells was augmented in response to IL-18 on day 7. These results are consistent with the increase in CD4+ T cells secreting IFN-gamma, but not CD8+ T cells. The marked reduction of tumor growth in tumor-bearing mice was associated with the maintenance of IFN-gamma production in spleen in response to IL-18. These antitumoral effects were maintained until 14 days after plasmid injection.


CONCLUSIONS
Our results suggest that direct plasmid DNA transfer of IL-18 with no accompanying reagents to augment transfection efficiency may be useful in tumor immunotherapy.
Chang
Chi-Young
CY
Transplantation Research Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-Dong, Kangnam-Ku, Seoul, Republic of Korea. latefruit@naver.com <latefruit@naver.com>
Lee
Jienny
J
Kim
Eun-Young
EY
Park
Hae-Jung
HJ
Kwon
Choon-Hyuck
CH
Joh
Jae-Won
JW
Kim
Sung-Joo
SJ
D000230:Adenocarcinoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D000818:Animals; D004247:DNA / Q000008:administration & dosage*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D015552:Injections, Intralesional; D020382:Interleukin-18 / Q000235:genetics* / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D010957:Plasmids; D012680:Sensitivity and Specificity; D013601:T-Lymphocytes / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D016896:Treatment Outcome
D020382:Interleukin-18; D004247:DNA