Reduced tumorigenesis of EG7 after interleukin-10 gene transfer and enhanced efficacy in combination with intratumorally injection of adenovirus-mediated lymphotactin and the underlying mechanism |
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Authors: | Jianbin Zhang Zhidong Zhou Cheng Wang Jiangen Shen Yun Zheng Lihuang Zhang Jianli Wang Dajing Xia |
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Institution: | (1) Institute of Immunology, Zhejiang University, 388 Yuhangtang Road, 310058 Hangzhou, China;(2) Department of Immunology, Taizhou College, 318000 Taizhou, China; |
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Abstract: | Although interleukin-10 (IL-10) is commonly regarded as an immunosuppressive cytokine, a wealth of evidence is accumulating
that IL-10 also possesses some immunostimulating antitumor properties. Previous studies demonstrated that forced expression
of the IL-10 gene in tumor cells could unexpectedly produce antitumor effects. In this study, we explored the tumorigenesis
of EG7 cells transduced with IL-10 gene. In vivo, IL-10 gene transfer reduced tumorigenic capacity of EG7 cells and prolonged
survival of the EG7 tumor-bearing mice. It was found that the cytotoxicities of cytotoxic T lymphocytes (CTL) and natural
killer cells (NK cells) were enhanced. Assessment of the immune status of the animals showed prevalence of a systemic and
tumor-specific Th2 response (high levels of IL-4 and IL-10). To improve the therapeutic efficacy, we combined with intratumoral
injection of adenovirus-mediated lymphotactin (Ad-Lptn) into the overestablished EG7 tumor model. More significant inhibition
of tumor growth were observed in EG7 tumor-bearing mice that received combined treatment with IL-10 and Lptn gene than those
of mice treated with IL-10 or Lptn gene alone. The highest NK cells and CTL activity was induced in the combined therapy group,
increasing the production of IL-2 and interferon-γ (IFN-γ) significantly but decreasing the expression of immune suppressive
cells (CD4+Foxp3+ Treg cells and Gr1+CD11b+ MDSCs). The necrosis of tumor cells was markedly observed in the tumor tissues, accompanying with strongest expression of
Mig (monokine induced by interferon-gamma) and IP-10 (interferon-inducible protein 10), weakest expression of vascular endothelial
growth factor (VEGF) and matrix metalloproteinases-2 (MMP-2). In vivo, depletion analysis demonstrated that CD8+ T cells and NK cells were the predominant effector cell subset responsible for the antitumor effect of IL-10 or Lptn gene.
These findings may provide a potential strategy to improve the antitumor efficacy of IL-10 and Lptn. |
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