Cancer Immunology, Immunotherapy

, Volume 60, Issue 4, pp 559–573

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

  • Jianbin Zhang
  • Zhidong Zhou
  • Cheng Wang
  • Jiangen Shen
  • Yun Zheng
  • Lihuang Zhang
  • Jianli Wang
  • Dajing Xia
Original article

DOI: 10.1007/s00262-010-0955-5

Cite this article as:
Zhang, J., Zhou, Z., Wang, C. et al. Cancer Immunol Immunother (2011) 60: 559. doi:10.1007/s00262-010-0955-5

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.

Keywords

Interleukin-10 Lymphotactin Natural killer cells Cytotoxic T lymphocytes Cytokine gene therapy Antitumor immunity Regulatory T cells Myeloid-derived suppressor cells 

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Jianbin Zhang
    • 1
  • Zhidong Zhou
    • 1
    • 2
  • Cheng Wang
    • 1
  • Jiangen Shen
    • 1
  • Yun Zheng
    • 1
  • Lihuang Zhang
    • 1
  • Jianli Wang
    • 1
  • Dajing Xia
    • 1
  1. 1.Institute of ImmunologyZhejiang UniversityHangzhouChina
  2. 2.Department of ImmunologyTaizhou CollegeTaizhouChina

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