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.

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.

• Authors: Jianbin Zhang, Zhidong Zhou, Cheng Wang, Jiangen Shen, Yun Zheng, Lihuang Zhang, Jianli Wang, Dajing Xia
• Journal: Cancer immunology, immunotherapy : CII (Cancer Immunol Immunother) Vol. 60 Issue 4 Pg. 559-73 (Apr 2011) ISSN: 1432-0851 [Electronic] Germany
• PMID: 21240488 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chemokine CXCL10
• Chemokine CXCL9
• Lymphokines
• RNA, Messenger
• Sialoglycoproteins
• Vascular Endothelial Growth Factor A
• lymphotactin
• Interleukin-10
• Matrix Metalloproteinase 2

Topics

• Adenoviridae (genetics)
• Animals
• Cell Line, Tumor
• Cell Separation
• Chemokine CXCL10 (biosynthesis, immunology)
• Chemokine CXCL9 (biosynthesis, immunology)
• Female
• Flow Cytometry
• Gene Transfer Techniques
• Genetic Therapy
• Genetic Vectors
• Immunohistochemistry
• Immunotherapy (methods)
• Interleukin-10 (administration & dosage, genetics, immunology)
• Killer Cells, Natural (immunology)
• Lymphokines (administration & dosage, genetics, immunology)
• Matrix Metalloproteinase 2 (biosynthesis, immunology)
• Mice
• Mice, Inbred C57BL
• Neoplasms, Experimental (genetics, immunology, pathology)
• Pregnancy
• RNA, Messenger (analysis)
• Reverse Transcriptase Polymerase Chain Reaction
• Sialoglycoproteins (administration & dosage, genetics, immunology)
• T-Lymphocytes, Cytotoxic (immunology)
• Transduction, Genetic
• Vascular Endothelial Growth Factor A (biosynthesis, immunology)