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.
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.
Institute of Immunology, Zhejiang University, 388 Yuhangtang Road, 310058, Hangzhou, China.
Jianbin
J
Zhang
Zhidong
Z
Zhou
Cheng
C
Wang
Jiangen
J
Shen
Yun
Y
Zheng
Lihuang
L
Zhang
Jianli
J
Wang
Dajing
D
Xia
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D045744:Cell Line, Tumor; D002469:Cell Separation; D054357:Chemokine CXCL10 / Q000096:biosynthesis / Q000276:immunology; D054370:Chemokine CXCL9 / Q000096:biosynthesis / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods; D016753:Interleukin-10 / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology; D008222:Lymphokines / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D011247:Pregnancy; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012795:Sialoglycoproteins / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014161:Transduction, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000276:immunology
D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D008222:Lymphokines; D012333:RNA, Messenger; D012795:Sialoglycoproteins; D042461:Vascular Endothelial Growth Factor A; C018997:lymphotactin; D016753:Interleukin-10; D020778:Matrix Metalloproteinase 2
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