Combination of SLC administration and Tregs depletion is an attractive strategy for targeting hepatocellular carcinoma

Molecular Cancer

Research

Shenglong Ye¹  Binbin Liu¹  Long Chen²  Jie Qin²  Huiying Ma²  Cuiping Zhong²  Xuan Wang²  Guomin Zhou²  Heng Hu²  Shuang Zhou²  Jiaqi Ma²  Chunmin Liang³ 

[1] Key laboratory of Carcinogenesis and Cancer Invasion, Liver Cancer Institute, Zhongshan Hospital, Shanghai Medical College, Ministry of Education, Fudan University, Shanghai, P R China;Principle Investigator of the Lab of Tumor Immunology, the Department of Anatomy and Histology & Embryology, Shanghai Medical College, Fudan University, 138 Yixueyuan Road, 200032, Shanghai, P R China;Principle Investigator of the Lab of Tumor Immunology, the Department of Anatomy and Histology & Embryology, Shanghai Medical College, Fudan University, 138 Yixueyuan Road, 200032, Shanghai, P R China;Key laboratory of Carcinogenesis and Cancer Invasion, Liver Cancer Institute, Zhongshan Hospital, Shanghai Medical College, Ministry of Education, Fudan University, Shanghai, P R China;

关键词: SLC;    DCs;    Tregs;    HCC;    Anti-tumor immunity;   

DOI  :  10.1186/1476-4598-12-153

 received in 2013-07-23, accepted in 2013-11-27,  发布年份 2013

来源: Springer

【 摘 要 】

BackgroundSecondary lymphoid tissue chemokine (SLC) is a key CC chemokine for chemotaxis of immune cells and has been an attractive candidate for anti-tumor treatments. However, among the immune cells recruited by SLC to tumors, the CD25+ Foxp3+ regulatory T cells (Tregs) compromise the anti-tumor effects. In this study, we proposed the combination therapy of intratumoral co-administration of SLC and anti-CD25 monoclonal antibodies (mAbs). We hypothesized that the intratumoral injections of SLC and depletion of Tregs would have stronger inhibition effects on the progression of hepatocellular carcinoma (HCC) in mice.MethodsC57BL/6 mice were inoculated subcutaneously with the murine HCC cell line, and mice with visible tumors were treated intratumorally with SLC, SLC plus anti-CD25 mAbs or the control antibodies. The percentages of Tregs, effector CD8+ T cells and CD4+ T cells were checked in the tumors, lymph nodes, spleen and liver at regular intervals. The levels of intratumoral IL-12, IFN-γ, IL-10 and TGF-β1 were evaluated. The final anti-tumor effects were measured by the tumor volume and weight as well as the intratumoral activity of MMP2 and MMP9. Bone-marrow-derived dendritic cells were used to explore the mechanisms of maturation induced by SLC in vitro.ResultsOur experiments showed the combination therapy significantly decreased the frequency of Tregs, and increased CD8+ T cells and CD4+ T cells at tumor sites. These alterations were accompanied by an increased level of IL-12 and IFN-γ, and decreased level of IL-10 and TGF-β1. Unexpectedly, we observed a significantly decreased percentage of Tregs, and increased CD8+ T cells and CD4+ T cells in the lymph nodes, spleen and liver after the combination therapy. The growth and invasiveness of HCC was also maximally inhibited in the combination therapy compared with the SLC alone. Furthermore, we confirmed SLC induced the maturation of DCs via NF-κB p65 and this maturation would benefit the combination therapy.ConclusionsOur data demonstrated that intratumoral co-administration of SLC and anti-CD25 mAbs was an effective treatment for HCC, which was correlated with the altered tumor microenvironment and systemically optimized percentages of Tregs, CD8+ T cells and CD4+ T cells in peripheral immune organs.

【 授权许可】

Unknown   
© Chen et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.