Local Expression of Secondary Lymphoid Tissue Chemokine Delivered by Adeno-Associated Virus within the Tumor Bed Stimulates Strong Anti-Liver Tumor Immunity

Liang, Chao; Zhong, Cuiping; Sun, Ruixia; Liu, Binbin; Huang, Cheng; Qin, Jie; Zhou, Shuang; Shan, Junling; Liu, Yinkun; Ye, Sheng‐Long

doi:10.1128/jvi.00208-07

Cited by 37 publications

(36 citation statements)

References 55 publications

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“…These observations were consistent with previous studies from our lab and others which demonstrated the anti-tumor effects of SLC [3,7]. Importantly, although we did not found stronger anti-tumor effects of anti-CD25 treatment alone than that of SLC treatment alone in our preliminary experiments (data not shown), in the present study we found anti-CD25 mAbs treatment greatly boosted the anti-tumor effects of SLC, proving the efficacy of the combination therapy.…”

Section: Discussionsupporting

confidence: 94%

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

et al. 2013

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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.

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Section: Discussionsupporting

confidence: 94%

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

et al. 2013

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“…We have evaluated the antitumor responses in mice cancer models after administration of DCs genetically modified to express CCL21 [8,9]. More recent studies revealed a potential major role of Tregs in controlling the immune responses against tumors.…”

Section: Discussionmentioning

confidence: 99%

Depletion of CD4+ CD25+ Regulatory T Cells Promotes CCL21-Mediated Antitumor Immunity

et al. 2013

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CCL21 is known to attract dendritic cells (DCs) and T cells that may reverse tumor-mediated immune suppression. The massive infiltration of tumors by regulatory T cells (Tregs) prevents the development of a successful helper immune response. In this study, we investigated whether elimination of CD4+ CD25+ Tregs in the tumor microenvironment using anti-CD25 monoclonal antibodies (mAbs) was capable of enhancing CCL21-mediated antitumor immunity in a mouse hepatocellular carcinoma (HCC) model. We found that CCL21 in combination with anti-CD25 mAbs (PC61) resulted in improved antitumor efficacy and prolonged survival, not only inhibited tumor angiogenesis and cell proliferation, but also led to significant increases in the frequency of CD4+, CD8+ T cells and CD11c+ DCs within the tumor, coincident with marked induction of tumor-specific CD8+ cytotoxic T lymphocytes (CTLs) at the local tumor site. The intratumoral immune responses were accompanied by the enhanced elaboration of IL-12 and IFN-γ, but reduced release of the immunosuppressive mediators IL-10 and TGF-β1. The results indicated that depletion of Tregs in the tumor microenvironment could enhance CCL21-mediated antitumor immunity, and CCL21 combined with anti-CD25 mAbs may be a more effective immunotherapy to promote tumor rejection.

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“…Gene-modified DC coculture with T-lymphocyte will elicit specific immune responses. SLC and IL-2 have strong antitumor effects, respectively, and the SLC antitumor study was mainly for liver, prostate, and gastric cancers (22,23), while the IL-2 study was for lung, renal, prostate, and bladder cancers (24,25). Further, coculture of DC, TC, and bladder tumor cells will enhance their talk, as results revealed that TC-DC has strong toxicity to bladder tumor cells and induced bladder tumor cell apoptosis.…”

Section: Discussionmentioning

confidence: 90%

Dendritic Cell Transfected with Secondary Lymphoid-Tissue Chemokine and/or Interleukin-2 Gene-Enhanced Cytotoxicity of T-Lymphocyte in Human Bladder Tumor Cell SIn Vitro

Wang

Tian

et al. 2009

Cancer Investigation

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Local Expression of Secondary Lymphoid Tissue Chemokine Delivered by Adeno-Associated Virus within the Tumor Bed Stimulates Strong Anti-Liver Tumor Immunity

Cited by 37 publications

References 55 publications

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

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

Depletion of CD4+ CD25+ Regulatory T Cells Promotes CCL21-Mediated Antitumor Immunity

Dendritic Cell Transfected with Secondary Lymphoid-Tissue Chemokine and/or Interleukin-2 Gene-Enhanced Cytotoxicity of T-Lymphocyte in Human Bladder Tumor Cell SIn Vitro

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