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

Abstract

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.

Low‐dose paclitaxel improves the therapeutic efficacy of recombinant adenovirus encoding CCL21 chemokine against murine cancer

“…Thus, altered cytokine networks in the tumor microenvironment may contribute to the dysregulation of cellular functions in cancer cells. It has been shown that significant change in cytokine profiles can be observed in tumor sites after intratumoral delivery of CCL21 . Our findings that the cytokine production from tumor tissues (GM‐CSF, IFN‐γ, MIG, IP‐10, IL‐12, TGF‐β, IL‐10, and VEGF) was significantly altered by Ad‐mCCL21 or Ad‐mCCL21+Pac therapy are in agreement with previous reports.…”

“…The capacity to co‐localize DCs and lymphocytes makes CCL21 a good therapeutic candidate against cancer. Accordingly, intratumoral treatment with recombinant CCL21 or CCL21‐gene‐modified DCs would lead to immune‐mediated tumor growth inhibition . However, for the multifaceted nature of the tumor microenvironment, the antitumoral response of CCL21 is not sufficiently robust, which suggests that further treatment may require supplemental drugs.…”

Regulator Versus Effector Paradigm: Interleukin-10 as Indicator of the Switching Response

“…Several experimental bioengineering promising therapies may decrease the frequency of Treg and Th2-related IL-10 level, and increase CD8+ and CD4+ T cells at tumor sites or peripheral immune organs [126,132,[136][137][138].…”

“…With respect to modern strategies in the treatment of cancer patients, it is proposed that by activation of tumor-resident, tumor-specific CD8+ T cells, pegylated IL-10 can induce rejection of large and metastasizing tumors in mice [135,136]. Several experimental bioengineering promising therapies may decrease the frequency of Treg and Th2-related IL-10 level, and increase CD8+ and CD4+ T cells at tumor sites or peripheral immune organs [126,132,[136][137][138].…”

Biomarkers for hepatocellular carcinoma: diagnostic and therapeutic utility

“…The combining of intratumoral injection of secondary lymphoid-tissue chemokine (SLC) and depletion of CD25+ regulatory T-cells by anti-CD25 monoclonal antibodies has also emerged as an effective treatment for HCC in animal models. 102 OPN is another candidate biomarker that has been proposed as a promising target for therapy against HCC. Because OPN is an extracellular cytokine ligand, its interaction with receptors is more readily accessible to pharmaceuticals than intracellular targets.…”