Dihydroartemisinin inhibits melanoma by regulating CTL/Treg anti-tumor immunity and STAT3-mediated apoptosis via IL-10 dependent manner

Abstract

BackgroundIt has been shown that dihydroartemisinin (DHA) is effective in the treatment of malaria. Recently studies have demonstrated that DHA also regulates tumor cell growth, angiogenesis, T cell differentiation and generation. However, how DHA affects melanoma development remains poorly defined. ObjectivesTo investigate the effects of DHA on the proliferation and migration of melanoma in vivo and in vitro, and to explore its possible mechanism. MethodsB16F10 cells and melanoma-bearing BALB/c mice were used to investigate the effects of DHA on melanoma. ResultsDHA had inhibitory effect on melanoma proliferation in a time-and dose-dependent manner. Treatment of DHA attenuated melanoma severity and histopathological changes in BALB/c mice. DHA also inhibited melanoma invasion, migration, and community formation in a dose-dependent manner. Flow cytometry revealed a significant increase in IFN-γ+CD8+ T cells in the DHA groups. In tumor microenvironment and spleen, DHA induced expansion of CD8+CTL, while, CD4+CD25+Foxp3+ regulatory T (Treg) cells and IL-10+CD4+CD25+ T cells were normalized by DHA treatment. DHA diminished expression of IL-10 and IL-6, and increased the expression of IFN-γ in the tumor and spleen. Moreover, DHA administration significantly promoted the mitochondrial apoptosis of melanoma by regulating the STAT3 pathway. ConclusionDHA induces mitochondrial apoptosis and alters cytokines expression by inhibiting the phosphorylation of STAT3. DHA improves anti-tumor immunity in mice through controlling CD8+CTL function by counteracting IL-10-dependent Treg cells suppression, which promises to be an alternative drug for melanoma.