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

Abstract

Background: It 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.

Objectives: To investigate the effects of DHA on the proliferation and migration of melanoma in vivo and in vitro, and to explore its possible mechanism.

Methods: B16F10 cells and melanoma-bearing BALB/c mice were used to investigate the effects of DHA on melanoma.

Results: DHA 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.

Conclusion: DHA 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.

Keywords: CD8(+)CTL; Cytokines; Dihydroartemisinin; Melanoma; Treg.