A traditional herbal medicine formula reprograms melanoma immune microenvironment

A traditional Chinese medicine formula comprising Sophorae Flos and Lonicerae Japonicae Flos (SL for short) was used for treating melanoma. We have previously shown that an ethanolic extract of SL (SLE) possesses anti-melanoma effects and suppresses STAT3 signaling in vivo and in vitro. STAT3 has been linked to the development of melanoma immunosuppressive microenvironment. In this work, we investigated whether SLE inhibits melanoma growth by reprogramming the tumor microenvironment in mouse and co-culture cell models. In B16F10 melanoma bearing mice, we found that intragastric administration of SLE inhibited tumor growth and angiogenesis. These observations were associated with the downregulation of protein levels of p-STAT3 (Tyr 705) and STAT3-targeted genes. We also observed decreased immunosuppressive cytokines and increased Th, Tc and dendritic cells in B16F10 melanomas of the SLE-treated mice. In a co-culture system composed of B16F10 cells and mouse splenic lymphocytes, we found that SLE inhibited the proliferation of and STAT3 activation in B16F10 cells, and increased the percentages of Th, Tc and dendritic cells. In the co-culture setting, SLE downregulated mRNA levels of STAT3-targeted genes in the splenic lymphocytes. Over-activation of STAT3 diminished SLE's effects in remodeling immune cell subsets and in lowering immunosuppressive cytokine levels in a co-culture system. These findings indicate that reprograming immune microenvironment, partially mediated by inhibiting STAT3 signaling, contributes to the anti-melanoma mechanisms of SLE. This study provides pharmacological groundwork for developing SLE as a modern agent for melanoma prevention/treatment.