The Journal of investigative dermatology | 2021
EZH2 inhibitor enhances the STING agonist-induced antitumor immunity in melanoma.
Abstract
STING agonists are a new class of drugs for cancer immunotherapy that activate both innate and adaptive antitumor immunity. Recently, multiple clinical trials of STING agonists have been conducted in hematological malignancies and solid tumors. However, STING is commonly suppressed in melanoma via mechanisms that remain unclear. We found that STING expression was epigenetically suppressed by H3K27me3 in melanoma, and EZH2 inhibitor could induce an H3K27 shift from trimethylation to acetylation, resulting in increased expression of STING. Furthermore, a combination of STING agonist and EZH2 inhibitor upregulated major histocompatibility complex (MHC) class I expression and chemokines production. Whole-transcriptome analysis showed that type I interferon-related genes were significantly upregulated in the combination treatment group. In addition, the combination treatment synergistically reduced tumor growth and increased CD8+ T cell infiltration in a poorly immunogenic melanoma mouse model B16-F10. These results demonstrated a novel mechanism underlying the epigenetic regulation of STING expression in melanoma; combination of STING agonists and EZH2 inhibitors can boost the antitumor immune response and would be a promising treatment option for melanoma patients refractory to current immunotherapies.