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EZH2 Inhibitor Enhances the STING Agonist‒Induced Antitumor Immunity in Melanoma

  • Author Footnotes
    3 These authors contributed equally to this work.
    Tianxiao Xu
    Footnotes
    3 These authors contributed equally to this work.
    Affiliations
    Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing, China
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  • Author Footnotes
    3 These authors contributed equally to this work.
    Jie Dai
    Footnotes
    3 These authors contributed equally to this work.
    Affiliations
    Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing, China
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  • Lirui Tang
    Affiliations
    Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing, China
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  • Lu Yang
    Affiliations
    Department of Radiology, Peking University Shougang Hospital, Beijing, China
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  • Lu Si
    Affiliations
    Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing, China
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  • Xinan Sheng
    Affiliations
    Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing, China
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  • Chuanliang Cui
    Affiliations
    Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing, China
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  • Zhihong Chi
    Affiliations
    Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing, China
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  • Yan Kong
    Affiliations
    Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing, China
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  • Jun Guo
    Correspondence
    Correspondence: Jun Guo, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing, Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, 52# Fucheng Road, Haidian District, Beijing 100142, China.
    Affiliations
    Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing, China
    Search for articles by this author
  • Author Footnotes
    3 These authors contributed equally to this work.
Published:September 24, 2021DOI:https://doi.org/10.1016/j.jid.2021.08.437
      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 through 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 class I expression and chemokine production. Whole-transcriptome analysis showed that IFN-1‒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 showed, to our knowledge, a previously unreported mechanism underlying the epigenetic regulation of STING expression in melanoma; a combination of STING agonists and EZH2 inhibitors can boost the antitumor immune response and would be a promising treatment option for patients with melanoma who are refractory to current immunotherapies.

      Abbreviations:

      ChIP (chromatin immunoprecipitation), MHC (major histocompatibility complex)
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