MYC suppresses STING-dependent innate immunity by transcriptionally upregulating DNMT1 in triple-negative breast cancer

• DOI: 10.1136/jitc-2021-002528
• Publication Date: 2021-07-28T17:25:09Z
• Authors: Si-Yu Wu; Yi Xiao; Jin-Li Wei; Xiao-En Xu; Xi Jin; Xin Hu; Da-Qiang Li; Yi-Zhou Jiang; Zhi-Ming Shao
• Keywords: Sting; Triple-negative breast cancer

Triple-negative breast cancer (TNBC) is the most aggressive subtype of and lacks definite treatment targets. Tumor immune microenvironment (TIME) heterogeneity has a profound impact on immunotherapy response. Tumors with non-inflamed TIME derive limited benefit from immunotherapy. However, what drives formation in TNBC remains unclear.Using our multiomics database TNBC, we conducted an analysis to explore key genomic events driving TNBC. In vitro vivo studies further revealed potential mechanisms efficacy combination immunotherapy.With transcriptomic data, systematically analyzed that classical basal-like consisted two distinct phenotypes, defined as 'inflamed' 'non-inflamed' subtypes. We performed screening demonstrated MYC amplification overexpression led low infiltration cytolytic activity TIME. Mechanistically, bound DNMT1 promoter activated transcription cells, thus suppressing Cyclic GMP-AMP synthase (cGAS)-STING pathway via epigenetic regulatory way. MYC-overexpressing decitabine, Food Drug Administration (FDA)-approved DNA methyltransferase inhibitor, converted tumors inflamed by enhancing T cell infiltration. Furthermore, decitabine programmed death protein 1 (PD-1) inhibitor reversed exhaustion improved function mouse models, which elicited potent antitumor TNBC.Our work elucidates classic oncogene induces evasion repressing innate immunity. provide rationale for combining inhibition