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

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

uhrf1 and dnmt1 Loss Induces an Immune Response in Zebrafish Livers Due to Viral Mimicry by Transposable Elements.

Activation of transposable elements (TEs) can cause cellular damage. Cytoplasmic nucleic acid sensing pathways evolved to detect pathogens, but can also serve to cull cells with inappropriate TE activation as TEs can be viral mimetics. Epigenetic silencing of TEs is mediated in part by DNA methylation, but it is not clear if TE activation or the immune system contribute to the cellular damage caused by loss of DNA methylation. Here, we provide mechanistic insight into the observation of an activated interferon response in the liver of zebrafish larvae with deletion in critical components of the DNA methylation machinery, uhrf1 and dnmt1. We focus on dissecting the relationship between DNA methylation, TE activation and induction of an immune response through cytoplasmic DNA and double stranded RNA sensing pathways and identify tnfa as a mediator of cell death in the liver of these mutants. Integrated RNAseq and methylome analysis identified LTR transposons as the most upregulated in these mutants and also the most methylated in control larvae, indicating a direct role of DNA methylation in suppressing this TE subclass. RNAseq analysis from these same samples revealed expression signatures of a type-I interferon response and of tnfa activation, mimicking the pattern of gene expression in virally infected cells. CRISPR/Cas9 mediated depletion of the cellular antiviral sensors sting and mavs reduced expression of interferon response genes and tnfa depletion dramatically reduced cell death in uhrf1 mutant livers. This suggests that the antiviral response induced by DNA hypomethylation and TE activation in the liver is mediated by the signaling pathways activated by both cytoplasmic double stranded RNA and DNA and that tnfa mediates cell death as a potential mechanism to eliminate these damaged cells.

Regulation of Toll-like receptor-mediated inflammatory response by microRNA-152-3p-mediated demethylation of MyD88 in systemic lupus erythematosus.

OBJECTIVE: microRNAs (miRNAs) play critical roles in embryogenesis, cell differentiation and the pathogenesis of several human diseases, including systemic lupus erythematosus (SLE). Toll-like receptors (TLRs) are also known to exert crucial functions in the immune response activation occurring in the pathogenesis of autoimmune diseases like SLE. Herein, the current study aimed to explore the potential role of miR-152-3p in TLR-mediated inflammatory response in SLE. METHODS: We determined the miR-152-3p expression profiles in CD4+ T cells and peripheral blood mononuclear cells (PBMCs) harvested from patients with SLE and healthy controls, and analyzed the correlation between miR-152-3p expression and clinicopathological parameters. CD70 and CD40L expression patterns in CD4+ T cells were assessed by RT-qPCR and flow cytometry. ChIP was adopted to determine the enrichment of DNA methyltransferase 1 (DNMT1) in the promoter region of myeloid differentiation factor 88 (MyD88). RESULTS: The obtained findings revealed that miR-152-3p was highly-expressed in CD4+ T cells and PBMCs of patients with SLE, and this high expression was associated with facial erythema, joint pain, double-stranded DNA, and IgG antibody. DNMT1 could be enriched in the MyD88 promoter, and miR-152-3p inhibited the methylation of MyD88 by targeting DNMT1. We also found that silencing miR-152-3p inhibited MyD88 expression not only to repress the autoreactivity of CD4+ T cells and but also to restrain their cellular inflammation, which were also validated in vivo. CONCLUSION: Our study suggests that miR-152-3p promotes TLR-mediated inflammatory response in CD4+ T cells by regulating the DNMT1/MyD88 signaling pathway, which highlights novel anti-inflammatory target for SLE treatment.

The interaction between environmental triggers and epigenetics in autoimmunity.

Systemic lupus erythematosus flares when genetically predisposed people encounter environmental agents that cause oxidative stress, such as infections and sunlight. How these modify the immune system to initiate flares is unclear. Drug induced lupus models demonstrate that CD4+ T cells epigenetically altered with DNA methylation inhibitors cause lupus in animal models, and similar T cells are found in patients with active lupus. How infections and sun exposure inhibit T cell DNA methylation is unclear. DNA methylation patterns are replicated each time a cell divides in a process that requires DNA methyltransferase one (Dnmt1), which is upregulated as cells enter mitosis, as well as the methyl donor S-adenosylmethionine, created from dietary sources. Reactive oxygen species that inhibit Dnmt1 upregulation, and a diet poor in methyl donors, combine to cause lupus in animal models. Similar changes are found in patients with active lupus, indicating a mechanism contributing to lupus flares.