MYC suppresses STING-dependent innate immunity by transcriptionally upregulating DNMT1 in triple-negative breast cancer
| العنوان: | MYC suppresses STING-dependent innate immunity by transcriptionally upregulating DNMT1 in triple-negative breast cancer |
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| المؤلفون: | Yi Xiao, Zhi-Ming Shao, Xiao-En Xu, Si-Yu Wu, Xin Hu, Yi-Zhou Jiang, Da-Qiang Li, Xi Jin, Jin-Li Wei |
| المصدر: | Journal for Immunotherapy of Cancer Journal for ImmunoTherapy of Cancer, Vol 9, Iss 7 (2021) |
| بيانات النشر: | BMJ, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | DNA (Cytosine-5-)-Methyltransferase 1, 0301 basic medicine, Cancer Research, medicine.medical_treatment, T cell, Immunology, DNA Methyltransferase Inhibitor, Decitabine, Triple Negative Breast Neoplasms, Biology, Proto-Oncogene Proteins c-myc, Mice, 03 medical and health sciences, 0302 clinical medicine, Immune system, innate, medicine, Animals, Humans, tumor microenvironment, Immunology and Allergy, RC254-282, Triple-negative breast cancer, Clinical/Translational Cancer Immunotherapy, Pharmacology, Mice, Inbred BALB C, Tumor microenvironment, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Membrane Proteins, tumor escape, Immunotherapy, immunity, Immunity, Innate, Up-Regulation, 030104 developmental biology, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Cancer research, Heterografts, Molecular Medicine, Oncogene MYC, Female, immunotherapy, medicine.drug |
| الوصف: | BackgroundTriple-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.MethodsUsing 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.ResultsWith 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.ConclusionsOur 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. |
| تدمد: | 2051-1426 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d3c0c0c31d79db09f7af19a3cfd461e0Test https://doi.org/10.1136/jitc-2021-002528Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....d3c0c0c31d79db09f7af19a3cfd461e0 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20511426 |
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