MYC suppresses STING-dependent innate immunity by transcriptionally upregulating DNMT1 in triple-negative breast cancer.
MYC suppresses STING-dependent innate immunity by transcriptionally upregulating DNMT1 in triple-negative breast cancer.
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DOI：
10.1136/jitc-2021-002528
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发表时间：
2021-07
影响因子：
10.9
通讯作者：
Shao ZM
中科院分区：
文献类型：
--
作者：
Wu SY;Xiao Y;Wei JL;Xu XE;Jin X;Hu X;Li DQ;Jiang YZ;Shao ZM
三阴性乳腺癌（TNBC）是乳腺癌中最具侵袭性的亚型，缺乏明确的治疗靶点。肿瘤免疫微环境（TIME）异质性对免疫治疗反应有着深远的影响。非炎症时间的肿瘤从免疫治疗中获益有限。然而，是什么推动了TNBC中非炎症时间的形成仍不清楚。使用我们的TNBC多组学数据库，我们进行了分析，以探索驱动TNBC中非炎症TIME形成的关键基因组事件。体外和体内研究进一步揭示了与免疫疗法联合治疗的潜在机制和疗效。利用转录组学和基因组数据，我们系统地分析了TNBC的TIME，并揭示了TNBC的经典基底样亚型由两种不同的微环境表型组成，定义为“发炎”和“非发炎”亚型。我们进行了进一步的筛选，并证明MYC扩增和过表达导致TIME中的低免疫浸润和细胞溶解活性。MYC与DNMT 1启动子结合，激活DNMT 1的转录，通过表观遗传调控途径抑制环GMP-AMP合酶（cGAS）-STING通路。在MYC过表达的TNBC中，地西他滨，一种食品和药物管理局（FDA）批准的DNA甲基转移酶抑制剂，通过增强T细胞浸润将肿瘤从非炎症肿瘤转化为炎症肿瘤。此外，地西他滨与程序性细胞死亡蛋白1（PD-1）抑制剂的组合逆转了小鼠模型中的T细胞耗竭并改善了T细胞功能，这在MYC过表达的TNBC中引起了有效的抗肿瘤活性。我们的工作阐明了经典的癌基因MYC通过抑制先天免疫来诱导免疫逃避。此外，我们提供了一个合理的结合DNA甲基转移酶抑制与免疫治疗MYC过度表达TNBC的治疗。
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. 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. 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. 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.
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影响因子：
28.2
作者：
Peng W;Chen JQ;Liu C;Malu S;Creasy C;Tetzlaff MT;Xu C;McKenzie JA;Zhang C;Liang X;Williams LJ;Deng W;Chen G;Mbofung R;Lazar AJ;Torres-Cabala CA;Cooper ZA;Chen PL;Tieu TN;Spranger S;Yu X;Bernatchez C;Forget MA;Haymaker C;Amaria R;McQuade JL;Glitza IC;Cascone T;Li HS;Kwong LN;Heffernan TP;Hu J;Bassett RL Jr;Bosenberg MW;Woodman SE;Overwijk WW;Lizée G;Roszik J;Gajewski TF;Wargo JA;Gershenwald JE;Radvanyi L;Davies MA;Hwu P
通讯作者：
Hwu P
三阴性乳腺癌的基因组和转录组景观：亚型和治疗策略
影响因子：
50.3
作者：
Jiang, Yi-Zhou;Ma, Ding;Shao, Zhi-Ming
通讯作者：
Shao, Zhi-Ming
综合转录组分析鉴定出三阴性乳腺癌的新分子亚型和亚型特异性 RNA
DOI：
10.1186/s13058-016-0690-8
发表时间：
2016-03-15
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Liu YR;Jiang YZ;Xu XE;Yu KD;Jin X;Hu X;Zuo WJ;Hao S;Wu J;Liu GY;Di GH;Li DQ;He XH;Hu WG;Shao ZM
通讯作者：
Shao ZM
影响因子：
10.3
作者：
Bareche, Yacine;Buisseret, Laurence;Sotiriou, Christos
通讯作者：
Sotiriou, Christos
影响因子：
168.9
作者：
Denkert, Carsten;Liedtke, Cornelia;von Minckwitz, Gunter
通讯作者：
von Minckwitz, Gunter