Brd7缺失通过形成免疫抑制生态位重新唤醒肺中休眠的转移起始细胞

IF 15.7 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES
Jayanta Mondal, Junfeng Zhang, Feng Qing, Shunping Li, Dhiraj Kumar, Jason T. Huse, Filippo G. Giancotti
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引用次数: 0

摘要

癌症的转移受表观遗传因素的影响。通过体内筛选,我们证明了多染色体相关的BAF (PBAF)染色质重塑复合体的几个亚基,特别是Brd7,是维持雌性小鼠肺部乳腺癌转移性休眠所必需的。Brd7缺失诱导转移性再觉醒,并伴随表观基因组景观的改变和致癌信号的上调。Brd7失活的乳腺癌细胞也通过下调MHC-1表达和促进促转移细胞因子谱来重编程周围的免疫微环境。流式细胞术和单细胞分析显示,brd7缺陷转移的雌性小鼠肺中促肿瘤炎性和移行性中性粒细胞、CD8+耗竭T细胞和CD4+应激反应T细胞水平升高。最后,通过中性粒细胞耗竭、中性粒细胞胞外陷阱(NET)抑制或免疫检查点治疗来减弱这种免疫抑制环境,消除转移性生长。这些发现暗示Brd7和PBAF在癌症中引发转移性生长,指出了涉及特异性免疫细胞区室的可靶向的潜在机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Brd7 loss reawakens dormant metastasis initiating cells in lung by forging an immunosuppressive niche

Brd7 loss reawakens dormant metastasis initiating cells in lung by forging an immunosuppressive niche

Metastasis in cancer is influenced by epigenetic factors. Using an in vivo screen, we demonstrate that several subunits of the polybromo-associated BAF (PBAF) chromatin remodeling complex, particularly Brd7, are required for maintaining breast cancer metastatic dormancy in the lungs of female mice. Brd7 loss induces metastatic reawakening, along with modifications in epigenomic landscapes and upregulated oncogenic signaling. Breast cancer cells harboring Brd7 inactivation also reprogram the surrounding immune microenvironment by downregulating MHC-1 expression and promoting a pro-metastatic cytokine profile. Flow cytometric and single-cell analyses reveal increased levels of pro-tumorigenic inflammatory and transitional neutrophils, CD8+ exhausted T cells, and CD4+ stress response T cells in lungs from female mice harboring Brd7-deficient metastases. Finally, attenuating this immunosuppressive milieu by neutrophil depletion, neutrophil extracellular trap (NET) inhibition, or immune checkpoint therapy abrogates metastatic outgrowth. These findings implicate Brd7 and PBAF in triggering metastatic outgrowth in cancer, pointing to targetable underlying mechanisms involving specific immune cell compartments.

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来源期刊
Nature Communications
Nature Communications Biological Science Disciplines-
CiteScore
24.90
自引率
2.40%
发文量
6928
审稿时长
3.7 months
期刊介绍: Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.
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