Abstract：
Although survival from breast cancer has dramatically increased, many will develop recurrent, metastatic disease. Unfortunately, survival for this stage of disease remains very low. Activating the immune system has incredible promise since it has the potential to be curative. However, immune checkpoint blockade (ICB) which works through T cells has been largely disappointing for metastatic breast cancer. One reason for this is a suppressive myeloid immune compartment that is unaffected by ICB. Cholesterol metabolism and proteins involved in cholesterol homeostasis play important regulatory roles in myeloid cells. Here, we demonstrate that NR0B2, a nuclear receptor involved in negative feedback of cholesterol metabolism, works in several myeloid cell types to impair subsequent expansion of regulatory T cells (Tregs); Tregs being a subset known to be highly immune suppressive and associated with poor therapeutic response. Within myeloid cells, NR0B2 serves to decrease many aspects of the inflammasome, ultimately resulting in decreased IL1β; IL1β driving Treg expansion. Importantly, mice lacking NR0B2 exhibit accelerated tumor growth. Thus, NR0B2 represents an important node in myeloid cells dictating ensuing Treg expansion and tumor growth, thereby representing a novel therapeutic target to re-educate these cells, having impact across different solid tumor types. Indeed, a paper co-published in this issue demonstrates the therapeutic utility of targeting NR0B2.
摘要：
尽管乳腺癌的生存率急剧增加，许多人将反复发作，转移性疾病。不幸的是,这个阶段的疾病存活率仍然很低。激活免疫系统具有令人难以置信的前景，因为它具有治愈的潜力。然而,通过T细胞起作用的免疫检查点阻断(ICB)对转移性乳腺癌的治疗在很大程度上令人失望.其一个原因是不受ICB影响的抑制性骨髓免疫区室。胆固醇代谢和参与胆固醇稳态的蛋白质在骨髓细胞中起重要的调节作用。这里,我们证明NR0B2是一种参与胆固醇代谢负反馈的核受体，在几种骨髓细胞类型中起作用，以损害随后的调节性T细胞（Tregs）的扩增;Tregs是已知具有高度免疫抑制性并且与不良治疗反应相关的子集。在骨髓细胞内，NR0B2用于减少炎症的许多方面，最终导致IL1β减少；IL1β驱动Treg膨胀。重要的是,缺乏NR0B2的小鼠表现出加速的肿瘤生长。因此，NR0B2代表骨髓细胞中的重要节点，决定随后的Treg扩增和肿瘤生长，从而代表了一种新的治疗靶点来重新教育这些细胞，对不同实体瘤类型有影响。的确,本期共同发表的一篇论文证明了靶向NR0B2的治疗效用。
