Abstract：
Immune checkpoint blockade (ICB) has had limited utility in several solid tumors such as breast cancer, a major cause of cancer-related mortality in women. Therefore, there is considerable interest in alternate strategies to promote an anti-cancer immune response. A paper co-published in this issue describes how NR0B2, a protein involved in cholesterol homeostasis, functions within myeloid immune cells to modulate the inflammasome and reduce the expansion of immune-suppressive regulatory T cells (Treg). Here, we develop NR0B2 as a potential therapeutic target. NR0B2 in tumors is associated with improved survival for several cancer types including breast. Importantly, NR0B2 expression is also prognostic of ICB success. Within breast tumors, NR0B2 expression is inversely associated with FOXP3, a marker of Tregs. While a described agonist (DSHN) had some efficacy, it required high doses and long treatment times. Therefore, we designed and screened several derivatives. A methyl ester derivative (DSHN-OMe) emerged as superior in terms of (1) cellular uptake, (2) ability to regulate expected expression of genes, (3) suppression of Treg expansion using in vitro co-culture systems, and (4) efficacy against the growth of primary and metastatic tumors. This work identifies NR0B2 as a target to re-educate myeloid immune cells and a novel ligand with significant anti-tumor efficacy in preclinical models.
摘要：
免疫检查点阻断（ICB）在乳腺癌等几种实体瘤中的应用有限。女性癌症相关死亡的主要原因。因此,对促进抗癌免疫反应的替代策略有相当大的兴趣.本期共同发表的一篇论文描述了NR0B2，一种参与胆固醇稳态的蛋白质，在髓样免疫细胞内发挥功能以调节炎症小体并减少免疫抑制性调节性T细胞（Treg）的扩增。这里,我们开发NR0B2作为一个潜在的治疗靶点。肿瘤中的NR0B2与包括乳腺癌在内的几种癌症类型的生存率提高有关。重要的是,NR0B2的表达也是ICB成功的预后因素。在乳腺肿瘤中，NR0B2的表达与Tregs的标记物FOXP3呈负相关。虽然描述的激动剂（DSHN）有一些功效，它需要高剂量和长治疗时间。因此,我们设计并筛选了几种衍生物。甲酯衍生物（DSHN-OMe）在（1）细胞摄取方面表现优异，(2)调节基因预期表达的能力，（3）使用体外共培养系统抑制Treg扩增，和(4)对抗原发性和转移性肿瘤生长的功效。这项工作将NR0B2鉴定为重新教育髓样免疫细胞的靶标和在临床前模型中具有显着的抗肿瘤功效的新型配体。
