开发 NR0B2 作为肿瘤相关骨髓细胞再教育的治疗靶点。
Development of NR0B2 as a therapeutic target for the re-education of tumor associated myeloid cells.
发表日期：2024 Jun 27
作者：
Hashni Epa Vidana Gamage, Samuel T Albright, Amanda J Smith, Rachel Farmer, Sayyed Hamed Shahoei, Yu Wang, Emma C Fink, Elise Jacquin, Erin Weisser, Rafael O Bautista, Madeline A Henn, Claire P Schane, Adam T Nelczyk, Liqian Ma, Anasuya Das Gupta, Shruti V Bendre, Tiffany Nguyen, Srishti Tiwari, Natalia Krawczynska, Sisi He, Evelyn Tjoanda, Hong Chen, Maria Sverdlov, Peter H Gann, Romain Boidot, Frederique Vegran, Sean W Fanning, Lionel Apet, Paul J Hergenrother, Erik R Nelson
来源：
CANCER LETTERS
摘要：
免疫检查点阻断（ICB）在乳腺癌等多种实体瘤中的作用有限，乳腺癌是女性癌症相关死亡的主要原因。因此，人们对促进抗癌免疫反应的替代策略非常感兴趣。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）如何在骨髓免疫细胞内发挥作用，调节炎症小体并减少免疫抑制性调节性 T 细胞 (Treg) 的扩张。在这里，我们开发 NR0B2 作为潜在的治疗靶点。肿瘤中的 NR0B2 与包括乳腺癌在内的多种癌症类型的生存率提高相关。重要的是，NR0B2 表达也是 ICB 成功的预后。在乳腺肿瘤中，NR0B2 表达与 Tregs 标志物 FOXP3 呈负相关。虽然所描述的激动剂（DSHN）具有一定的功效，但它需要高剂量和长治疗时间。因此，我们设计并筛选了几个衍生品。甲酯衍生物 (DSHN-OMe) 在以下方面表现出优越性：(1) 细胞摄取，(2) 调节预期基因表达的能力，(3) 使用体外共培养系统抑制 Treg 扩增，以及 (4 ）对抗原发性和转移性肿瘤生长的功效。这项工作将 NR0B2 确定为再教育骨髓免疫细胞的靶点和在临床前模型中具有显着抗肿瘤功效的新型配体。版权所有 © 2024。由 Elsevier B.V. 出版。
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.Copyright © 2024. Published by Elsevier B.V.