Mucosal Immunology Section, National Institute of Dental and Craniofacial Research (NIDCR), National Institute of Health, Bethesda, MS, United States.
Department of Immunology, Graduate School of Medicine, Akita University, Akita, Japan.
Front Immunol. 2021 Jun 23;12:687669. doi: 10.3389/fimmu.2021.687669. eCollection 2021.
Regulatory T cells (Tregs) play a crucial role in preventing antitumor immune responses in cancer tissues. Cancer tissues produce large amounts of transforming growth factor beta (TGF-β), which promotes the generation of Foxp3 Tregs from naïve CD4 T cells in the local tumor microenvironment. TGF-β activates nuclear factor kappa B (NF-κB)/p300 and SMAD signaling, which increases the number of acetylated histones at the locus and induces gene expression. TGF-β also helps stabilize Foxp3 expression. The curcumin analog and antitumor agent, GO-Y030, prevented the TGF-β-induced generation of Tregs by preventing p300 from accelerating NF-κB-induced Foxp3 expression. Moreover, the addition of GO-Y030 resulted in a significant reduction in the number of acetylated histones at the Foxp3 promoter and at the conserved noncoding sequence 1 regions that are generated in response to TGF-β. tumor models demonstrated that GO-Y030-treatment prevented tumor growth and reduced the Foxp3 Tregs population in tumor-infiltrating lymphocytes. Therefore, GO-Y030 exerts a potent anticancer effect by controlling Treg generation and stability.
调节性 T 细胞（Tregs）在防止肿瘤组织中的抗肿瘤免疫反应中起着至关重要的作用。肿瘤组织产生大量转化生长因子-β（TGF-β），促进了 Foxp3 Tregs 的生成，Foxp3 Tregs 来源于局部肿瘤微环境中的幼稚 CD4 T 细胞。TGF-β激活核因子 κB（NF-κB）/p300 和 SMAD 信号通路，增加 基因座处乙酰化组蛋白的数量，并诱导 基因表达。TGF-β还有助于稳定 Foxp3 的表达。姜黄素类似物和抗肿瘤药物 GO-Y030 通过阻止 p300 加速 NF-κB 诱导的 Foxp3 表达，从而防止 TGF-β诱导的 Tregs 的生成。此外，GO-Y030 的添加导致 Foxp3 启动子和保守非编码序列 1 区域处乙酰化组蛋白的数量显著减少，这些区域是对 TGF-β的反应生成的。在肿瘤模型中，GO-Y030 的治疗可防止肿瘤生长并减少肿瘤浸润淋巴细胞中的 Foxp3 Tregs 群体。因此，GO-Y030 通过控制 Treg 的生成和稳定性发挥强大的抗癌作用。
