Department of Pharmacology, School of Basic Medical Sciences, School of Pharmacy, Fudan University, Shanghai 201203, China.
Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
Pharmacol Res. 2021 Oct;172:105793. doi: 10.1016/j.phrs.2021.105793. Epub 2021 Jul 31.
To date, the overall response rate to checkpoint blockade remains unsatisfactory, partially due to the limited understanding of the tumor immune microenvironment. The retinoic acid-related orphan receptor γt (RORγt) is the key transcription factor of T helper cell 17 (Th17) cells and plays an essential role in tumor immunity. In this study, we used JG-1, a potent and selective small-molecule RORγt agonist to evaluate the therapeutic potential and mechanism of action of targeting RORγt in tumor immunity. JG-1 promotes Th17 cells differentiation and inhibition of regulatory T (Treg) cells differentiation. JG-1 demonstrates robust tumor growth inhibition in multiple syngeneic models and shows a synergic effect with the Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) antibody. In tumors, JG-1 not only promotes Th17 cells differentiation and increases C-C Motif Chemokine Receptor 6 (CCR6)- Chemokine (C-C motif) ligand 20 (CCL20) expression, but also inhibits both the expression of transforming growth factor-β1 (TGF-β1) and the differentiation and infiltration of Treg cells. In summary, JG-1 is a lead compound showing a potent activity in vitro and robust tumor growth inhibition in vivo with synergetic effects with anti-CTLA-4.
迄今为止，由于对肿瘤免疫微环境的有限理解，检查点阻断的总体反应率仍不令人满意。维甲酸相关孤儿受体 γt（RORγt）是辅助性 T 细胞 17（Th17）细胞的关键转录因子，在肿瘤免疫中发挥重要作用。在这项研究中，我们使用了一种有效的、选择性的小分子 RORγt 激动剂 JG-1，来评估靶向 RORγt 在肿瘤免疫中的治疗潜力和作用机制。JG-1 促进 Th17 细胞分化并抑制调节性 T（Treg）细胞分化。JG-1 在多种同源模型中均表现出强大的肿瘤生长抑制作用，并与细胞毒性 T 淋巴细胞相关抗原 4（CTLA-4）抗体具有协同作用。在肿瘤中，JG-1 不仅促进 Th17 细胞分化并增加 C-C 基序趋化因子受体 6（CCR6）-趋化因子（C-C 基序）配体 20（CCL20）的表达，而且还抑制转化生长因子-β1（TGF-β1）的表达以及 Treg 细胞的分化和浸润。综上所述，JG-1 是一种具有很强活性的先导化合物，在体内具有强大的肿瘤生长抑制作用，并与抗 CTLA-4 具有协同作用。
