RORγt agonist synergizes with CTLA-4 antibody to inhibit tumor growth through inhibition of Treg cells via TGF-β signaling in cancer

  • Pharmacol Res. 2021 Oct;172:105793. doi: 10.1016/j.phrs.2021.105793.
En-Ming Tian  1 ,  Ming-Cheng Yu  2 ,  Mei Feng  1 ,  Li-Xue Lu  2 ,  Cheng-Long Liu  1 ,  Li-An Shen  1 ,  Yong-Hui Wang  2 ,  Qiong Xie  3 ,  Di Zhu  4
Affiliations
  • 1. Department of Pharmacology, School of Basic Medical Sciences, School of Pharmacy, Fudan University, Shanghai 201203, China.
  • 2. Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
  • 3. Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China. Electronic address: [email protected].
  • 4. Department of Pharmacology, School of Basic Medical Sciences, School of Pharmacy, Fudan University, Shanghai 201203, China; School of Basic Medical Sciences, Fudan Unvieristy, Shanghai 200032, China. Electronic address: [email protected].
PMID: 34339836 DOI: 10.1016/j.phrs.2021.105793
Abstract

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.

Keywords
CCL20; CCR6; Immunotherapy; JG-1 (PubChem CID: 72193937); LYC-55716 (PubChem CID: 124126348); RORγt agonist; TGF-β; Th17; Treg.
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