Journal
PHARMACOLOGICAL RESEARCH
Volume 172, Issue -, Pages -Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.phrs.2021.105793
Keywords
Immunotherapy; Th17; Treg; ROR gamma t agonist; TGF-beta; CCR6; CCL20
Categories
Funding
- National Natural Science Foundation of China [81872895, 82073881]
- Shanghai Science and Technology Commission [18ZR1403900, 20430713600, 18JC1413800]
- Fudan-SIMM Joint Research Fund [FU-SIMM20181010]
- Fudan School of Pharmacy [RHJJ2018-03, ROMY201712]
- Fudan Pudong hospital [RHJJ2018-03]
- Fudan Minhang hospital [ROMY201712]
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The study demonstrates that JG-1, a potent and selective small-molecule ROR gamma t agonist, promotes Th17 cells differentiation and inhibits regulatory T cells, leading to robust tumor growth inhibition in multiple syngeneic models. JG-1 also shows a synergistic effect with CTLA-4 antibody, indicating its potential as a promising therapeutic agent for tumor immunity.
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 gamma t (ROR gamma t) 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 ROR gamma t agonist to evaluate the therapeutic potential and mechanism of action of targeting ROR gamma t 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-beta 1 (TGF-beta 1) 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.
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