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

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.

Automated summary

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.