Gallic acid induces T-helper-1-like Treg cells and strengthens immune checkpoint blockade efficacy

Journal article

Background Foxp3⁺ regulatory T (T_reg) cells facilitate tumor immune evasion by forming a suppressive tumor microenvironment. Therefore, immune therapies promoting T_reg fragility may greatly enhance immune checkpoint blockade (ICB) efficacy in cancers.

Methods We have screened 2640 compounds and identified the gut microbial metabolite gallic acid, which promotes Foxp3 degradation and T_reg instability by repressing Usp21 gene transcription. In vivo and in vitro experiments have been performed to explore the roles of Usp21 in T_reg cells. Importantly, we treated tumor-bearing mice with gallic acid and anti-PD-1 antibody to explore the potential therapeutic value of gallic acid in clinical cancer immunotherapy.

Results Mechanistically, gallic acid prevents STAT3 phosphorylation and the binding of phosphorylated STAT3 to Usp21 gene promoter. The deubiquitinated Usp21 and stabilized PD-L1 proteins boost the function of T_reg cells. Combination of gallic acid and anti-PD-1 antibody, in colorectal cancer (CRC) treatment, not only significantly dampen T_reg cell function by impairing PD-L1/PD-1 signaling and downregulating Foxp3 stability, but also promote CD8⁺ T cells’ production of IFN-γ and limited tumor growth.

Conclusion Our findings have implications for improving the efficacy of ICB therapy in CRC by inducing T-helper-1-like Foxp3^lo T_reg cells.

Authors: Deng, B; Yang, B; Chen, J; Wang, S; Zhang, W

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: BMJ Publishing Group
• Journal: Journal for ImmunoTherapy of Cancer
• Volume: 10
• Issue: 7
• Article number: e004037
• Publication date: 2022-07-11
• Acceptance date: 2022-06-09
• DOI: 10.1136/jitc-2021-004037
• EISSN: 2051-1426
• Language: English
• Keywords: FFR