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

Abstract

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.

Keywords: T-Lymphocytes; immunotherapy; tumor microenvironment.