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Gallic Acid Induces T-helper-1-like T Cells and Strengthens Immune Checkpoint Blockade Efficacy

Abstract

Background: Foxp3 regulatory T (T) cells facilitate tumor immune evasion by forming a suppressive tumor microenvironment. Therefore, immune therapies promoting T 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 instability by repressing gene transcription. In vivo and in vitro experiments have been performed to explore the roles of Usp21 in T 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 gene promoter. The deubiquitinated Usp21 and stabilized PD-L1 proteins boost the function of T cells. Combination of gallic acid and anti-PD-1 antibody, in colorectal cancer (CRC) treatment, not only significantly dampen T 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 T cells.

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