Journal
JOURNAL FOR IMMUNOTHERAPY OF CANCER
Volume 10, Issue 7, Pages -Publisher
BMJ PUBLISHING GROUP
DOI: 10.1136/jitc-2021-004037
Keywords
immunotherapy; T-Lymphocytes; tumor microenvironment
Categories
Funding
- NSFC [31525008, 81830051, 31961133011, 31700775]
- National Key R&D Program of China [2019YFA09006100]
- Innovative research team of high-level local universities in Shanghai [SSMU-ZDCX20180101]
- Shanghai 'Rising Star' program [10QA1407900]
- CAS '100-talent' program and National Science Foundation for Distinguished Young Scholars [31525008]
- Program of Shanghai Academic Research Leader [16XD1403800]
- Fundamental Research Funds for Central Universities
- National Postdoctoral Program for Innovative Talents [BX201700159]
- China Postdoctoral Science Foundation [2017M621497]
- Shanghai Jiao Tong University (SJTU)-The Chinese University of Hong Kong (CUHK) Joint Research Collaboration Fund
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This study identifies gallic acid as a compound that promotes the instability of T-reg cells, thereby enhancing the efficacy of immune checkpoint blockade (ICB) therapy in cancer treatment.
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-gamma 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.
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