2,5-dimethylcelecoxib alleviated NK and T-cell exhaustion in hepatocellular carcinoma via the gastrointestinal microbiota-AMPK-mTOR axis

• DOI: 10.1136/jitc-2023-006817
• Publication Date: 2023-06-14T17:30:18Z
• Authors: Banglun Pan; Zhanfei Chen; Xiaoxia Zhang; Zengbin Wang; Yuxin Yao; Xiaoxuan Wu; Jiacheng Qiu; Hua Lin; Liumin Yu; Haijian Tu; Nanhong Tang
• Keywords: Carcinoma, Hepatocellular; Liver Neoplasms; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; Basic Tumor Immunology; AMP-Activated Protein Kinases; T-Cell Exhaustion; Dinoprostone; 3. Good health; Gastrointestinal Microbiome; Mice; Celecoxib; Tumor Microenvironment; Animals; RC254-282

2,5-dimethylcelecoxib (DMC), a derivative of celecoxib, is an inhibitor microsomal prostaglandin E synthase-1 (mPGES-1). Our previous studies have demonstrated that DMC inhibits the expression programmed death-ligand 1 on hepatocellular carcinoma (HCC) cells to prevent tumor progression. However, effect and mechanism HCC infiltrating immune remain unclear. In this study, single-cell-based high-dimensional mass cytometry was performed microenvironment mice treated with DMC, celecoxib MK-886 (a known mPGES-1 inhibitor). Moreover, 16S ribosomal RNA sequencing employed analyze how improved by remodeling gastrointestinal microflora. We found (1) significantly inhibited growth prognosis mice, depended stronger antitumor activity natural killer (NK) T cells; (2) compared MK-886, enhanced cytotoxic stem-like potential, exhaustion NK (3) mechanistically, cell death protein-1 upregulated interferon-γ via microbiota (Bacteroides acidifaciens, Odoribacter laneus, splanchnicus)-AMPK-mTOR axis. study uncovers role in improving HCC, which not only enriches relationship between mPGES-1/prostaglandin E2 pathway function cells, but also provide important strategic reference for multitarget or combined immunotherapy HCC.Cite Now.