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

Abstract

BACKGROUND:

2,5-dimethylcelecoxib (DMC), a derivative of celecoxib, is an inhibitor of microsomal prostaglandin E synthase-1 (mPGES-1). Our previous studies have demonstrated that DMC inhibits the expression of programmed death-ligand 1 on hepatocellular carcinoma (HCC) cells to prevent tumor progression. However, the effect and mechanism of DMC on HCC infiltrating immune cells remain unclear.

METHODS:

In this study, single-cell-based high-dimensional mass cytometry was performed on the tumor microenvironment of HCC mice treated with DMC, celecoxib and MK-886 (a known mPGES-1 inhibitor). Moreover, 16S ribosomal RNA sequencing was employed to analyze how DMC improved the tumor microenvironment of HCC by remodeling the gastrointestinal microflora.

RESULTS:

We found that (1) DMC significantly inhibited the growth of HCC and improved the prognosis of the mice, and this depended on the stronger antitumor activity of natural killer (NK) and T cells; (2) compared with celecoxib and MK-886, DMC significantly enhanced the cytotoxic and stem-like potential, and inhibited exhaustion of NK and T cells; (3) mechanistically, DMC inhibited the expression of programmed cell death protein-1 and upregulated interferon-γ expression of NK and T cells via the gastrointestinal microbiota (Bacteroides acidifaciens, Odoribacter laneus, and Odoribacter splanchnicus)-AMPK-mTOR axis.

CONCLUSIONS:

Our study uncovers the role of DMC in improving the tumor microenvironment of HCC, which not only enriches the relationship between the mPGES-1/prostaglandin E2 pathway and the antitumor function of NK and T cells, but also provide an important strategic reference for multitarget or combined immunotherapy of HCC.Cite Now.

• Authors: Banglun Pan, Zhanfei Chen, Xiaoxia Zhang, Zengbin Wang, Yuxin Yao, Xiaoxuan Wu, Jiacheng Qiu, Hua Lin, Liumin Yu, Haijian Tu, Nanhong Tang
• Journal: Journal for immunotherapy of cancer (J Immunother Cancer) Vol. 11 Issue 6 (06 2023) ISSN: 2051-1426 [Electronic] England
• PMID: 37316264 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Chemical References

• 2,5-dimethylcelecoxib
• MK-886
• AMP-Activated Protein Kinases
• Celecoxib
• Dinoprostone

Topics

• Animals
• Mice
• Carcinoma, Hepatocellular (drug therapy)
• T-Cell Exhaustion
• AMP-Activated Protein Kinases
• Celecoxib (pharmacology, therapeutic use)
• Gastrointestinal Microbiome
• Liver Neoplasms (drug therapy)
• Dinoprostone
• Tumor Microenvironment