2,5-dimethylcelecoxib improves immune microenvironment of hepatocellular carcinoma by promoting ubiquitination of HBx-induced PD-L1.

Abstract

BACKGROUND:

2,5-dimethylcelecoxib (DMC) is a targeted inhibitor of microsomal prostaglandin E synthase-1 (mPGES-1), a key enzyme in the PGE2 synthesis pathway of inflammatory mediators. Previous studies have confirmed that DMC can inhibit the growth of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). However, it is not known whether DMC is involved in the changes of tumor immune microenvironment.

METHODS:

In this study, we explored the effects of DMC on HBV-related HCC immune microenvironment, and deeply analyzed its unique effect and mechanism on programmed death receptor 1 (PD-1)/and its ligand 1 (PD-L1) pathway.

RESULTS:

Clinical hepatoma tissues detection showed that compared with non-virus-related HCC, the level of CD8 of HBV-related HCC was significantly lower, while the levels of PD-L1 and CD163 were higher. In vivo experiments indicated that DMC could increase the level of tumor infiltrating CD8+ T cells in hepatitis B virus X (HBx) (+) hepatoma cells implanted mouse models, and inhibit the expression of PD-L1 and CD163 in tumor tissues. DMC combined with atezolizumab had more significant antitumor effect and stronger blocking effect on PD-1/PD-L1 pathway. Mechanism studies have shown that DMC can promote ubiquitin degradation of HBx-induced PD-L1 protein in HCC cells by activating adenosine 5'-monophosphate-activated protein kinase pathway. Further experiments confirmed that this process was mainly mediated by E3 ligase RBX1.

CONCLUSIONS:

Our results uncover a role for DMC in promoting HBV-related HCC immune microenvironment, which not only enrich the relationship between inflammatory factors (mPGES-1/PGE2 pathway) and immunosuppression (PD-L1), but also provide an important strategic reference for multitarget or combined immunotherapy of HBV-related HCC.

• Authors: Zhanfei Chen, Yiyin Chen, Lirong Peng, Xiaoqian Wang, Nanhong Tang
• Journal: Journal for immunotherapy of cancer (J Immunother Cancer) Vol. 8 Issue 2 (10 2020) ISSN: 2051-1426 [Electronic] England
• PMID: 33028694 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Chemical References

• 2,5-dimethylcelecoxib
• Immune Checkpoint Inhibitors
• Pyrazoles
• Sulfonamides

Topics

• Animals
• Carcinoma, Hepatocellular (drug therapy, pathology)
• Drug Therapy (methods)
• Humans
• Immune Checkpoint Inhibitors (therapeutic use)
• Liver Neoplasms (drug therapy, pathology)
• Mice
• Pyrazoles (pharmacology, therapeutic use)
• Sulfonamides (pharmacology, therapeutic use)
• Tumor Microenvironment
• Ubiquitination