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

Abstract

Background2,5-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.MethodsIn 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.ResultsClinical 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.ConclusionsOur 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.

LncRNA KCNQ1OT1 Secreted by Tumor Cell-Derived Exosomes Mediates Immune Escape in Colorectal Cancer by Regulating PD-L1 Ubiquitination via MiR-30a-5p/USP22

“…Numerous studies have shown that PD-1 is the main and key inhibitory receptor in tumor immunity. Immunotherapy aimed at blocking PD-1 and its ligand (PD-L1) has become an important means of treating tumors ( Chen Z. et al, 2020 ). It is precisely because we did not find significant differences in the detection of PD-L1 mRNA expression.…”

Transcriptome Analysis Reveals Possible Immunomodulatory Activity Mechanism of Chlorella sp. Exopolysaccharides on RAW264.7 Macrophages

“…Siyuan Ding found that siRNA knockdown and chemical inhibition of the activity of Rbx1 could suppress the degradation of β-TrCP mediated by RV encoding non-structural protein 1 (NSP1), which was beneficial to the activation of NF-κB signaling pathway, effectively reducing the ability of NSP1 to mount an antagonistic host immune response and inhibiting virus reproduction [ 51 ]. Rbx1 is also associated with the antitumor DMC that can improve the immune microenvironment of hepatocellular carcinoma cells [ 52 ]. ISG15 , which was wildly studied in immune processes, is a 15 kDa ubiquitin type I IFN that stimulates proteins and has various functions, such as activating immune cells, inducing the secretion of cytokines, and acting as a mediator of the immune response [ 53 , 54 , 55 ].…”

Emerging Role of Ubiquitination in the Regulation of PD-1/PD-L1 in Cancer Immunotherapy

“…Another study demonstrated that 2,5-dimethylcelecoxib (DMC), a targeted inhibitor of mPGES-1, could enhance ubiquitin-mediated degradation of HBxinduced PD-L1 protein in HCCs. 135 Further evidence demonstrates that this process is mainly regulated by E3 ligase RBX1. 135 Moreover, the small molecule WP1130, a selective deubiquitinase suppressor, attenuates the deubiquitinating potential of several DUBs, including USP5, USP9X, USP14, and USP37.…”

“…135 Further evidence demonstrates that this process is mainly regulated by E3 ligase RBX1. 135 Moreover, the small molecule WP1130, a selective deubiquitinase suppressor, attenuates the deubiquitinating potential of several DUBs, including USP5, USP9X, USP14, and USP37. WP1130 has been demonstrated to effectively inhibit cancers by triggering aggresome formation and promoting cancer cell apoptosis and chemosensitivity.…”