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NRIR promotes immune escape in hepatocellular cancer by regulating IFNγ-induced PD-L1 expression
Yan Zhou1, Jing Wang2, Yuanhang Chen1
1Department of Medical Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China; Department of Pathology & Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Introduction:
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, with insensitive treatment and poor prognosis; in recent years, breakthroughs in IFN signaling pathway and PDL1/PD1 signaling pathway in HCC immunotherapy research.
Objectives:
This study aimed to investigate the molecular mechanisms controlling the immune response and immune evasion.
Methods:
NRIR was identified as a differential gene affecting the IFN signaling pathway and PDL1/PD1 signaling pathway in HCC by bioinformatics, and the function of NRIR was investigated in the HCC cell model and the xenograft mouse model. Quantitative Real-time PCR (qRT-PCR) was used to detect NRIR and PD-L1 mRNAs in hepatocellular carcinoma tissues, and dual luciferase reporter gene assay, fluorescence in situ hybridization, western blot and RNA immunoprecipitation (RIP) to explore the molecular mechanisms between NRIR and target genes.
Results:
In this study, we observed a significant positive correlation between NRIR and PD-L1 expression in HCC, and NRIR upregulated PD-L1 expression in HCC by modulating the IFNγ signaling pathway. We demonstrated that NRIR recruited the transcription factor ZNF384 to initiate CMPK2 transcription. Furthermore, CMPK2 regulates ATP production to modulate STAT1 activation to affect PD-L1 expression.
Conclusion:
Our findings revealed the important players of NRIR in regulating PD-L1 expression in HCC and provided new insights for the clinical application of immune-targeted therapies.
Insights
Hepatocellular carcinoma (HCC) research reveals NRIR upregulates PD-L1 expression by influencing the IFNγ pathway. This finding offers new avenues for immune-targeted HCC therapies.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Hepatocellular carcinoma (HCC) presents significant treatment challenges and poor prognosis globally.
- Recent advancements in HCC immunotherapy focus on the Interferon (IFN) and PD-L1/PD-1 signaling pathways.
Purpose of the Study:
- To elucidate the molecular mechanisms governing immune response and evasion in HCC.
- To investigate the role of NRIR in regulating immune evasion pathways within HCC.
Main Methods:
- Bioinformatic analysis identified NRIR as a key gene in IFN and PD-L1/PD-1 signaling in HCC.
- NRIR function was assessed in HCC cell and xenograft mouse models.
- Quantitative Real-time PCR (qRT-PCR), dual luciferase reporter gene assays, FISH, Western blot, and RIP were employed to explore molecular interactions.
Main Results:
- A significant positive correlation was observed between NRIR and PD-L1 expression in HCC.
- NRIR was found to upregulate PD-L1 expression by modulating the IFNγ signaling pathway.
- NRIR recruits ZNF384 to initiate CMPK2 transcription, which regulates ATP production and STAT1 activation, ultimately affecting PD-L1 expression.
Conclusions:
- NRIR plays a crucial role in regulating PD-L1 expression in HCC.
- These findings provide novel insights for developing targeted immune therapies for HCC.
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