NRIR promotes immune escape in hepatocellular cancer by regulating IFNγ-induced PD-L1 expression.

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.