Targeting USP47 enhances immunotherapy in hepatocellular carcinoma by destabilizing PD-L1.

Background: Substantial clinical benefits have been achieved in the realm of immunotherapies for HCC by focusing on the interaction between PD-1/PD-L1. Nevertheless, just about 20 % of patients with HCC exhibited signs of measurable clinical improvement from PD-1 or PD-L1 blockade alone. Since the PD-L1 level is critical to influencing efficacy, it is urgent to gain an in-depth understanding of the mechanisms controlling PD-L1 protein expression promptly.

Methods: TCGA and GEO database identified USP47 through screening. Protein levels were examined by Western blot and immunohistochemistry. Co-immunoprecipitation was conducted to identify the interaction between proteins. Capacity for cell proliferation, migration and invasion was measured using a variety of in vitro assays. The immune evasion capacity of HCC cells was assessed by a T cell-based assay for killing tumor cells. A mouse model of HCC was created to evaluate the effectiveness of a USP47 inhibitor, both as a standalone treatment and in combination with a PD-1 antibody.

Results: We find that USP47 is frequently upregulated and significantly correlated with prognosis in HCC. Deficiency of USP47 hinders the proliferation, migration, invasion and immune evasion of HCC cells, as well as reduces PD-L1 protein expression without downregulating its mRNA levels. Mechanismly, USP47 modulates PD-L1 protein stability by deubiquitination of PD-L1. Moreover, the use of the USP47 inhibitor P5091 has been shown to significantly reduce tumoral PD-L1 levels, leading to improved therapeutic outcomes in HCC when combined with anti-PD-1 therapy.

Conclusions: USP47 is essential for modulating proliferation, migration, invasion, and immune evasion of HCC cells. Inhibiting USP47 in combination with PD-1 blockade can enhance the suppression of HCC growth, potentially holding clinical importance. This investigation elucidates the role of USP47 in PD-L1 stability via deubiquitination, offering a new prognostic indicator and potential target for treating HCC.