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BCLAF1 binds SPOP to stabilize PD-L1 and promotes the development and immune escape of hepatocellular carcinoma
Zongdong Yu1,2, Xiang Wu1,2, Jie Zhu1
1Department of Hepatobiliary and Pancreatic Surgery, Affiliated Li Huili Hospital, Ningbo University, Ningbo, 315040, China.
Abstract:
Interaction between programmed death-1 (PD-1) ligand 1 (PD-L1) on tumor cells and PD-1 on T cells allows tumor cells to evade T cell-mediated immune surveillance. Strategies targeting PD-1/PD-L1 have shown clinical benefits in a variety of cancers. However, limited response rates in hepatocellular carcinoma (HCC) have prompted us to investigate the molecular regulation of PD-L1. Here, we identify B cell lymphoma-2-associated transcription factor 1 (BCLAF1) as a key PD-L1 regulator in HCC. Specifically, BCLAF1 interacts with SPOP, an E3 ligase that mediates the ubiquitination and degradation of PD-L1, thereby competitively inhibiting SPOP-PD-L1 interaction and subsequent ubiquitination and degradation of PD-L1. Furthermore, we determined an SPOP-binding consensus (SBC) motif mediating the BCLAF1-SPOP interaction on BCLAF1 protein and mutation of BCLAF1-SBC motif disrupts the regulation of the SPOP-PD-L1 axis. In addition, BCLAF1 expression was positively correlated with PD-L1 expression and negatively correlated with biomarkers of T cell activation, including CD3 and CD8, as well as with the level of immune cell infiltration in HCC tissues. Besides, BCLAF1 depletion leads to a significant reduction of PD-L1 expression in vitro, and this reduction of PD-L1 promoted T cell-mediated cytotoxicity. Notably, overexpression of BCLAF1 sensitized tumor cells to checkpoint therapy in an in vitro HCC cells-Jurkat cells co-culture model, whereas BCLAF1-SBC mutant decreased tumor cell sensitivity to checkpoint therapy, suggesting that BCLAF1 and its SBC motif serve as a novel therapeutic target for enhancing anti-tumor immunity in HCC.
Insights
B cell lymphoma-2-associated transcription factor 1 (BCLAF1) regulates programmed death-1 ligand 1 (PD-L1) in liver cancer. BCLAF1 inhibition reduces PD-L1, enhancing anti-tumor immunity and checkpoint therapy response in hepatocellular carcinoma.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Programmed death-1 (PD-1) ligand 1 (PD-L1) interaction with PD-1 on T cells facilitates tumor immune evasion.
- While PD-1/PD-L1 targeting improves cancer therapy, response rates in hepatocellular carcinoma (HCC) remain limited.
- Understanding PD-L1 regulation is crucial for enhancing HCC treatment efficacy.
Purpose of the Study:
- To identify key molecular regulators of PD-L1 in hepatocellular carcinoma.
- To investigate the role of B cell lymphoma-2-associated transcription factor 1 (BCLAF1) in PD-L1 regulation.
- To explore BCLAF1 as a potential therapeutic target for HCC immunotherapy.
Main Methods:
- Investigated BCLAF1 interaction with SPOP, an E3 ligase targeting PD-L1 for degradation.
- Identified and mutated the SPOP-binding consensus (SBC) motif on BCLAF1.
- Assessed correlations between BCLAF1 expression and PD-L1, T cell activation markers (CD3, CD8), and immune infiltration in HCC tissues.
- Utilized in vitro models to evaluate the impact of BCLAF1 modulation on PD-L1 levels, T cell cytotoxicity, and checkpoint therapy response.
Main Results:
- BCLAF1 acts as a key regulator of PD-L1 in HCC by inhibiting SPOP-mediated PD-L1 ubiquitination and degradation.
- BCLAF1 expression positively correlates with PD-L1 and negatively with T cell activation markers and immune infiltration.
- BCLAF1 depletion reduces PD-L1, enhancing T cell-mediated cytotoxicity.
- BCLAF1 overexpression sensitizes HCC cells to checkpoint therapy, while SBC motif mutation abrogates this effect.
Conclusions:
- BCLAF1 is a novel regulator of PD-L1 in HCC, impacting anti-tumor immunity.
- BCLAF1 and its SBC motif represent promising therapeutic targets for improving HCC immunotherapy.
- Targeting BCLAF1 may enhance the efficacy of checkpoint blockade therapy in hepatocellular carcinoma.
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