DEAD-box helicase 1 inhibited CD8+ T cell antitumor activity by inducing PD-L1 expression in hepatocellular carcinoma
Junhao Liu1, Ti Yang1,2, Yurong Luo1,2
1Department of Hepatobiliary-Pancreatic & Hernia Surgery, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong, China.
Abstract:
Hepatocellular carcinoma (HCC) does not respond well to current treatments, even immune checkpoint inhibitors. PD-L1 (programmed cell death ligand 1 or CD274 molecule)-mediated immune escape of tumor cells may be a key factor affecting the efficacy of immune checkpoint inhibitor (ICI) therapy. However, the regulatory mechanisms of PD-L1 expression and immune escape require further exploration. Here, we observed that DDX1 (DEAD-box helicase 1) was overexpressed in HCC tissues and associated with poor prognosis in patients with HCC. Additionally, DDX1 expression correlated negatively with CD8+ T cell frequency. DDX1 overexpression significantly increased interferon gamma (IFN-γ)-mediated PD-L1 expression in HCC cell lines. DDX1 overexpression decreased IFN-γ and granzyme B production in CD8+ T cells and inhibited CD8+ T cell cytotoxic function in vitro and in vivo. In conclusion, DDX1 plays an essential role in developing the immune escape microenvironment, rendering it a potential predictor of ICI therapy efficacy in HCC.
Insights
DEAD-box helicase 1 (DDX1) is overexpressed in hepatocellular carcinoma (HCC), promoting immune escape by increasing PD-L1 expression. This hinders CD8+ T cell function, suggesting DDX1 as a biomarker for immune checkpoint inhibitor therapy in HCC.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Hepatocellular carcinoma (HCC) exhibits poor response to current treatments, including immune checkpoint inhibitors (ICIs).
- Tumor immune escape, particularly via programmed cell death ligand 1 (PD-L1), is a critical factor limiting ICI efficacy.
- Mechanisms regulating PD-L1 expression and immune escape in HCC require further elucidation.
Purpose of the Study:
- To investigate the role of DEAD-box helicase 1 (DDX1) in HCC progression and immune evasion.
- To determine the impact of DDX1 on PD-L1 expression and CD8+ T cell function in the HCC microenvironment.
- To evaluate DDX1 as a potential predictive biomarker for ICI therapy in HCC.
Main Methods:
- Analysis of DDX1 expression in HCC tissues and correlation with patient prognosis and CD8+ T cell infiltration.
- In vitro studies using HCC cell lines to assess the effect of DDX1 overexpression on interferon gamma (IFN-γ)-mediated PD-L1 induction.
- Evaluation of DDX1's impact on CD8+ T cell function, including cytokine production (IFN-γ, granzyme B) and cytotoxic activity, in vitro and in vivo.
Main Results:
- DDX1 was found to be overexpressed in HCC tissues, correlating with poorer patient prognosis.
- DDX1 expression showed a negative correlation with the frequency of CD8+ T cells in the tumor microenvironment.
- Overexpression of DDX1 significantly enhanced IFN-γ-induced PD-L1 expression in HCC cells.
- DDX1 overexpression suppressed IFN-γ and granzyme B production in CD8+ T cells, impairing their cytotoxic function both in vitro and in vivo.
Conclusions:
- DDX1 plays a crucial role in establishing an immune-suppressive microenvironment in HCC.
- DDX1 contributes to tumor immune escape by upregulating PD-L1 and inhibiting anti-tumor T cell responses.
- DDX1 represents a potential predictive biomarker for the efficacy of immune checkpoint inhibitor therapy in hepatocellular carcinoma.
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