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Published on: February 28, 2019
CK2B Induces CD8+ T-Cell Exhaustion through HDAC8-Mediated Epigenetic Reprogramming to Limit the Efficacy of
Shaochuan Liu1,2,3,4,5,6, Shiya Ma1,2,3,4,5,7, Gen Liu1,2,3,4,5,7
1Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China.
Abstract:
Anti-PD-1 therapy has left an indelible mark in the field of non-small-cell lung cancer (NSCLC) treatment; however, its efficacy is limited in clinical practice owing to differences in the degree of effector T-cell exhaustion. Casein kinase 2 (CK2) is a protein kinase that plays an important role in T-cell immunity. In this study, it is aimed to explore the potential of targeting CK2 and its regulatory subunit CK2B to prevent or reverse T-cell exhaustion, thereby enhancing the efficacy of anti-PD-1 therapy in NSCLC. In this study, it is found that CK2B expression is closely associated with T-cell exhaustion as well as the efficacy of anti-PD-1 therapy based on scRNA-seq and in vitro and in vivo experiments. Utilization of CK2 inhibitors or knockdown of CK2B expression can upregulate TBX21 expression through HDAC8-mediated epigenetic reprogramming, restoring the effector function of CD8+ T cells and enhancing the efficacy of anti-PD-1 therapy in NSCLC. These findings underscore CK2B as a promising target for overcoming the exhaustion of effector CD8+ T cells, thereby enhancing the efficacy of anti-PD-1 and adoptive cell therapies in NSCLC. Moreover, CK2B expression serves as a novel predictor of immunotherapy efficacy for NSCLC.
Insights
Targeting Casein Kinase 2 (CK2) and its subunit CK2B can reverse T-cell exhaustion. This approach enhances anti-PD-1 therapy effectiveness in non-small-cell lung cancer (NSCLC) by restoring CD8+ T-cell function.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Anti-programmed cell death protein 1 (anti-PD-1) therapy shows promise for non-small-cell lung cancer (NSCLC).
- Therapeutic efficacy is often limited by effector T-cell exhaustion.
- Casein kinase 2 (CK2) is a protein kinase crucial for T-cell immunity.
Purpose of the Study:
- To investigate the role of CK2 and its regulatory subunit CK2B in T-cell exhaustion within NSCLC.
- To evaluate the potential of targeting CK2/CK2B to enhance anti-PD-1 therapy efficacy.
Main Methods:
- Single-cell RNA sequencing (scRNA-seq) analysis.
- In vitro and in vivo experimental models.
- Assessment of T-cell exhaustion markers and effector functions.
- Investigation of epigenetic mechanisms involving HDAC8.
Main Results:
- CK2B expression correlates with T-cell exhaustion and anti-PD-1 therapy response in NSCLC.
- CK2 inhibition or CK2B knockdown restores CD8+ T-cell effector function.
- Upregulation of TBX21 expression via HDAC8-mediated epigenetic reprogramming is observed.
- Enhanced efficacy of anti-PD-1 therapy in NSCLC models was achieved.
Conclusions:
- CK2B is a potential therapeutic target for overcoming T-cell exhaustion in NSCLC.
- Targeting CK2B can improve the efficacy of anti-PD-1 and adoptive cell therapies.
- CK2B expression may serve as a predictive biomarker for immunotherapy response in NSCLC.
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