Protein Kinase STK24 Promotes Tumor Immune Evasion via the AKT-PD-L1 Axis
Ning Wang1, Yu Jiang2, Mengjie Li1
1Institute of Immunology and Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
Abstract:
Immunotherapy targeting PD-L1 is still ineffective for a wide variety of tumors with high unpredictability. Deploying combined immunotherapy with alternative targeting is practical to overcome this therapeutic resistance. Here, the deficiency of serine-threonine kinase STK24 is observed in tumor cells causing substantial attenuation of tumor growth in murine syngeneic models, a process relying on cytotoxic CD8+ T and NK cells. Mechanistically, STK24 in tumor cells associates with and directly phosphorylates AKT at Thr21, which promotes AKT activation and subsequent PD-L1 induction. Deletion or inhibition of STK24, by contrast, blocks IFN-γ-mediated PD-L1 expression. Various murine models indicate that in vivo silencing of STK24 can significantly enhance the efficacy of the anti-PD-1 blockade strategy. Elevated STK24 levels are observed in patient specimens in multiple tumor types and inversely correlated with intratumoral infiltration of cytotoxic CD8+ T cells and with patient survival. The study collectively identifies STK24 as a critical modulator of antitumor immunity, which engages in AKT and PD-L1/PD-1 signaling and is a promising target for combined immunotherapy.
Insights
STK24 deficiency in tumor cells enhances anti-PD-1 immunotherapy by boosting CD8+ T cell activity. Inhibiting STK24 shows promise for overcoming tumor resistance to immunotherapy.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Immunotherapy targeting PD-L1 shows variable efficacy in many tumors.
- Overcoming therapeutic resistance requires combined immunotherapy strategies.
- STK24's role in tumor immunity is not fully understood.
Purpose of the Study:
- To investigate the role of serine-threonine kinase 24 (STK24) in tumor growth and anti-PD-1 therapy response.
- To elucidate the mechanism by which STK24 influences anti-tumor immunity.
- To evaluate STK24 as a potential therapeutic target for combined immunotherapy.
Main Methods:
- Utilized murine syngeneic models to assess tumor growth upon STK24 deficiency.
- Investigated STK24's interaction with AKT and its effect on PD-L1 expression.
- Analyzed STK24 levels in patient tumor specimens.
- Evaluated the efficacy of STK24 inhibition combined with anti-PD-1 blockade in vivo.
Main Results:
- STK24 deficiency significantly attenuated tumor growth by enhancing cytotoxic CD8+ T and NK cell activity.
- STK24 directly phosphorylates AKT at Thr21, promoting AKT activation and PD-L1 induction.
- STK24 inhibition blocked IFN-γ-mediated PD-L1 expression and enhanced anti-PD-1 therapy efficacy.
- Elevated STK24 levels in patients correlated with reduced CD8+ T cell infiltration and poorer survival.
Conclusions:
- STK24 is a critical regulator of anti-tumor immunity, modulating AKT and PD-L1/PD-1 signaling.
- STK24 deficiency enhances the efficacy of anti-PD-1 immunotherapy.
- STK24 represents a promising novel target for combined immunotherapy strategies to overcome tumor resistance.
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