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Kinome-Wide Screening Identifies FAK as a Novel Post-Translational Regulator of PD-L1 Stability and Immune Evasion in
Asia-Lily Boyd1, Prem Khanal1, Tynan Kelly1
1Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON K7L 3N6, Canada.
Abstract:
Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by limited treatment options and poor prognosis. Although immune checkpoint inhibitors targeting the PD-1/PD-L1 axis have shown clinical promise, many TNBC patients exhibit resistance or limited response, underscoring the need to understand regulatory mechanisms of PD-L1 expression. Here, we performed a kinome-wide inhibitor screen using a HEK293A cell line stably expressing a NanoLuc-tagged PD-L1 construct lacking its endogenous promoter, to identify post-translational regulators of PD-L1 stability. We identified focal adhesion kinase (FAK) as a novel modulator of PD-L1. FAK inhibition significantly decreased PD-L1 levels in HEK293A cells but paradoxically increased PD-L1 expression in TNBC cell lines. Mechanistically, FAK directly interacts with PD-L1 to modulate its stability independently of its kinase activity. Functionally, FAK inhibition enhanced membrane PD-L1 expression and reduced T-cell-mediated cancer cell killing, suggesting increased immune evasion. These findings reveal a novel role for FAK in immune modulation and suggest that combining FAK inhibitors with PD-L1 blockade may offer a promising strategy for TNBC treatment.
Insights
Focal adhesion kinase (FAK) regulates PD-L1 stability. FAK inhibition paradoxically increased PD-L1 in triple-negative breast cancer, enhancing immune evasion and suggesting new treatment strategies.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Triple-negative breast cancer (TNBC) is aggressive with poor prognosis and limited treatments.
- Immune checkpoint inhibitors show promise but many TNBC patients lack response, highlighting the need to understand PD-L1 regulation.
Purpose of the Study:
- To identify post-translational regulators of PD-L1 stability.
- To investigate the role of focal adhesion kinase (FAK) in PD-L1 regulation in TNBC.
Main Methods:
- A kinome-wide inhibitor screen was conducted using HEK293A cells with a NanoLuc-tagged PD-L1 construct.
- FAK was identified as a novel PD-L1 modulator.
- Mechanistic studies explored FAK's interaction with PD-L1 and its effect on stability and cell surface expression.
Main Results:
- FAK inhibition decreased PD-L1 in HEK293A cells but paradoxically increased PD-L1 in TNBC cell lines.
- FAK directly interacts with PD-L1, modulating its stability independently of kinase activity.
- FAK inhibition enhanced membrane PD-L1 and reduced T-cell-mediated cancer cell killing, indicating increased immune evasion.
Conclusions:
- FAK plays a novel role in immune modulation within TNBC.
- Combining FAK inhibitors with PD-L1 blockade may be a promising therapeutic strategy for TNBC treatment.
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