Alpha-Lipoic Acid Inhibits IFN-γ-Induced PD-L1 Expression in Prostate Cancer Cells and Enhances T-Cell-Mediated...

Area of Science:

• Immunology
• Oncology
• Biochemistry

Background:

• Programmed death-ligand 1 (PD-L1) is crucial for cancer immune evasion, but resistance to PD-L1 immunotherapy limits its use.
• α-lipoic acid (ALA) is an endogenous antioxidant, and its effect on PD-L1 expression is currently unknown.

Purpose of the Study:

• To investigate the effect of ALA on PD-L1 expression in prostate cancer cells.
• To explore the mechanisms underlying ALA's regulation of PD-L1.
• To evaluate ALA's impact on T-cell-mediated tumor killing.

Main Methods:

• Western blotting, RT-PCR, and immunofluorescence were used to determine PD-L1 and regulatory gene expression in IFN-γ-stimulated PC3 and DU145 cells.
• A co-culture system of cancer cells and Jurkat T cells assessed T-cell-mediated tumor-killing activity.

Main Results:

• ALA significantly inhibited IFN-γ-induced PD-L1 protein and mRNA expression.
• ALA suppressed key upstream regulators of PD-L1, including the JAK1/STAT1/IRF-1 cascade, c-Myc, HIF-1α, and GSK3β.
• ALA reduced mTOR/p70S6K/4EBP1-dependent protein translation and reactive oxygen species (ROS) production.
• ALA treatment markedly increased T-cell-mediated tumor-killing activity.

Conclusions:

• ALA inhibits PD-L1 expression through multiple mechanisms, including suppression of key signaling pathways and protein translation.
• ALA enhances T-cell-mediated anti-tumor immunity.
• ALA shows potential as an adjuvant agent to augment cancer immunotherapy, particularly for castration-resistant prostate cancer (CRPC).