GABA/baclofen stabilizes PD-L1 and enhances immunotherapy of breast cancer

Area of Science:

• Immunology
• Oncology
• Pharmacology

Background:

• Immune checkpoint blockade (ICB) targeting PD-1/PD-L1 offers clinical benefits in cancer but faces response limitations.
• Tumor cell PD-L1 expression levels correlate with response to PD-1/PD-L1 blockade therapy.
• Novel strategies are needed to regulate PD-L1 expression and improve ICB efficacy.

Purpose of the Study:

• To identify novel regulators of PD-L1 expression.
• To investigate the potential of GABA and baclofen in modulating PD-L1 levels.
• To evaluate the efficacy of combining baclofen with anti-PD-L1 therapy in breast cancer.

Main Methods:

• Investigated the effect of GABA and baclofen on PD-L1 expression in cancer cells.
• Assessed the impact of these compounds on STUB1 (an E3 ubiquitin ligase) mRNA and protein levels.
• Evaluated the interaction between STUB1 and PD-L1 using biochemical assays.
• Tested the therapeutic efficacy of baclofen combined with anti-PD-L1 antibody in a mouse model of breast cancer, analyzing CD8+ T cell infiltration and anti-tumor immunity.

Main Results:

• GABA and baclofen upregulate PD-L1 protein levels by reducing STUB1 expression.
• These drugs decrease the interaction between STUB1 and PD-L1, leading to PD-L1 stabilization.
• Baclofen did not affect cancer cell proliferation in vitro.
• Combination therapy with baclofen and anti-PD-L1 antibody significantly improved therapeutic outcomes in mice compared to anti-PD-L1 alone, evidenced by increased CD8+ T cell infiltration and enhanced anti-tumor immunity.

Conclusions:

• GABA and baclofen represent a novel mechanism for stabilizing PD-L1 by targeting STUB1.
• This stabilization enhances the efficacy of anti-PD-L1 immunotherapy in preclinical breast cancer models.
• These findings suggest a potential new therapeutic strategy to improve responses to immune checkpoint blockade therapy.