PD-L1 expression in triple-negative breast cancer

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Early trials show T-cell inhibitory molecule programmed cell death ligand 1 (PD-L1) has clinical efficacy in cancer.
• Triple-negative breast cancer (TNBC) is an aggressive subtype with limited targeted therapies.
• PTEN loss is implicated in various cancers and can affect immune responses.

Purpose of the Study:

• To determine if PD-L1 is overexpressed in TNBC.
• To investigate the role of PTEN loss in regulating PD-L1 expression in TNBC.
• To assess the impact of altered PD-L1 expression on T-cell function.

Main Methods:

• Analysis of Cancer Genome Atlas (TCGA) RNA sequencing data for PD-L1 gene expression in TNBC vs. non-TNBC.
• Evaluation of PD-L1 expression in TNBC tumor tissue microarrays.
• Generation of PTEN-knockdown cell lines using short hairpin RNA (shRNA) to study PD-L1 regulation.
• Inhibition of the phosphoinositide 3-kinase (PI3K) pathway using AKT inhibitor MK-2206 or rapamycin.
• Coculture experiments to assess the functional effects of altered PD-L1 expression on T-cells.

Main Results:

• PD-L1 gene expression was significantly higher in TNBC compared to non-TNBC (P < 0.001).
• PD-L1 was present in 19% of TNBC specimens, with PD-L1(+) tumors showing greater CD8(+) T-cell infiltrate (P < 0.0001).
• PTEN knockdown led to increased cell-surface PD-L1 expression and transcripts, suggesting transcriptional regulation.
• PI3K pathway inhibition decreased PD-L1 expression, linking PTEN and PI3K signaling to PD-L1 regulation.
• Increased PD-L1 expression on tumor cells induced by PTEN loss reduced T-cell proliferation and increased apoptosis.

Conclusions:

• PD-L1 is expressed in approximately 20% of TNBCs, indicating its potential as a therapeutic target.
• Loss of PTEN is a mechanism for PD-L1 upregulation in TNBC.
• Agents targeting the PI3K pathway may enhance antitumor adaptive immune responses by modulating PD-L1 expression.