Identification of chemical compounds regulating PD-L1 by introducing HiBiT-tagged cells

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Programmed death-ligand 1 (PD-L1) is a key immunosuppressive molecule on tumor cells.
• Immune checkpoint inhibitors targeting PD-L1 are crucial in cancer therapy.
• Understanding PD-L1 regulation is vital, but high-throughput screening systems are lacking.

Purpose of the Study:

• To establish a high-throughput system for evaluating small compounds' effects on PD-L1 expression.
• To identify novel regulators of PD-L1 using a screening approach.

Main Methods:

• Development of a HiBiT-tagged lung adenocarcinoma cell line (PC9-KI) for sensitive PD-L1 detection.
• Screening of 1280 compounds from the Library of Pharmacologically Active Compounds.
• Identification of compounds modulating PD-L1 protein levels.

Main Results:

• Microtubule polymerization inhibitors were identified as PD-L1 upregulators.
• Thapsigargin was found to upregulate PD-L1 expression.
• A p97 inhibitor was identified as a PD-L1 downregulator.

Conclusions:

• The developed PC9-KI cell line enables efficient screening of PD-L1 modulators.
• Novel classes of compounds, including microtubule inhibitors and p97 inhibitors, regulate PD-L1.
• This platform facilitates the discovery of new therapeutic strategies targeting the PD-L1 pathway in cancer.