A New Functional Screening Platform Identifies Colistin Sulfate as an Enhancer of Natural Killer Cell Cytotoxicity

Area of Science:

• Immunology
• Pharmacology
• Oncology

Background:

• Natural killer (NK) cells are crucial for tumor immunity and are a key target for cancer immunotherapies.
• While NK cell-based therapies like adoptive transfer and NK cell engagers are advancing clinically, few studies explore small molecules to enhance NK cell activity against cancer.
• Repurposing existing drugs offers an efficient strategy to discover novel immunotherapies.

Purpose of the Study:

• To develop a high-throughput screening platform to identify small molecule compounds that enhance NK cell cytotoxicity.
• To screen FDA-approved drugs for their potential to boost NK cell anti-cancer activity.
• To investigate the efficacy and conditions required for NK cell potentiation by identified compounds.

Main Methods:

• Developed a high-throughput luciferase-release cytotoxicity assay for screening small molecules.
• Screened 1200 FDA-approved drugs from the Prestwick Chemical Library.
• Assessed the impact of candidate compounds on human NK cell cytotoxicity against cancer cells.

Main Results:

• Identified the antibiotic colistin sulfate as a compound that increases the cytotoxic potential of human NK cells against cancer cells.
• Observed that colistin sulfate's potentiating effect is transient and dependent on its presence during the NK cell-target cancer cell interaction.
• Found no enhancement when NK cells were pretreated with colistin sulfate before encountering cancer cells.

Conclusions:

• Colistin sulfate demonstrates potential as an NK cell-boosting agent for cancer immunotherapy.
• The mechanism of action requires colistin to be present during the effector-target cell interaction phase.
• Further research, including mechanistic studies and preclinical evaluation in mouse cancer models, is warranted to validate colistin sulfate's therapeutic potential.