Light-controlled elimination of PD-L1+ cells

Area of Science:

• Oncology
• Immunology
• Drug Delivery

Background:

• Programmed death ligand-1 (PD-L1) is crucial in tumor progression and immune evasion.
• Current immune checkpoint inhibitors (ICIs) show limited response rates, necessitating novel strategies.
• Targeting both tumor and immunosuppressive cells in the tumor microenvironment (TME) is key to overcoming resistance.

Purpose of the Study:

• To investigate the efficacy of photochemical internalization (PCI) in enhancing the cytotoxic effects of a PD-L1-targeting immunotoxin.
• To explore the potential of a light-controlled combinatorial strategy for cancer immunotherapy.

Main Methods:

• Utilized PD-L1-targeting immunotoxin (anti-PD-L1-saporin) combined with PCI in PD-L1+ and PD-L1- cancer cell lines.
• Employed fluorescence microscopy to track antibody and photosensitizer localization and cellular uptake.
• Confirmed PD-L1 expression in various human and murine cancer cell lines, including induction by interferon-gamma.

Main Results:

• PCI significantly enhanced the cytotoxic effects of anti-PD-L1-saporin in PD-L1+ triple-negative breast cancer cells.
• No enhanced efficacy was observed in PD-L1-negative cancer cells, demonstrating specificity.
• Demonstrated light-controlled endosomal/lysosomal escape of the antibody and photosensitizer into the cytosol.
• Confirmed PD-L1 expression in subpopulations of breast, prostate, and colon cancer cell lines.

Conclusions:

• Provided in vitro proof-of-concept for PCI-enhanced targeting and eradication of PD-L1-positive immunosuppressive cells.
• This light-controlled approach offers a potential strategy to advance cancer immunotherapy.
• Further preclinical studies are warranted to explore this combinatorial strategy.