Engineering a PD-L1-sensing synthetic receptor for programmable macrophage response.

Area of Science:

• Synthetic biology
• Immunology
• Cellular engineering

Background:

• Cellular decision-making integrates extracellular cues for functional responses.
• Synthetic biology enables rewiring cellular processes with engineered receptors.
• Programmed death-ligand 1 (PD-L1) is a key immune-regulatory ligand.

Purpose of the Study:

• To engineer a synthetic receptor that enables monocytic-like cells to sense PD-L1.
• To conditionally activate a phagocytic program in response to PD-L1.
• To establish a modular framework for ligand-responsive control of engineered macrophage behavior.

Main Methods:

• Engineered a synthetic Notch-based receptor (SNIPR) to detect PD-L1.
• Programmed SNIPR to trigger outputs like fluorescent reporters or CV1-Fc upon PD-L1 engagement.
• Utilized THP-1-derived macrophages and SKOV-3 ovarian cancer cells for in vitro experiments.

Main Results:

• SNIPR activation scaled with PD-L1 levels.
• The circuit partially attenuated PD-1/PD-L1 signaling.
• Conditional CV1-Fc expression enhanced macrophage engulfment of cancer cells.

Conclusions:

• PD-L1 can be repurposed from a therapeutic target to a programmable input signal for synthetic circuits.
• This work establishes a modular framework for ligand-responsive control of engineered macrophage behavior.
• The engineered system offers a novel approach for modulating immune responses in cellular therapies.