Mechanical force regulates the inhibitory function of PD-1.

Area of Science:

• Immunology
• Biophysics
• Cancer Biology

Background:

• Programmed cell death 1 (PD-1) is a critical immune checkpoint regulating T-cell activation.
• Its precise inhibitory mechanism, especially under force, remains incompletely understood.
• PD-1 is a key target in cancer immunotherapy.

Purpose of the Study:

• To elucidate the molecular mechanism of PD-1 inhibition under mechanical force.
• To investigate the role of force-induced bound states in PD-1 function.
• To explore the therapeutic potential of soluble PD-1 ligands.

Main Methods:

• Biomembrane force probe (BFP) to measure PD-1/PD-L1/PD-L2 bond dynamics under force.
• Steered molecular dynamics (SMD) simulations to reveal force-induced bound states.
• Tumor growth studies with gain-of-function mutants.

Main Results:

• A distinct force-induced bound state of PD-1 was identified, differing from the force-free state.
• Disrupting interactions stabilizing either bound state weakened the catch bond and PD-1 inhibition.
• Soluble PD-L1/PD-L2 competed with surface-bound ligands, attenuating T-cell inhibition.
• Soluble PD-L1 demonstrated anti-cancer activity in vivo.

Conclusions:

• Mechanical force plays a critical role in regulating PD-1's inhibitory function.
• PD-1 may act as a mechanical sensor for T-cell suppression.
• Mechanical regulation should be considered in designing PD-1 blocking therapies.
• Soluble PD-1 ligands show potential as anti-PD-1 drugs.