Gal-3 blocks the binding between PD-1 and pembrolizumab.

Area of Science:

• Immunology
• Oncology
• Biochemistry

Background:

• Immune checkpoint inhibitors (ICI) have improved metastatic malignant melanoma (MM) survival.
• Predictive biomarkers for ICI response are crucial due to treatment resistance in some patients.
• Galectin-3 (Gal-3) is a potential biomarker and therapeutic target for ICI therapy.

Purpose of the Study:

• Investigate the interaction between programmed cell death 1 (PD-1), pembrolizumab, and Gal-3 in metastatic MM.
• Determine if Gal-3 influences pembrolizumab efficacy.
• Explore Gal-3 as a predictive biomarker for ICI treatment response.

Main Methods:

• Surface plasmon resonance (SPR) and cryogenic electron microscopy (cryo-EM) to visualize binding interactions.
• In vitro T cell cultures to assess cytokine production.
• Measurement of soluble PD-1 and Gal-3 levels in metastatic MM patients treated with pembrolizumab.

Main Results:

• Gal-3 was shown to block PD-1 and pembrolizumab binding via steric inhibition.
• Gal-3 reduced T cell pro-inflammatory cytokine production, unaffected by pembrolizumab.
• High tumor Gal-3 correlated with disease progression, while high plasma Gal-3 correlated with longer progression-free survival.
• Soluble PD-1 levels increased post-pembrolizumab treatment and correlated with disease progression.

Conclusions:

• The interaction between PD-1 and Gal-3 interferes with pembrolizumab binding.
• Gal-3-induced immune suppression in the tumor microenvironment is not overcome by pembrolizumab.
• Gal-3 exhibits differential roles in plasma and tumor tissue regarding ICI treatment outcomes.