Do galectins serve as soluble ligands for immune checkpoint receptors?

NICOLAS TORRES; FEDERICO G BAUDOU; MARCO A SCHEIDEGGER; TOMÁS DALOTTO-MORENO; GABRIEL A. RABINOVICH

Journal for ImmunoTherapy of Cancer

BMJ Publishing Group

Año: 2024

2051-1426

Hardly any set of molecules have been studied more extensively in immuno-oncology than immune checkpoint receptors and their ligands. However, with intense research both in experimental models and clinical settings, additional immune evasion mechanisms and immunosuppressive pathways are continuously being discovered. These include galectins, a family of soluble glycan-binding proteins that shape the nature and magnitude of antitumor immune responses by reprogramming the fate and function of lymphoid and myeloid cells. Extracellularly, they interact with a variety of glycosylated receptors, modulating their cell surface retention, endocytosis, segregation, and signaling. Remarkably, a growing body of evidence suggests that galectins can bind to immune checkpoint receptors, including the T cell immunoglobulin domain and mucin domain-3 (TIM-3), programmed death-1 (PD- 1), lymphocyte activating gene-3 (LAG-3), cytotoxic T lymphocyte antigen-4 (CTLA-4) and the leukocyte Ig-like receptor subfamily B3 (LILRB3) and B4 (LILRB4), favoring their signaling activity and inhibitory function. However, more work is needed to dissect the precise mechanisms underlying these effects, particularly the interplay between galectins and canonical immune checkpoint ligands as well as the biochemical nature and glycan-binding dependence of these interactions. A better understanding of ‘galectin-immune checkpoint’ hubs will contribute to design novel immunotherapeutic modalities aimed at targeting galectin-driven circuits in a wide range of cancer settings.