Available online 11 August 2022, 101110

Immune inhibitory Siglecs on the surface of human immune cells engage Siglec ligands in their local tissue environment.

Siglec ligands may be cell surface or secreted sialoglycans (glycoproteins or glycolipids).

Siglec ligands are often distinctive sialoglycans carried on a restricted number of glycoproteins in each target tissue.

Siglec ligands may be minor glycoforms of common glycoproteins in which the carrier protein plays an ancillary function.

Siglec ligand research focuses on their roles in immune regulation and as immune checkpoint inhibitors in cancer.

Most human Siglecs (sialic acid binding immunoglobulin-like lectins) are expressed on the surfaces of overlapping subsets of immune cells, and most carry immunoreceptor tyrosine-based inhibitory domains on their intracellular motifs. When immune inhibitory Siglecs bind to complementary sialoglycans in their local milieu, engagement results in down-regulation of the immune response. Siglecs have come under scrutiny as potential targets of drugs to modify the course of inflammation (and other immune system responses) and as immune checkpoints in cancer. Human Siglecs bind to endogenous human sialoglycans. The identities of these endogenous human sialoglycan immune regulators are beginning to emerge, along with some general principles that may inform future investigations in this area. Among these principles is the finding that a cell type or tissue may express a ligand for a particular Siglec on a single or a very few of its sialoglycoproteins. The selected protein carrier for a particular Siglec may be unique in a certain tissue, but vary tissue-to-tissue. The binding affinity of endogenous Siglec ligands may surpass that of its binding to synthetic sialoglycan determinants by several orders of magnitude. Since most human Siglecs have evolved rapidly and are distinct from those in most other mammals, this review describes endogenous human Siglec ligands for several human immune inhibitory Siglecs. As the identities of these immune regulatory sialoglycan ligands are defined, additional opportunities to target Siglecs therapeutically may emerge.

immune Checkpoint

Inflammation

Cancer

Sialic acid

Glycoprotein

Lectin

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