Recent progress in targeting the sialylated glycan-SIGLEC axis in cancer immunotherapy

Abstract

Malignant tumors are complex structures composed of cancer cells and tumor microenvironmental cells. In this complex structure, cells cross-talk and interact, thus jointly promoting cancer development and metastasis. Recently, immunoregulatory molecule-based cancer immunotherapy has greatly improved treatment efficacy for solid cancers, thus enabling some patients to achieve persistent responses or cure. However, owing to the development of drug-resistance and the low response rate, immunotherapy against the available targets PD-1/PD-L1 or CTLA-4 has limited benefits. Although combination therapies have been proposed to enhance the response rate, severe adverse effects are observed. Thus, alternative immune checkpoints must be identified. The SIGLECs are a family of immunoregulatory receptors (known as glyco-immune checkpoints) discovered in recent years. This review systematically describes the molecular characteristics of the SIGLECs, and discusses recent progress in areas including synthetic ligands, monoclonal antibody inhibitors, and Chimeric antigen receptor T (CAR-T) cells, with a focus on available strategies for blocking the sialylated glycan-SIGLEC axis. Targeting glyco-immune checkpoints can expand the scope of immune checkpoints and provide multiple options for new drug development.

Keywords: SIGLEC; anti-SIGLEC antibodies; glyco-immune checkpoint; high affinity SIGLEC-ligands; sialylated glycan.

Figure 1

The 15 SIGLECs identified in humans. SIGLEC1, SIGLEC2, SIGLEC4, and SIGLEC15 are evolutionarily conserved, and the others are evolutionary non-conserved. SIGLEC1 is the longest SIGLEC without intracellular signaling motif, and human SIGLEC12 has lost the ability to bind Sias.

Figure 2

Diversity of sialoside structures. (A) Chemical structures of Neu5Ac, Neu5Gc, and Kdn. (B) Common linkage types of sialosides. (C) Underlying glycan backbones for sialylation, including glycoproteins (N-/O-glycan, Tn-, and T-antigen), as well as glycolipids. N-glycan is covalently attached to the amide side chain of the asparagine (Asn) residue, whereas O-glycan is attached to the hydroxyl groups of threonine/serine (Thr/Ser). Glycolipid is linked to the C-1 hydroxyl group of the ceramide. Structures are presented with SNFG symbol nomenclature (https://www.ncbi.nlm.nih.gov/glycans/snfg.html).

Figure 3

Strategies for targeting the sialylated glycan-SIGLEC axis. (1) Liposomal nanoparticles coated with high affinity ligands deliver anti-tumor drugs to lymphoma cells, which express SIGLEC2 or SIGLEC3. (2) Antibody-sialidase conjugates destroy the sialic acids on tumor cells and release the SIGLEC receptors. (3) Anti-SIGLEC antibodies block the specific sialoside-SIGLEC axis. (4) Antibody-drug conjugates target and are endocytosed into tumor cells by SIGLECs. (5) Sialyltransferase inhibitors decrease sialyltransferase expression. (6) SIGLEC-specific CAR-T increases the cytotoxicity of immune cells.