Targeting the Siglec-Sialic Acid Immune Axis in Cancer: Current and Future Approaches

Abstract

The sialic acid-binding immunoglobulin-like lectin (Siglec)-sialic acid immune axis is an evolutionarily conserved immunoregulatory pathway that provides a mechanism for establishing self-recognition and combatting invasive pathogens. Perturbations in the pathway lead to many immune dysregulated diseases, including autoimmunity, neurodegeneration, allergic conditions, and cancer. The purpose of this review is to provide a brief overview of the relationship between Siglecs and sialic acid as they relate to human health and disease, to consider current Siglec-based therapeutics, and to discuss new therapeutic approaches targeting the Siglec-sialic acid immune axis, with a focus on cancer.

Figure 1.

Sugar building blocks of human cell-surface immune markers. The sugar moieties shown in A are common carbohydrate components of cell-surface molecules, including sialoglycans, in humans, some of which serve as immune markers. The composition, branching anomeric form, and linkage lead to a diversity of molecules, with Neu5Ac often being the sialic acid moiety in the outermost position and playing a key role in the interaction between cells. B shows an example of an N-linked glycan in which glycosylation occurs at an asparagine residue (N) and an O-glycan in which glycosylation occurs at a serine or threonine residue (S/T). Sialic acids other than Neu5Ac including O-acetylated-Neu5Ac or Neu5Gc can be sometimes found in cancer.

Figure 2.

Illustration of the structure and diversity of Siglecs. There are two main groups of Siglecs, those which are highly conserved, as shown on the left, and a more diverse group of CD33-related Siglecs, as shown on the right. All Siglecs have an extracellular V-type Ig domain and at least one C2-type Ig domain. Many Siglecs also contain at least one cytoplasmic ITIM domain, involved in immunosuppressive signaling.

Figure 3.

Therapies targeting Siglecs on malignant myeloid and lymphoid cells. A, Illustrates ADCs composed of an anti-Siglec conjugated to a cytotoxic small-molecule payload. The antibody portion of the drug targets Siglecs, which are displayed on the surface of cancer cells, leading to internalization of the antibody and the drug and subsequent release of the cytotoxic payload within the cancer cell. B, Depicts the use of anti-Siglec BiTEs to link cytotoxic T cells to cancer cells, resulting in destruction of the cancer cell. As shown in C, CAR T-cell therapies have been developed that target Siglecs displayed on the surface of cancer cells, leading to cytotoxicity in those cells. Cytotoxic granules are depicted as red dots. TCR, T-cell receptor; VH, variable heavy chain; VL, variable light chain.

Figure 4.

Therapies targeting Siglecs as immune modulators. To overcome immune evasion mechanisms of cancer cells, several approaches are being evaluated, including Siglec-blocking antibodies, targeted sialidases, and targeted sialic acid traps. A, Illustrates an interaction between an inhibitory Siglec on an immune cell and a sialylated glycan on a cancer cell, leading to immunosuppression. B, Illustrates an anti-Siglec binding to a Siglec to block binding, thus preventing their ability to suppress an immune response. C, Shows a sialidase conjugated to an antibody that targets it to cancer cells. Once bound, it desialylates the ligand, preventing immune suppression from Siglec–sialic acid interactions. D, Depicts a Siglec-Fc fusion that functions as a sialic acid trap. The Fc portion allows localization to immune cells, whereas the Siglec portion can bind sialic acid on tumor or immune cells, blocking inhibitory immune signaling. Cytotoxic granules are depicted as red dots.