Sialyl Lewis X and related sialylated glycan ligands of Siglec-9 (sLeX)

Sialyl Lewis X (sLeX) and related sialylated glycans are complex carbohydrate structures that serve as the primary ligands for Siglec-9, an inhibitory receptor predominantly expressed on myeloid cells such as neutrophils, monocytes, and natural killer cells (Läubli & Varki, 2020). In healthy physiology, these interactions help maintain immune homeostasis and prevent overactive inflammatory responses by providing "self" signals to the immune system (Stanczak et al., 2018). However, many cancer types exhibit hypersialylation, overexpressing these glycans to create a "sialic acid checkpoint" that suppresses the anti-tumor immune response by engaging Siglec-9 and triggering inhibitory signaling via ITIM motifs (Duan & Paulson, 2020). Therapeutic strategies targeting these ligands include the use of sialidases, such as E-602, which enzymatically remove sialic acids from the tumor surface to "unmask" the cancer cells for immune recognition and destruction (Palleon Pharmaceuticals, 2023). By disrupting the sLeX/Siglec-9 axis, these therapies aim to enhance the activity of myeloid cells and natural killer cells within the tumor microenvironment (Gray et al., 2020). Monitoring the expression of these glycans via immunohistochemistry or flow cytometry serves as a potential biomarker for identifying patients who may benefit from desialylation-based immunotherapies.

Other names

sLeXCD15sSialyl-Lewis XSialylated glycansSiglec-9 ligandsTumor-associated sialylated glycans

Enzymatic removal of sialic acid residues (desialylation) from the cell surface to prevent the engagement of inhibitory Siglec-9 receptors on immune cells, thereby restoring anti-tumor immunity (Läubli & Varki, 2020; Palleon Pharmaceuticals, 2023).