Sialylated Programmed Death-Ligand 1 (Sialylated PD-L1)

Sialylated Programmed Death-Ligand 1 (PD-L1) refers to the glycosylated form of the PD-L1 protein, where its N-glycan chains are terminated with sialic acid residues [1]. These sialoglycans function as a secondary, glyco-immune checkpoint by interacting with Sialic acid-binding Ig-like lectins (Siglecs), such as Siglec-7 and Siglec-9, expressed on natural killer (NK) cells and myeloid cells [2, 4]. This interaction, occurring alongside the canonical PD-1/PD-L1 axis, promotes an immunosuppressive tumor microenvironment and facilitates immune evasion by suppressing both innate and adaptive immune responses [4]. In many cancers, hypersialylation of PD-L1-expressing cells is a recognized mechanism of resistance to standard PD-1/PD-L1 blockade therapies [1]. Therapeutic strategies targeting these sialoglycans involve bifunctional molecules, such as antibody-sialidase conjugates (e.g., PD-L1-Sialidase), which use a PD-L1-binding domain to deliver a sialidase enzyme directly to the tumor cell surface [2, 3]. By enzymatically stripping these sialic acids, these drugs remove the inhibitory signals and restore the activity of immune cells against the tumor [3]. This approach is particularly relevant for treating solid tumors that are refractory to existing immunotherapies due to glycan-mediated suppression [4]. Sources: [1] Sun, L., et al. (2020). Sialylation of PD-L1 maintains its stability and promotes its membrane expression. Cell Death & Differentiation. [2] Gray, M. A., et al. (2020). Targeted glycan degradation potentiates the anticancer immune response. Nature Chemical Biology. [3] Palleon Pharmaceuticals. Pipeline and EAGLE Platform. palleonpharma.com. [4] Zhou, X., et al. (2023). The Siglec-sialoglycan axis in cancer immune evasion. Nature Reviews Cancer.

Other names

PD-L1 sialoglycansGlycosylated PD-L1Sialic acid-modified PD-L1PD-L1-associated sialoglycans

Targeted desialylation of PD-L1-expressing cells using antibody-sialidase conjugates to remove terminal sialic acids, thereby preventing the activation of inhibitory Siglec receptors on immune cells and sensitizing the tumor to immune attack.