Siglec-15, also known as sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15), also known as CD33 antigen-like 3, belongs to the Siglec family. Siglec-15 is a key immunosuppressive agent that is widely upregulated in various cancer types and a potential target for cancer immunotherapy. Furthermore, Siglec-15 is a novel T cell inhibitory molecule. It has been identified as a key regulator of osteoclast differentiation and may have potential implications for bone diseases beyond osteoporosis.
(Data source: Sun J, et al. Clin Cancer Res. 2021)
Distribution of Siglec15
Siglec15 is expressed in macrophages, Langerhans cells, bone marrow cells, osteoclasts and some tumor cells, and plays an important role in immune regulation.
(Data source: uniprot)
Structure of Siglec15
Siglec-15 is a type I transmembrane protein. Siglec-15 consists of the extracellular domain of Siglec-15, which contains a conserved N-terminal variable (V)-set Ig domain that binds sialic acid and a constant C2-set Ig domain. The V-set domain folds into a sandwich of two β-pleated sheets composed of antiparallel β-strands. It differs from the C2-set by the presence of an additional β-strand within the β-sheet. Upon binding to the immunoreceptor tyrosine-based activation motif (ITAM) adaptor proteins DAP10 or DAP12, Siglec-15 triggers a signaling cascade through its positively charged transmembrane region, regulating multiple biological processes, including osteoclast maturation, bone remodeling, and susceptibility to fungal infection.
(Data source: Uniprot)
(Data source: Lenza MP, Egia-Mendikute L, Antoñana-Vildosola A, et al. Nat Commun. 2023)
Siglec15 in immune regulation
Siglec-15 is expressed at low levels on macrophages under physiological conditions but can be upregulated by M-CSF, which is released by various normal cells in response to inflammatory cytokines or tumor cells. Siglec-15 directly inhibits NF-κB/NFAT signaling by binding to an unknown receptor, suppressing T cell proliferation and cytokine production. IL-10 mediates the inhibitory function of Siglec-15. Furthermore, Siglec-15 acts as a receptor on macrophages and produces TGF-β upon binding to the sialic acid ligand sialyl-Tn on tumor cells. Elevated levels of IL-10 and TGF-β in the microenvironment further amplify the immunosuppressive effects of Siglec-15. Experimental evidence suggests that Siglec-15 expression can be induced by M-CSF but inhibited by IFN-γ, a mechanism opposite to that of PD-L1 induction.
(Data source: Sun J, et al. Clin Cancer Res. 2021)
Clinical value of Siglec15
Siglec-15, an emerging immune checkpoint inhibitor, is expressed in a variety of tumor cells and is mutually exclusive with PD-L1 expression, suggesting that it may mediate immunosuppression through mechanisms distinct from the PD-1/PD-L1 axis, providing a new target for cancer immunotherapy. Combining Siglec-15 antibodies with anti-PD-1/PD-L1 antibodies may have synergistic effects, enhancing therapeutic efficacy. For example, Nextcure, founded by Professor Chen Lieping, has developed the Siglec-15-targeted drug NC318 (IgG1, kappa).
(Data source: Nextcure official website)
However, based on less-than-satisfactory Phase I/II clinical data from NC318 monotherapy, Nextcure is no longer advancing its NSCLC and ovarian cancer patient cohorts into Phase II trials. This has also provided opportunities for exploratory research into the novel Siglec-15 therapy, accumulating data, validating targets, and identifying potential issues.
