Siglec-15 and its glycan ligands in tumor-associated macrophage biology and immunotherapy

Siglec-15 has recently emerged as an important regulator at the interface of glyco-immunology and cancer-immunology. The transmembrane immune receptor links cancer-associated glycosylation to immune suppression in the tumor microenvironment (TME). Siglec-15 signals through the adapter protein DAP12, using its immunoreceptor tyrosine-based activation motif to induce signaling. While typically expressed by osteoclasts, increased expression of Siglec-15 holds critical implications for tumor-associated macrophages (TAMs). Current evidence suggests that Siglec-15 modulates anti-tumor immunity via reprogramming of TAMs toward an M2-like, protumorigenic phenotype characterized by direct suppression of effector T cells through interleukin-10 and transforming growth factor-β production. Identification of its ligands is ongoing, but Siglec-15 has been shown to interact both with N-linked and O-linked sialoglycans and binding can be enhanced by glycan sulfation. In addition, ligand specificity appears to be determined by glycan presentation on specific glycoprotein scaffolds, among others found in CD44 and CD11b. Siglec-15 expression is detected in many solid and hematological cancers and has been shown to negatively correlate with programmed cell death protein 1/programmed death-ligand 1 expression in several studies, providing rationale for targeting this Siglec. Defining the physiological and cancer-associated ligands of Siglec-15 is critical for understanding its signaling and the functional consequences thereof. Blocking antibodies for Siglec-15 show promising effects in (pre)clinical studies. Here, we provide an overview of current insights into the glycan ligands of Siglec-15, discuss its role in controlling TAMs phenotypes, and functions in the TME. Moreover, we discuss current therapeutic strategies aimed at targeting Siglec-15 and its glycan ligands in cancer immunotherapy.