2.8 Siglec-15 (Sialic acid-binding Ig-like lectin 15)
Sialic acid-binding Ig-like lectin 15 (Siglec-15) is an emerging immune checkpoint receptor that has gained attention for its role in regulating immune responses within the TME [208]. Dr. Takashi Angata characterized Siglec-15 in 2007, identifying it as one of the most evolutionarily conserved Siglecs in vertebrates, distinctively distant from other members of its family phylogenetically [209]. It belongs to the Siglec (sialic acid-binding immunoglobulin-like lectin) family of proteins, which are characterized by their ability to bind to sialic acids present on glycoproteins and glycolipids [209, 210]. It contains only a V-set immunoglobulin (Ig) structural domain and a C2-set immunoglobulin, which has a high structural similarity to PD-L1 [208].
Siglec-15 is predominantly expressed on tumor-associated macrophages (TAMs) and other myeloid cells within the TME. It is also expressed on cancer cells [211, 212]. TAMs are a crucial component of the innate immune system and play diverse roles in tumor progression, including promoting immunosuppression and facilitating tumor growth [213].. The expression of Siglec-15 on TAMs contributes to the creation of an immunosuppressive TME by dampening anti-tumor immune responses. Chen et al. conducted research on Siglec-15 expression in tumor tissues from 60 human glioma patients and GL261 tumor models. Their findings indicated that elevated Siglec-15 levels in tumor tissues were associated with poorer survival outcomes in glioma patients. Additionally, Siglec-15 was mainly expressed on peritumoral CD68+ tumor-associated macrophages [214]. Activated macrophages expressing Siglec-15 have been shown to enhance TGF-β secretion via the DAP12-Syk pathway and suppress CD4+ and CD8+ T cell activity by binding to their respective receptors. This process contributes to tumor progression by modulating intratumoral microenvironments through TGF-β. [215]. Another study found that inhibiting Siglec-15 expression in cultured osteosarcoma cells reduced the DUSP1-mediated suppression of p38/MAPK and JNK/MAPK expression. Additionally, DUSP1 overexpression facilitated the proliferation, migration, and invasion of osteosarcoma cells. The group concluded that Siglec-15 promotes the malignant progression of osteosarcoma cells by suppressing DUSP1-mediated suppression of the MAPK pathway [216].  Data analyzed from 13 observational studies involving 1,376 patients revealed that Siglec-15 expression is significantly associated with poor outcomes in human solid tumors. However the authors of this meta-analysis concluded that further studies are needed to determine the prognostic value of Siglec-15 in solid tumors [217]. Bioinformatics analyses revealed that elevated Siglec-15 levels are associated with poor clinical prognosis and shorter recurrence times in glioma patients. and high Siglec15 expression was related to M2 tumor-associated macrophages (TAMs), N2 tumor-infiltrating neutrophils and suppressive tumor immune microenvironment [218]. However, some studies have observed an opposite or equivocql relationship regarding prognosis. According to Chen et al., positivity for Siglec-15 is associated with a good prognosis in pancreatic ductal adenocarcinoma (PDAC) [211]. Shafi et al., in their study using quantitative immunofluorescence (QIF), assessed Siglec-15 expression in lung, breast, head and neck squamous, and bladder cancers. They observed increased expression in both tumor and immune cells. Importantly, they found that Siglec-15 expression was not prognostic for either overall survival (OS) or progression-free survival (PFS) [212].
The ligands of Siglec-15 are less characterized. The interaction of Siglec-15 with its ligands (CD44, CD11b,  Muc5B) or other components of the T cell receptor (TCR) and immune synapse, triggers inhibitory signals that suppress immune activation and effector functions [219, 220]. This includes reducing the production of pro-inflammatory cytokines and inhibiting the cytotoxic activity of T cells and NK cells against tumor cells. Moreover, Siglec-15 expression on TAMs can promote their polarization towards an M2-like phenotype, which further supports tumor growth and immune evasion [221]. Siglec15 interacts with sialic acids expressed on pancreatic ductal adenocarcinoma (PDAC) cells, particularly α-2,3-linked sialic acids, to induce SYK phosphorylation in tumor-associated macrophages (TAMs). This interaction further promotes the production of immunoregulatory cytokines and chemokines by TAMs. In vivo studies have shown that SIglec15-positive TAMs exhibit an M2-like phenotype, which accelerates tumor growth and contributes to an immunosuppressive microenvironment. These effects were significantly reduced when a SYK inhibitor was administered, indicating the potential therapeutic benefit of targeting this pathway [222].
In the context of cancer, targeting Siglec-15 has emerged as a potential therapeutic strategy to reprogram the immunosuppressive TME and enhance anti-tumor immunity [222, 223]. Siglec15 is rising as a promising immunotherapeutic target in glial, bladder, breast, gastric, colon and pancreatic cancers.  Preclinical studies have shown that blocking Siglec-15 using monoclonal antibodies or other inhibitors can alleviate immune suppression and promote immune surveillance against cancer cells. A study by Sun et al documented that Siglec-15 blocking mAbs significantly slowed down the tumor growth in mice [224]. According to a study by Wang et al., genetic ablation or antibody blockade of Siglec-15 enhances anti-tumor immunity within the TME and inhibits tumor growth in certain mouse models. [208].
By inhibiting Siglec-15, researchers also aim to shift TAMs towards an M1-like phenotype, which is associated with anti-tumor activity and the promotion of T cell-mediated immune responses [222].
Clinical trials are underway to evaluate the safety, efficacy, and optimal dosing of Siglec-15 inhibitors as monotherapy and in combination with other immunotherapies or standard treatments. Considering the preclinical functional activity and expression pattern of Siglec-15, the safety of a humanized anti-Siglec-15 monoclonal antibody, designated NC318, was assessed in a phase I clinical trial (NCT03665285) involving patients with advanced solid tumors, Result demonstrated improved outcomes for those treated with the Siglec-15 inhibitor NC318 (NCT03665285). A Phase 2 clinical trial evaluating the combination of the anti-Siglec-15 antibody NC318 with pembrolizumab (NCT04699123) has shown promising clinical activity in patients with advanced non-small cell lung cancer (NSCLC) refractory to PD-1 axis inhibitors.