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.