• Siglec15 is xpressed on a subset of macrophages and preferentially recognizes the sialyl-Tn (sTn) antigen, a tumor-associated glycan structure. Upregulation of S15 in tumor cells and tumor-associated macrophages (TAM), leading to severe immunosuppression in tumor microenvironment (TME). As an immune checkpoint, inhibitors of Siglec 15 activate anti-tumor immunity by blocking tumor-mediated suppression of T cells.
• Siglec15 mediates tumor microenvironment through TGF-β and promotes tumor progression: M-CSF secreted by tumor cells induces monocytes to differentiate into macrophages and produce Siglec15, which interacts with sialic acid Tn antigen to activate the DAP12-Syk pathway and stimulate macrophages to produce TGF-β.

Gene targeting strategy for B-hSIGLEC15 mice(C). The exons 2-4 of mouse Siglec15 gene that encode extracellular domain are replaced by human counterparts in B-hSIGLEC15 mice. The genomic region of mouse Siglec15 gene that encodes signal peptide, transmembrane domain and cytoplasmic portion is retained. The promoter, 5’UTR and 3’UTR region of the mouse gene are also retained. The chimeric SIGLEC15 expression is driven by endogenous mouse Siglec15 promoter, while mouse Siglec15 gene transcription and translation will be disrupted.

Strain specific analysis of SIGLEC15 mRNA expression in wild-type BALB/cCrSlcNifdc mice and B-hSIGLEC15 mice(C) by RT-PCR. Ovary RNA was isolated from wild-type BALB/cCrSlcNifdc mice (+/+) and homozygous B-hSIGLEC15 mice(C) (H/H), and then cDNA libraries were synthesized by reverse transcription, followed by PCR with human SIGLEC15 primers. Mouse Siglec15 mRNA was detectable only in wild-type BALB/cCrSlcNifdc mice. Human SIGLEC15 mRNA was exclusively detectable in homozygous B-hSIGLEC15 mice(C) but not in wild-type mice.