Significance of Siglec-15 expression in colorectal cancer: association with advanced disease stage and fewer tumor-infiltrating lymphocytes

Siglec-15, a novel immune suppressor, is upregulated in many human cancers. The aim of this study was to explore the expression of Siglec-15 in colorectal cancer (CRC), and investigate whether Siglec-15 could be a potential target for cancer immunotherapy in patients with CRC. We performed immunohistochemical analyses of Siglec-15 on a cohort of 805 patients with CRC and made comparisons between clinicopathological characteristics, PD-L1 expression, CD3, CD8, CD45RO tumor-infiltrating lymphocytes (TILs), and prognosis. We found that Siglec-15 expression was commonly detected in tumor cells (48.3%) and tumor-associated stromal cells (33.4%), and was more frequently observed than PD-L1 expression in tumor cells. In contrast, Siglec-15 expression was weakly and scarcely found in normal mucosa (13%). Siglec-15 overexpression in tumor cells was associated with advanced TNM stage (p = 0.020). Co-expression of Siglec-15 and PD-L1 in tumor cells was found in 14.4% of patients, and Siglec-15 expression was detected in almost half of PD-L1 negative cases. Elevated Siglec-15 expression in tumor and stromal cells was associated with sparser CD45RO and CD8 TILs (p = 0.035 and p = 0.004, respectively). The expression of Siglec-15 did not have prognostic significance. In summary, compared to PD-L1, Siglec-15 protein expression is more prevalent in CRC and is associated with advanced disease stage and fewer TILs. These findings support Siglec-15 as a potential cancer immunotherapy target, in addition to PD-1/PD-L1 inhibitors, in patients with CRC.