Siglec-15 on macrophages suppress the immune microenvironment in patients with PD-L1 negative non-metastasis lung adenocarcinoma

Abstract Sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) is an immune checkpoint molecule with sequence homology to programmed cell death ligand 1 (PD-L1), which is mainly expressed on macrophages and tumor cells. However, whether Siglec-15-induced immunosuppression and poor prognosis are independent of PD-L1 remains unclear. In this study, we collected samples of 135 non-small cell lung cancers and found that Siglec-15 and PD-L1 expression were independent in non-small cell lung cancer by multiple immunofluorescence staining. Siglec-15 on macrophages (Mφ-Siglec-15) was significantly associated with DFS ( p < 0.05) in PD-L1 − patients with non-metastasis lung adenocarcinoma, not in PD-L1 + or lung squamous cell carcinoma patients. Moreover, stromal Siglec-15 + macrophages of Mφ-Siglec-15 + PD-L1 − patients were significantly more than those of Mφ-Siglec-15 − PD-L1 − patients ( p = 0.002). We further found that Siglec-15 + macrophages polarized toward M2 and produced more IL-10, negatively associated with inflamed immunophenotype in PD-L1 − patients and may inhibit CD8 + T cells infiltration. In conclusion, PD-L1-independent Siglec-15 + macrophages contribute to the formation of an immunosuppressive microenvironment in non-metastasis lung adenocarcinoma patients, which may cause a higher risk of recurrence. Siglec-15 could be a potential target for normalizing cancer immunotherapy, benefiting patients who fail to respond to anti-PD-L1 therapy.