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.

唾液酸结合免疫球蛋白样凝集素 15 (Siglec-15) 是一种与程序性细胞死亡配体 1 (PD-L1) 具有序列同源性的免疫检查点分子，主要表达于巨噬细胞和肿瘤细胞上。然而，Siglec-15 诱导的免疫抑制和不良预后是否独立于 PD-L1 仍不清楚。在本研究中，我们收集了135例非小细胞肺癌样本，通过多重免疫荧光染色发现Siglec-15和PD-L1在非小细胞肺癌中的表达是独立的。^{巨噬细胞上的 Siglec-15 (Mφ-Siglec-15) 与 PD-L1 -}非转移性肺腺癌患者的DFS 显着相关 ( p  < 0.05) ，而与 PD-L1 ⁺或肺鳞状细胞癌患者无关。此外，Mφ-Siglec-15 ⁺ PD-L1 ^{-患者的基质 Siglec-15 +}巨噬细胞显着多于 Mφ-Siglec-15 ^- PD-L1 ^-患者（p  = 0.002）。我们进一步发现 Siglec-15 ^{+巨噬细胞向 M2 极化并产生更多的 IL-10，与 PD-L1 -}患者的炎症免疫表型呈负相关，并可能抑制 CD8 ⁺ T 细胞浸润。总之，PD-L1独立的Siglec-15 ⁺巨噬细胞有助于非转移性肺腺癌患者形成免疫抑制微环境，这可能导致较高的复发风险。Siglec-15 可能成为癌症免疫治疗正常化的潜在靶标，使对抗 PD-L1 治疗无效的患者受益。