School of Medicine, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058 Zhejiang, China.
Department of General Surgery, Sir Run Run Shaw Hospital, The Medicine School of Zhejiang University, Hangzhou, China.
Oxid Med Cell Longev. 2022 Sep 5;2022:3341038. doi: 10.1155/2022/3341038. eCollection 2022.
Tumor-associated macrophages especially M2 phenotype macrophages play an important role in tumor progression and the formation of immunosuppressive tumor microenvironment. Previous studies indicated that infiltration of a large number of M2-macrophages was positively associated with a low survival rate and poor prognosis of patients with pancreatic ductal cancer. However, the mechanisms responsible for M2-macrophage polarization remain unclear. Recently, Siglec-15 appears as an emerging target for the normalization of the tumor immune microenvironment. Hence, we detected the Sigelc-15 expression on macrophages by using qPCR and Western blot assay and found that the expression of Siglec-15 was upregulated on M2 macrophages induced by IL-4 and conditioned media from pancreatic ductal cancer. In addition, after knocking out Siglec-15, the expression of M2 phenotype macrophage biomarkers such as Arg1 and CD206 was significantly downregulated. Besides, in our study we also found that Siglec-15 could upregulate the glycolysis of macrophage possibly by interacting with Glut1 to regulate the M2-macrophage polarization. The regulation was also partly dependent on STING, and Glut1-related glycose metabolism was involved in regulating cGAS/STING signaling. When utilizing a subcutaneous transplantation mouse model, we observed that knocking out of Siglec-15 or co-injecting tumor cells with macrophage from Siglec-15 KO mice could significantly inhibit the growth of subcutaneous tumors in mice. Taken together, these findings suggest that Siglec-15 is essential for the M2-macrophage polarization to shape an immune suppressive tumor microenvironment in pancreatic cancer and makes it an attractive target for pancreatic cancer immunotherapy.
肿瘤相关巨噬细胞，尤其是 M2 表型巨噬细胞，在肿瘤进展和免疫抑制性肿瘤微环境的形成中发挥重要作用。先前的研究表明，大量 M2 巨噬细胞的浸润与胰腺导管癌患者的低生存率和预后不良呈正相关。然而，导致 M2 巨噬细胞极化的机制尚不清楚。最近，Siglec-15 似乎成为了肿瘤免疫微环境正常化的新兴靶点。因此，我们通过 qPCR 和 Western blot 检测了巨噬细胞上 Sigelc-15 的表达，发现 Siglec-15 在 IL-4 诱导的 M2 巨噬细胞和胰腺导管癌细胞条件培养基中表达上调。此外，敲除 Siglec-15 后，M2 表型巨噬细胞标志物 Arg1 和 CD206 的表达显著下调。此外，在我们的研究中，我们还发现 Siglec-15 可能通过与 Glut1 相互作用来上调巨噬细胞的糖酵解，从而调节 M2 巨噬细胞极化。这种调节部分依赖于 STING，Glut1 相关糖代谢参与调节 cGAS/STING 信号通路。在利用皮下移植小鼠模型时，我们观察到敲除 Siglec-15 或与 Siglec-15 KO 小鼠来源的巨噬细胞共注射肿瘤细胞可显著抑制小鼠皮下肿瘤的生长。总之，这些发现表明 Siglec-15 对于 M2 巨噬细胞极化形成胰腺癌细胞中的免疫抑制性肿瘤微环境至关重要，使其成为胰腺癌症免疫治疗的一个有吸引力的靶点。
