{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T05:57:51Z","timestamp":1790834271611,"version":"4.1.0"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,5,10]],"date-time":"2023-05-10T00:00:00Z","timestamp":1683676800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Sialic acid-binding immunoglobulin-like lectin-15 (Siglec-15) was reported to be a novel immune checkpoint molecule comparable to programmed cell death 1 ligand 1 (PD-L1). However, its expression profile and immunosuppressive mechanisms in the glioma tumor microenvironment have not yet been fully explored.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objectives<\/jats:title><jats:p>To identify the expression profile and potential function of Siglec-15 in glioma tumor microenvironment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We investigated Siglec-15 and PD-L1 expression in tumor tissues from 60 human glioma patients and GL261 tumor models. Next, Siglec-15 knockout macrophages and mice were used to elucidate the immunosuppressive mechanism of Siglec-15 impacting macrophage function.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Our results demonstrated that high levels of Siglec-15 in tumor tissues was positively correlated with poor survival in glioma patients. Siglec-15 was predominantly expressed on peritumoral CD68<jats:sup>+<\/jats:sup> tumor-associated macrophages, which accumulated to the highest level in grade II glioma and then declined as grade increased. The Siglec-15 expression pattern was mutually exclusive with that of PD-L1 in glioma tissues, and the number of Siglec-15<jats:sup>+<\/jats:sup>PD-L1<jats:sup>-<\/jats:sup> samples (n = 45) was greater than the number of Siglec-15<jats:sup>-<\/jats:sup>PD-L1<jats:sup>+<\/jats:sup> samples (n = 4). The dynamic change in and tissue localization of Siglec-15 expression were confirmed in GL261 tumor models. Importantly, after <jats:italic>Siglec15<\/jats:italic> gene knockout, macrophages exhibited enhanced capacities for phagocytosis, antigen cross-presentation and initiation of antigen-specific CD8<jats:sup>+<\/jats:sup> T-lymphocyte responses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our findings suggested that Siglec-15 could be a valuable prognostic factor and potential target for glioma patients. In addition, our data first identified dynamic changes in Siglec-15 expression and distribution in human glioma tissues, indicating that the timing of Siglec-15 blockade is critical to achieve an effective combination with other immune checkpoint inhibitors in clinical practice.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2023.1159085","type":"journal-article","created":{"date-parts":[[2023,5,10]],"date-time":"2023-05-10T18:35:38Z","timestamp":1683743738000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":20,"title":["Dynamic change in Siglec-15 expression in peritumoral macrophages confers an immunosuppressive microenvironment and poor outcome in 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