Siglec-15 antibody–GM-CSF chimera suppresses tumor progression via reprogramming tumor-associated macrophages

作者：Zemeng Ma, Xiaoyao Hao, Shuang Qu, Quanli Zhang, Jiajing Luo, Hongyan Li, Jinyu Liu, Wenwen Dai, Jun Li, Shouyong Gu, Dihan Zhu, Mingjiu Chen, Ke Zen · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2025 · DOI：10.1136/jitc-2024-010580 · 被引用次数：7 · 研究领域：Immune cells in cancer、Immunotherapy and Immune Responses、CAR-T cell therapy research

BACKGROUND: T cell exhaustion and limiting immunotherapy efficacy. Both blockade of immune checkpoint molecule Siglec-15 and promotion of granulocyte-macrophage colony-stimulating factor (GM-CSF) have been respectively employed in anticancer immunotherapy. METHODS: Murine CT26 or MC38 cancer cells were used to establish subcutaneous tumor models in BALB/c or C57BL/6 mice. Tumors were treated with anti-Siglec-15 antibody-GM-CSF chimera (anti-S15×GM CSF) or anti-Siglec-15 antibody via intraperitoneal injection. The TME was analyzed by flow cytometry and ELISA for immune cell infiltration and cytokine levels. Biodistribution and half-life of anti-S15×GM CSF were assessed by intravenous injection in tumor-bearing mice, with GM-CSF levels measured by ELISA. Macrophage reprogramming and antigen presentation were evaluated using bone marrow-derived macrophages and human peripheral blood mononuclear cell-derived macrophages treated with anti-S15×GM CSF, followed by flow cytometry and immunofluorescence assays. RESULTS: Here we report that anti-S15×GM CSF displays superior function to suppress the progression of Siglec-15-overexpressing MC38 colon cancer engrafted in mice compared to anti-Siglec-15 antibody or GM-CSF alone. Different from the injected GM-CSF which is distributed broadly in various organs and tissues of mouse, the injected anti-S15×GM CSF is preferentially accumulated in Siglec-15-positive tumor cells and TAMs. Anti-S15×GM CSF not only extends the half-life of GM-CSF i...