肿瘤细胞治疗研究
英文原题：Targeting GD2 with naxitamab overcomes GD3 synthase-driven immune suppression in triple-negative breast cancer.
神经节苷脂是一类酸性鞘糖脂，参与细胞黏附、信号转导和肿瘤进展。
神经节苷脂是一类参与细胞黏附、信号转导和肿瘤进展的酸性糖鞘脂。GD3 合成酶（GD3S/ST8SIA1）是神经节苷脂生物合成中的关键酶，在多种癌症中表达上调，包括三阴性乳腺癌（TNBC）中的 GD2 + 乳腺癌干细胞样细胞（BCSCs）。在本研究中，我们证实了 GD3S 的免疫调节作用，并鉴定出全人源化抗 GD2 抗体 naxitamab 可作为靶向 GD3S/GD2 + 乳腺肿瘤的治疗工具。GD3S 表达与免疫检查点激活及免疫浸润减少相关。在乳腺癌（BC）细胞中，GD3S 异位过表达抑制了巨噬细胞介导的吞噬作用以及 NK 细胞或 T 细胞诱导的细胞死亡。脂质组学分析鉴定出 GD2 是 TNBC 细胞中 GD3S 过表达后发生变化的主要效应神经节苷脂。此外，在 TNBC 患者来源的异种移植模型中，naxitamab 治疗增强了巨噬细胞介导的吞噬作用和 NK 细胞介导的细胞毒性，并抑制了肿瘤生长。我们的研究结果凸显了 GD3S 驱动的免疫抑制作用，并提供了概念验证，即 naxitamab 联合活化的免疫细胞可逆转这一效应，揭示了其在治疗 GD2 + BC 方面的治疗潜力。
Gangliosides are acidic glycosphingolipids involved in cell-adhesion, signal-transduction and tumor progression. GD3 synthase (GD3S/ST8SIA1), a key enzyme in ganglioside biosynthesis, is upregulated in many cancers, including GD2 + breast cancer stem-like cells (BCSCs) in triple-negative breast cancer (TNBC). Here, we demonstrated the immunomodulatory role of GD3S and identified a fully humanized anti-GD2 antibody, naxitamab, as a therapeutic tool to target GD3S/GD2 + breast tumors. GD3S expression correlates with immune-checkpoint activation and reduced immune infiltration. Ectopic overexpression of GD3S suppressed macrophage-mediated phagocytosis and NK or T cell-induced cell death in BC cells. Lipidomic analysis identified GD2 as the major effector ganglioside altered upon GD3S overexpression in TNBC cells. Moreover, naxitamab treatment enhanced macrophage-mediated phagocytosis and NK cell-mediated cytotoxicity and inhibited tumor growth in a TNBC patient-derived xenograft model. Our findings highlight GD3S-driven immunosuppression and provide proof-of-concept that naxitamab, with activated immune cells, reverses this effect, revealing its therapeutic potential in treating GD2 + BC.
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