Macrophage N-glycan processing inhibits antibody-dependent cellular phagocytosis.
Macrophage N-glycan processing inhibits antibody-dependent cellular phagocytosis.
复制标题
巨噬细胞 N-聚糖加工抑制抗体依赖性细胞吞噬作用。
DOI：
10.1093/glycob/cwad078
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发表时间：
2023
期刊：
影响因子：
4.3
通讯作者：
Barb,AdamW
中科院分区：
文献类型：
--
作者：
DíazdeLeón,JesúsSAguilar;Aguilar,Isaac;Barb,AdamW
调节巨噬细胞效应器功能的因子是优化抗体介导的治疗效果的潜在靶点。巨噬细胞是一种髓系细胞，能够吞噬和摧毁患病或受损的靶细胞。与靶细胞表面结合的抗体可与巨噬细胞Fcγ受体(FcγR)结合，诱导抗体依赖的细胞吞噬作用，这一过程有助于抗肿瘤抗体介导的治疗。相反，巨噬细胞ADCP对T细胞的凋亡也与肿瘤环境中的耐受性有关。在这里，我们评估了天冬酰胺(N)连接的多糖在来源于原代人类单核细胞的巨噬细胞功能中的作用。用N-糖链加工抑制剂Kifunensine处理的巨噬细胞表现出更强的靶向结合和抗体包被的靶细胞的ADCP。Kifunensine处理增加了利妥昔单抗包被的Raji B细胞和曲妥珠单抗包被的SKBR3细胞的ADCP。在大多数供者中，抑制CD6 4/FCγRI的作用最大，其次是CD32/FCγRII，然后是CD16/FCγRIII。Kifunensine治疗也提高了CD16的抗体结合亲和力。包括Siglec-9、CD32a和LAIR-1在内的磷酸化免疫受体丰度的差异与ADCP的增加有关。这些结果表明N-葡聚糖加工对巨噬细胞效应功能具有调节作用。
Factors regulating macrophage effector function represent potential targets to optimize the efficacy of antibody-mediated therapies. Macrophages are myeloid cells capable of engulfing and destroying diseased or damaged target cells. Antibodies binding to the target cell surface can engage macrophage Fc gamma receptors (FcγRs) to elicit antibody-dependent cellular phagocytosis (ADCP), a process that contributes to treatments mediated by anti-tumor antibodies. Conversely, macrophage ADCP of apoptotic T cells is also linked to tolerance in the tumor environment. Here we evaluated the role of asparagine(N)-linked glycans in the function of macrophages derived from primary human monocytes. Macrophages treated with kifunensine, an inhibitor of N-glycan processing, exhibited greater target binding and ADCP of antibody-coated target cells. Kifunensine treatment increased ADCP of both rituximab-coated Raji B cells and trastuzumab-coated SKBR3 cells. ADCP required FcγRs; inhibiting CD64 / FcγRI led to the greatest reduction, followed by CD32 / FcγRII and then CD16 / FcγRIII in most donors. Kifunensine treatment also increased the antibody-binding affinity of CD16. Differences in the abundance of phosphorylated immune receptors, including Siglec-9, CD32a, and LAIR-1 correlated with the increased ADCP. These results demonstrate that N-glycan processing regulates macrophage effector function.