Glycocalyx engineering reveals a Siglec-based mechanism for NK cell immunoevasion.
Glycocalyx engineering reveals a Siglec-based mechanism for NK cell immunoevasion.
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DOI：
10.1038/nchembio.1388
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发表时间：
2014-01
影响因子：
14.8
通讯作者：
Bertozzi, Carolyn R.
中科院分区：
文献类型：
--
作者：
Hudak, Jason E.;Canham, Stephen M.;Bertozzi, Carolyn R.
细胞表面唾液酸的增加是许多肿瘤类型共有的特征。已经观察到唾液酸化过度和免疫保护之间的相关性，但是很少有假说提供了对这种免疫抑制现象的机制性理解。在这里，我们表明癌细胞上增加唾液酸化聚糖通过募集Siglec-7抑制人NK细胞活化。这些发现的关键是使用磷脂末端官能化的糖共聚物，其能够将合成定义的聚糖引入到癌细胞表面上。在多种肿瘤类型中，癌细胞的唾液酸化状态重塑通过Siglec-7参与影响对NK细胞细胞毒性的易感性。这些结果支持一种模型，其中高唾液酸化通过增加Siglec配体在NK免疫监视的压力下为肿瘤细胞提供选择性优势。我们还利用这一发现来保护同种异体和异种原代细胞免受NK介导的杀伤，这表明Siglecs作为细胞移植疗法中的治疗靶标的潜力。
The increase of cell surface sialic acid is a characteristic shared by many tumor types. A correlation between hypersialylation and immunoprotection has been observed, but few hypotheses have provided a mechanistic understanding of this immunosuppressive phenomenon. Here, we show that increasing sialylated glycans on cancer cells inhibits human NK cell activation through the recruitment of Siglec-7. Key to these findings was the use of glycopolymers end-functionalized with phospholipids, which enable the introduction of synthetically defined glycans onto cancer cell surfaces. Remodeling the sialylation status of cancer cells affected the susceptibility to NK cell cytotoxicity via Siglec-7 engagement in a variety of tumor types. These results support a model in which hypersialylation offers a selective advantage to tumor cells under pressure from NK immunosurveillance by increasing Siglec ligands. We also exploited this finding to protect allogeneic and xenogeneic primary cells from NK-mediated killing suggesting the potential of Siglecs as therapeutic targets in cell transplant therapy.
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影响因子：
15
作者：
Belardi, Brian;O'Donoghue, Geoff P.;Smith, Adam W.;Groves, Jay T.;Bertozzi, Carolyn R.
通讯作者：
Bertozzi, Carolyn R.
影响因子：
4.4
作者：
Cohen, Merav;Elkabets, Moshe;Lichtenstein, Rachel G.
通讯作者：
Lichtenstein, Rachel G.
影响因子：
4.4
作者：
Forte, P;Lilienfeld, BG;Seebach, JD
通讯作者：
Seebach, JD
DOI：
10.1084/jem.190.6.793
发表时间：
1999-09-20
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Falco M;Biassoni R;Bottino C;Vitale M;Sivori S;Augugliaro R;Moretta L;Moretta A
通讯作者：
Moretta A
影响因子：
4.3
作者：
Kawasaki, Yoshihide;Ito, Akihiro;Arai, Yoichi
通讯作者：
Arai, Yoichi