Modulation of Siglec-7 Signaling Via In Situ-Created High-Affinity cis-Ligands.
Modulation of Siglec-7 Signaling Via In Situ-Created High-Affinity cis-Ligands.
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通过原位创建的高亲和力顺式配体调节 Siglec-7 信号传导。
DOI：
10.1021/acscentsci.1c00064
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发表时间：
2021-08-25
影响因子：
18.2
通讯作者：
Wu P
中科院分区：
文献类型：
--
作者：
Hong S;Yu C;Rodrigues E;Shi Y;Chen H;Wang P;Chapla DG;Gao T;Zhuang R;Moremen KW;Paulson JC;Macauley MS;Wu P
唾液酸结合的免疫球蛋白样凝集素，也被称为Siglecs，最近被指定为糖免疫检查点。通过与肿瘤细胞过度表达的唾液酸糖配体相互作用，天然免疫细胞和获得性免疫细胞上的抑制性Siglecs调节信号级联反应，从而抑制抗肿瘤免疫反应。然而，对这些过程背后的机制的阐明才刚刚开始。我们发现，当人类自然杀伤(NK)细胞攻击肿瘤细胞时，免疫突触处的靶细胞发生糖链重塑。这种重塑既是通过将唾液酸化的多糖从NK细胞转移到靶肿瘤细胞进行的，也是通过从新合成的唾液酸苷在肿瘤细胞上积累而发生的。NK细胞与Siglec-7高亲和力配体的功能化导致了调节Siglec-7调节的NK激活的多方面结果。在高配体水平下，酶促添加的Siglec-7配体通过将Siglec-7重新募集到免疫突触来抑制NK细胞毒作用，而在低配体水平下，酶促添加的Siglec-7配体触发Siglec-7从细胞表面释放到培养液中，从而阻止Siglec-7介导的NK细胞毒性抑制。这些结果表明，NK细胞的糖链工程可能为相关应用提供一种增强NK效应功能的手段。在基于NK的杀伤过程中，随着免疫突触的形成，癌细胞主要通过积累新唾液酸来上调其细胞表面唾液酸化水平，其介导的免疫抑制可以被化学酶产生的顺式高亲和力配体阻断，从而导致更好的肿瘤生长控制。
Sialic acid-binding immunoglobulin-like lectins, also known as Siglecs, have recently been designated as glyco-immune checkpoints. Through their interactions with sialylated glycan ligands overexpressed on tumor cells, inhibitory Siglecs on innate and adaptive immune cells modulate signaling cascades to restrain anti-tumor immune responses. However, the elucidation of the mechanisms underlying these processes is just beginning. We find that when human natural killer (NK) cells attack tumor cells, glycan remodeling occurs on the target cells at the immunological synapse. This remodeling occurs through both the transfer of sialylated glycans from NK cells to target tumor cells and the accumulation of de novo synthesized sialosides on the tumor cells. The functionalization of NK cells with a high-affinity ligand of Siglec-7 leads to multifaceted consequences in modulating a Siglec-7-regulated NK-activation. At high levels of ligand, an enzymatically added Siglec-7 ligand suppresses NK cytotoxicity through the recruitment of Siglec-7 to an immune synapse, whereas at low levels of ligand an enzymatically added Siglec-7 ligand triggers the release of Siglec-7 from the cell surface into the culture medium, preventing a Siglec-7-mediated inhibition of NK cytotoxicity. These results suggest that a glycan engineering of NK cells may provide a means to boost NK effector functions for related applications. With the formation of an immune synapse during an NK-based killing, a cancer cell upregulates its cell-surface sialylation level primarily via an accumulation of neosialylation, and its mediated immune inhibition can be blocked with a cis high-affinity ligand created chemoenzymatically, which resulted in a better tumor growth control.
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影响因子：
11.8
作者：
Macia, Eric;Ehrlich, Marcelo;Kirchhausen, Tomas
通讯作者：
Kirchhausen, Tomas
DOI：
10.1002/anie.202005934
发表时间：
2021-02-15
期刊：
Angewandte Chemie (International ed. in English)
影响因子：
--
作者：
Hong S;Yu C;Wang P;Shi Y;Cao W;Cheng B;Chapla DG;Ma Y;Li J;Rodrigues E;Narimatsu Y;Yates JR 3rd;Chen X;Clausen H;Moremen KW;Macauley MS;Paulson JC;Wu P
通讯作者：
Wu P
DOI：
10.1073/pnas.0400851101
发表时间：
2004-04-20
影响因子：
11.1
作者：
Collins, BE;Blixt, O;Paulson, JC
通讯作者：
Paulson, JC
影响因子：
14.8
作者：
Hudak, Jason E.;Canham, Stephen M.;Bertozzi, Carolyn R.
通讯作者：
Bertozzi, Carolyn R.
DOI：
10.1073/pnas.1409580111
发表时间：
2014-09-30
影响因子：
11.1
作者：
Laubli, Heinz;Pearce, Oliver M. T.;Varki, Ajit
通讯作者：
Varki, Ajit