FUT8-mediated aberrant N-glycosylation of B7H3 suppresses the immune response in triple-negative breast cancer.
FUT8-mediated aberrant N-glycosylation of B7H3 suppresses the immune response in triple-negative breast cancer.
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FUT8 介导的 B7H3 异常 N-糖基化抑制三阴性乳腺癌的免疫反应
DOI：
10.1038/s41467-021-22618-x
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发表时间：
2021-05-11
影响因子：
16.6
通讯作者：
Deng R
中科院分区：
文献类型：
--
作者：
Huang Y;Zhang HL;Li ZL;Du T;Chen YH;Wang Y;Ni HH;Zhang KM;Mai J;Hu BX;Huang JH;Zhou LH;Yang D;Peng XD;Feng GK;Tang J;Zhu XF;Deng R
大多数三阴性乳腺癌（TNBC）患者对抗PD 1/PDL 1免疫治疗无应答，表明有必要探索免疫检查点靶点。B7 H3是一种高度糖基化的蛋白质。然而，B7 H3糖基化调节的机制以及糖部分是否有助于免疫抑制尚不清楚。在这里，我们鉴定了异常的B7 H3糖基化，并表明NXT基序位点处的B7 H3的N-糖基化是其在TNBC肿瘤中的蛋白质稳定性和免疫抑制的原因。岩藻糖基转移酶FUT 8催化N-聚糖处的B7 H3核心岩藻糖基化以维持其高表达。FUT 8的敲低挽救了TNBC细胞中糖基化B7 H3介导的免疫抑制功能。FUT 8过表达介导的异常B7 H3糖基化在TNBC患者中可能具有生理学重要性和临床相关性。值得注意的是，核心岩藻糖基化抑制剂2F-Fuc和抗PDL 1的组合导致B7 H3阳性TNBC肿瘤中的治疗功效增强。这些发现表明，靶向FUT 8-B7 H3轴可能是改善TNBC患者抗肿瘤免疫应答的有前景的策略。
Most patients with triple negative breast cancer (TNBC) do not respond to anti-PD1/PDL1 immunotherapy, indicating the necessity to explore immune checkpoint targets. B7H3 is a highly glycosylated protein. However, the mechanisms of B7H3 glycosylation regulation and whether the sugar moiety contributes to immunosuppression are unclear. Here, we identify aberrant B7H3 glycosylation and show that N-glycosylation of B7H3 at NXT motif sites is responsible for its protein stability and immunosuppression in TNBC tumors. The fucosyltransferase FUT8 catalyzes B7H3 core fucosylation at N-glycans to maintain its high expression. Knockdown of FUT8 rescues glycosylated B7H3-mediated immunosuppressive function in TNBC cells. Abnormal B7H3 glycosylation mediated by FUT8 overexpression can be physiologically important and clinically relevant in patients with TNBC. Notably, the combination of core fucosylation inhibitor 2F-Fuc and anti-PDL1 results in enhanced therapeutic efficacy in B7H3-positive TNBC tumors. These findings suggest that targeting the FUT8-B7H3 axis might be a promising strategy for improving anti-tumor immune responses in patients with TNBC.
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影响因子：
16.6
作者：
Fang P;Ji Y;Silbern I;Doebele C;Ninov M;Lenz C;Oellerich T;Pan KT;Urlaub H
通讯作者：
Urlaub H
DOI：
10.1073/pnas.0405025101
发表时间：
2004-08-24
影响因子：
11.1
作者：
Castriconi, R;Dondero, A;Bottino, C
通讯作者：
Bottino, C
影响因子：
3.8
作者：
Jezequel, Pascal;Campone, Mario;Campion, Loic
通讯作者：
Campion, Loic
影响因子：
4.4
作者：
Hu, Zhiyuan;Fan, Cheng;Perou, Charles M.
通讯作者：
Perou, Charles M.
DOI：
10.1016/j.bbrc.2009.11.098
发表时间：
2010-01-01
影响因子：
3.1
作者：
Kamei, Naoki;Fukui, Rie;Tsuji, Takashi
通讯作者：
Tsuji, Takashi