Eradication of Triple-Negative Breast Cancer Cells by Targeting Glycosylated PD-L1.
Eradication of Triple-Negative Breast Cancer Cells by Targeting Glycosylated PD-L1.
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DOI：
10.1016/j.ccell.2018.01.009
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发表时间：
2018-02-12
期刊：
影响因子：
50.3
通讯作者：
Hung MC
中科院分区：
文献类型：
--
作者：
Li CW;Lim SO;Chung EM;Kim YS;Park AH;Yao J;Cha JH;Xia W;Chan LC;Kim T;Chang SS;Lee HH;Chou CK;Liu YL;Yeh HC;Perillo EP;Dunn AK;Kuo CW;Khoo KH;Hsu JL;Wu Y;Hsu JM;Yamaguchi H;Huang TH;Sahin AA;Hortobagyi GN;Yoo SS;Hung MC
蛋白质糖基化在调节蛋白质定位、稳定性和活性方面提供了蛋白质组学多样性;糖部分是否有助于免疫抑制在很大程度上仍是未知的。在免疫受体糖基化的研究中，我们发现EGF诱导PD-L1和受体程序性细胞死亡蛋白-1（PD-1）相互作用，需要β-1，3-N-乙酰葡糖胺基转移酶（B3 GNT 3）在三阴性乳腺癌中表达。B3 GNT 3的下调增强细胞毒性T细胞介导的抗肿瘤免疫。靶向糖基化PD-L1（gPD-L1）的单克隆抗体可阻断PD-L1/PD-1相互作用并促进PD-L1内化和降解。除了免疫再激活外，药物偶联的gPD-L1抗体还可诱导强效细胞杀伤作用以及对缺乏PD-L1表达的相邻癌细胞的旁观者杀伤作用，且无任何可检测的毒性。我们的工作表明靶向蛋白糖基化是增强免疫检查点治疗的潜在策略。Li等人表明，PD-L1的糖基化对于三阴性乳腺癌（TNBC）中的PD-L1/PD-1相互作用和免疫抑制至关重要。它们产生诱导PD-L1内化的糖基化特异性抗体和在TNBC模型中具有强效抗肿瘤活性的抗体-药物缀合物。
Protein glycosylation provides proteomic diversity in regulating protein localization, stability and activity; it remains largely unknown whether the sugar moiety contributes to immunosuppression. In the study of immune receptor glycosylation, we showed EGF induces PD-L1 and receptor programmed cell death protein-1 (PD-1) interaction, requiring β-1,3-N-acetylglucosaminyl transferase (B3GNT3) expression in triple-negative breast cancer. Downregulation of B3GNT3 enhances cytotoxic T cell-mediated anti-tumor immunity. A monoclonal antibody targeting glycosylated PD-L1 (gPD-L1) blocks PD-L1/PD-1 interaction and promotes PD-L1 internalization and degradation. In addition to immune reactivation, drug-conjugated gPD-L1 antibody induces potent cell-killing effect as well as bystander-killing effect on adjacent cancer cells lacking PD-L1 expression without any detectable toxicity. Our work suggests targeting protein glycosylation as a potential strategy to enhance immune checkpoint therapy. Li et al. show that glycosylation of PD-L1 is essential for PD-L1/PD-1 interaction and immunosuppression in triple-negative breast cancer (TNBC). They generate a glycosylation-specific antibody that induces PD-L1 internalization and an antibody-drug conjugate with potent anti-tumor activities in TNBC models.
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DOI：
10.1038/nrc3239
发表时间：
2012-03-22
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Pardoll DM
通讯作者：
Pardoll DM
影响因子：
16.6
作者：
Perillo, Evan P.;Liu, Yen-Liang;Dunn, Andrew K.
通讯作者：
Dunn, Andrew K.
影响因子：
4.8
作者：
Hennet, T;Dinter, A;Berger, EG
通讯作者：
Berger, EG
影响因子：
45.3
作者：
Nanda, Rita;Chow, Laura Q. M.;Buisseret, Laurence
通讯作者：
Buisseret, Laurence
影响因子：
50.3
作者：
Lim SO;Li CW;Xia W;Cha JH;Chan LC;Wu Y;Chang SS;Lin WC;Hsu JM;Hsu YH;Kim T;Chang WC;Hsu JL;Yamaguchi H;Ding Q;Wang Y;Yang Y;Chen CH;Sahin AA;Yu D;Hortobagyi GN;Hung MC
通讯作者：
Hung MC