Beyond antibody fucosylation: α-(1,6)-fucosyltransferase (Fut8) as a potential new therapeutic target for cancer immunotherapy.
Beyond antibody fucosylation: α-(1,6)-fucosyltransferase (Fut8) as a potential new therapeutic target for cancer immunotherapy.
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DOI：
10.1093/abt/tbad004
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发表时间：
2023-04
影响因子：
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通讯作者：
Gao, Wenda
中科院分区：
文献类型：
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作者：
Mao, Changchuin;Li, Jun;Feng, Lili;Gao, Wenda
异常翻译后糖基化是癌症的公认标志。α-（1，6）-岩藻糖基转移酶（Fut 8）介导的核心岩藻糖基化改变是肿瘤聚糖模式的关键变化之一，有助于肿瘤转化、肿瘤转移和免疫逃避。Fut 8表达和活性的增加与许多类型的人类癌症相关，包括肺癌、乳腺癌、黑色素瘤、肝癌、结直肠癌、卵巢癌、前列腺癌、甲状腺癌和胰腺癌。在动物模型中，通过基因敲除、RNA干扰和小分子类似物抑制剂抑制Fut 8活性导致肿瘤生长/转移减少，免疫检查点分子PD-1、PD-L1/2和B7-H3下调，以及肿瘤微环境抑制状态逆转。虽然生物学领域长期以来从使用FUT 8 −/−中国仓鼠卵巢细胞生产IgG中受益匪浅，这些IgG具有大大增强的抗体依赖性细胞毒性效应器功能，用于治疗，但直到最近几年才研究了Fut 8本身在癌症生物学中的作用。在本文中，我们总结了由Fut 8介导的核心岩藻糖基化调节的癌症发展中涉及的原癌机制，并呼吁在这一领域进行更多的研究，其中修改负责核心岩藻糖基化的唯一酶的活性可能会在对抗癌症，感染和其他免疫相关疾病方面带来有益的惊喜。 由Fut 8催化的核心岩藻糖基化在生长因子信号传导、癌细胞转移和免疫功能调节中起关键作用。除了在CHO细胞中敲除FUT 8以产生具有增强的ADCC/ADCP的无岩藻糖基化治疗性IgG的工业关注之外，该酶本身是癌症免疫疗法的潜在治疗靶标。
Aberrant post-translational glycosylation is a well-established hallmark of cancer. Altered core fucosylation mediated by α-(1,6)-fucosyltransferase (Fut8) is one of the key changes in tumor glycan patterns that contributes to neoplastic transformation, tumor metastasis, and immune evasion. Increased Fut8 expression and activity are associated with many types of human cancers, including lung, breast, melanoma, liver, colorectal, ovarian, prostate, thyroid, and pancreatic cancer. In animal models, inhibition of Fut8 activity by gene knockout, RNA interference, and small analogue inhibitors led to reduced tumor growth/metastasis, downregulation of immune checkpoint molecules PD-1, PD-L1/2, and B7-H3, and reversal of the suppressive state of tumor microenvironment. Although the biologics field has long benefited tremendously from using FUT8−/− Chinese hamster ovary cells to manufacture IgGs with greatly enhanced effector function of antibody-dependent cellular cytotoxicity for therapy, it is only in recent years that the roles of Fut8 itself in cancer biology have been studied. Here, we summarize the pro-oncogenic mechanisms involved in cancer development that are regulated by Fut8-mediated core fucosylation, and call for more research in this area where modifying the activity of this sole enzyme responsible for core fucosylation could potentially bring rewarding surprises in fighting cancer, infections, and other immune-related diseases. Core fucosylation catalyzed by Fut8 plays a critical role in growth factor signaling, cancer cell metastasis, and immune function regulation. Apart from industrial attention on knocking out FUT8 in CHO cells for producing afucosylated therapeutic IgGs with enhanced ADCC/ADCP, the enzyme itself is a potential therapeutic target for cancer immunotherapy.