Dickkopf-1: A Promising Target for Cancer Immunotherapy.
Dickkopf-1: A Promising Target for Cancer Immunotherapy.
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DOI：
10.3389/fimmu.2021.658097
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发表时间：
2021
影响因子：
7.3
通讯作者：
Zhang G
中科院分区：
文献类型：
--
作者：
Chu HY;Chen Z;Wang L;Zhang ZK;Tan X;Liu S;Zhang BT;Lu A;Yu Y;Zhang G
一系列癌症的临床研究已经检测到患者血清或肿瘤中Wnt拮抗剂Dickkopf-1（DKK 1）水平升高，这通常与预后不良相关。我们使用TCGA数据对DKK 1基因谱的分析也证明了DKK 1在14种癌症中的高表达。许多临床前研究已经证明了DKK 1在体外细胞模型和体内动物模型中的促癌作用。此外，DKK 1显示出调节免疫细胞活性以及免疫抑制性癌症微环境的能力。在20种癌症中，DKK 1的表达水平与髓源性抑制细胞（MDSC）的浸润水平呈正相关，而在这20种癌症中的4种癌症中，DKK 1的表达水平与CD 8 + T细胞呈负相关。新出现的实验证据表明，DKK 1已参与T细胞分化和通过积累MDSC诱导癌症逃避免疫监视。因此，DKK 1已成为肿瘤免疫治疗的一个很有前途的靶点，DKK 1影响肿瘤和免疫细胞的机制受到了极大的关注。这篇综述介绍了快速增长的文献，揭示了DKK 1的促癌和免疫调节活性。此外，通过计算机模拟和功能研究，了解DKK 1不同结构域之间的相互作用，可以进一步阐明DKK 1的作用机制，从而有助于开发出更有效的抗DKK 1药物。
Clinical studies in a range of cancers have detected elevated levels of the Wnt antagonist Dickkopf-1 (DKK1) in the serum or tumors of patients, and this was frequently associated with a poor prognosis. Our analysis of DKK1 gene profile using data from TCGA also proves the high expression of DKK1 in 14 types of cancers. Numerous preclinical studies have demonstrated the cancer-promoting effects of DKK1 in both in vitro cell models and in vivo animal models. Furthermore, DKK1 showed the ability to modulate immune cell activities as well as the immunosuppressive cancer microenvironment. Expression level of DKK1 is positively correlated with infiltrating levels of myeloid-derived suppressor cells (MDSCs) in 20 types of cancers, while negatively associated with CD8+ T cells in 4 of these 20 cancer types. Emerging experimental evidence indicates that DKK1 has been involved in T cell differentiation and induction of cancer evasion of immune surveillance by accumulating MDSCs. Consequently, DKK1 has become a promising target for cancer immunotherapy, and the mechanisms of DKK1 affecting cancers and immune cells have received great attention. This review introduces the rapidly growing body of literature revealing the cancer-promoting and immune regulatory activities of DKK1. In addition, this review also predicts that by understanding the interaction between different domains of DKK1 through computational modeling and functional studies, the underlying functional mechanism of DKK1 could be further elucidated, thus facilitating the development of anti-DKK1 drugs with more promising efficacy in cancer immunotherapy.
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