Chu Hang Yin, Chen Zihao, Wang Luyao, Zhang Zong-Kang, Tan Xinhuan, Liu Shuangshuang, Zhang Bao-Ting, Lu Aiping, Yu Yuanyuan, Zhang Ge
Law Sau Fai Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.
Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery, Hong Kong, China.
Front Immunol. 2021 May 20;12:658097. doi: 10.3389/fimmu.2021.658097. eCollection 2021.
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 cell models and 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.
一系列癌症的临床研究发现，患者血清或肿瘤中Wnt拮抗剂Dickkopf-1（DKK1）水平升高，这通常与预后不良相关。我们利用TCGA数据对DKK1基因谱进行的分析也证实了DKK1在14种癌症中高表达。大量临床前研究已在细胞模型和动物模型中证实了DKK1的促癌作用。此外，DKK1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，DKK1的表达水平与髓系来源抑制细胞（MDSC）的浸润水平呈正相关，而在这20种癌症中的4种中，与CD8 T细胞呈负相关。新出现的实验证据表明，DKK1通过积累MDSC参与了T细胞分化和癌症逃避免疫监视的诱导。因此，DKK1已成为癌症免疫治疗的一个有前景的靶点，DKK1影响癌症和免疫细胞的机制受到了极大关注。本综述介绍了迅速增长的一批文献，揭示了DKK1的促癌和免疫调节活性。此外，本综述还预测，通过计算建模和功能研究了解DKK1不同结构域之间的相互作用，可进一步阐明DKK1的潜在功能机制，从而促进在癌症免疫治疗中具有更有前景疗效的抗DKK1药物的开发。
