Dickkopf-related protein 1 (Dkk1) regulates the accumulation and function of myeloid derived suppressor cells in cancer.
Dickkopf-related protein 1 (Dkk1) regulates the accumulation and function of myeloid derived suppressor cells in cancer.
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DOI：
10.1084/jem.20150950
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发表时间：
2016-05-02
期刊：
影响因子：
--
通讯作者：
Faccio R
中科院分区：
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作者：
D'Amico L;Mahajan S;Capietto AH;Yang Z;Zamani A;Ricci B;Bumpass DB;Meyer M;Su X;Wang-Gillam A;Weilbaecher K;Stewart SA;DeNardo DG;Faccio R
D 'Amico等研究表明，Dkk1通过直接靶向小鼠和人MDSCs中的β-catenin，促进其在癌症中的激活，从而发挥免疫抑制作用。肿瘤与基质的相互作用有助于肿瘤的发生。肿瘤细胞可以在原发和远处诱导基质，促进未成熟骨髓细胞异质群体的募集，即骨髓源性抑制细胞（myeloid-derived suppressor cells, MDSCs）。MDSCs抑制T细胞反应，促进肿瘤增殖。一个突出的问题是在肿瘤进展过程中，局部和远处基质如何调节MDSCs。在小鼠和人类中，β-catenin的下调对MDSC的积累和免疫抑制功能至关重要。在这里，我们证明基质来源的Dickkopf-1 （Dkk1）在MDSCs中靶向β-catenin，从而在肿瘤进展过程中发挥免疫抑制作用。骨外肿瘤小鼠骨微环境中Dkk1水平相对于肿瘤部位显著升高。引人注目的是，Dkk1中和通过挽救这些细胞中的β-catenin和恢复肿瘤部位的T细胞募集来降低肿瘤生长和MDSC数量。重组Dkk1抑制小鼠和人MDSCs中β-catenin靶基因，在骨髓细胞中缺乏β-catenin的小鼠或MDSCs缺失后，抗Dkk1失去抗肿瘤作用，表明Dkk1直接作用于MDSCs。此外，我们发现胰腺癌患者中CD15+髓样细胞与Dkk1之间存在相关性。我们在MDSCs中建立了Dkk1通过靶向β-catenin调节肿瘤诱导的免疫抑制的新免疫调节作用。
D’Amico et al. show that Dkk1 exerts immune-suppressive effects by directly targeting β-catenin in murine and human MDSCs and promoting their activation in cancer. Tumor–stroma interactions contribute to tumorigenesis. Tumor cells can educate the stroma at primary and distant sites to facilitate the recruitment of heterogeneous populations of immature myeloid cells, known as myeloid-derived suppressor cells (MDSCs). MDSCs suppress T cell responses and promote tumor proliferation. One outstanding question is how the local and distant stroma modulate MDSCs during tumor progression. Down-regulation of β-catenin is critical for MDSC accumulation and immune suppressive functions in mice and humans. Here, we demonstrate that stroma-derived Dickkopf-1 (Dkk1) targets β-catenin in MDSCs, thus exerting immune suppressive effects during tumor progression. Mice bearing extraskeletal tumors show significantly elevated levels of Dkk1 in bone microenvironment relative to tumor site. Strikingly, Dkk1 neutralization decreases tumor growth and MDSC numbers by rescuing β-catenin in these cells and restores T cell recruitment at the tumor site. Recombinant Dkk1 suppresses β-catenin target genes in MDSCs from mice and humans and anti-Dkk1 loses its antitumor effects in mice lacking β-catenin in myeloid cells or after depletion of MDSCs, demonstrating that Dkk1 directly targets MDSCs. Furthermore, we find a correlation between CD15+ myeloid cells and Dkk1 in pancreatic cancer patients. We establish a novel immunomodulatory role for Dkk1 in regulating tumor-induced immune suppression via targeting β-catenin in MDSCs.