DKK2 blockage-mediated immunotherapy enhances anti-angiogenic therapy of Kras mutated colorectal cancer.
DKK2 blockage-mediated immunotherapy enhances anti-angiogenic therapy of Kras mutated colorectal cancer.
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DOI：
10.1016/j.biopha.2020.110229
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发表时间：
2020-07
期刊：
影响因子：
--
通讯作者：
Xiao Q
中科院分区：
文献类型：
--
作者：
Hu J;Wang Z;Chen Z;Li A;Sun J;Zheng M;Wu J;Shen T;Qiao J;Li L;Li B;Wu D;Xiao Q
结直肠癌（CRC）的靶向治疗选择有限。抗EGFR治疗仅限于无KRAS突变的CRC。更糟糕的是，大多数CRC对目前的免疫检查点阻断是难治的。最近发现在CRC中上调的DKK 2抑制宿主免疫反应，并且在我们先前的研究中，其阻断有效地阻止了良性遗传CRC模型中的肿瘤进展。在此，我们最近的研究表明，在表达高水平DKK 2的人CRC肿瘤样品中，DKK 2阻断引起离体培养中肿瘤浸润性CD8+ T细胞的更强活化。有趣的是，我们也观察到了DKK 2高表达与这些CRC患者淋巴结转移发生率增加的相关性。此外，在APC和KRAS突变的小鼠遗传性CRC模型中，更接近地模拟晚期人类CRC，我们证实了DKK 2阻断的肿瘤抑制作用，其显著延缓肿瘤进展并延长生存期，同时增加免疫效应细胞活化和减少血管生成。基于此，我们进行了DKK 2阻断与次优抗VEGFR治疗的联合给药，并观察到对抑制肿瘤血管生成和进展以及延长生存期的协同作用，优于每种单一疗法。因此，本研究为DKK 2阻断剂在人CRC临床治疗中的潜在治疗应用提供了进一步的证据。
There are limited options for targeted therapies for colorectal cancer (CRC). Anti-EGFR therapy is limited to CRC without KRAS mutations. Even worse, most of CRC are refractory to currently immune checkpoint blockade. DKK2, which is upregulated in CRC, was recently found to suppress host immune responses, and its blockage effectively impeded tumor progression in benign genetic CRC models in our previous study. Here, our recent study demonstrated that in human CRC tumor samples expressing high levels of DKK2, DKK2 blockade caused stronger activation of tumor infiltrating CD8+ T cells in ex vivo culture. Intriguingly, we observed a correlation of high DKK2 expression with increased lymph node metastasis prevalence in these CRC patients as well. Furthermore, in a mouse genetic CRC model with mutations in APC and KRAS, which more closely mimics advanced human CRC, we confirmed the tumor inhibitory effect of DKK2 blockade, which significantly retarded tumor progression and extended survival, with increased immune effector cell activation and reduced angiogenesis. Based on this, we performed a combined administration of DKK2 blockade with sub-optimal anti-VEGFR treatment and observed a synergetic effect on suppressing tumor angiogenesis and progression, as well as extending survival, better than those of every single therapy. Thus, this study provides further evidence for the potential therapeutic application of DKK2 blockade in the clinical treatment of human CRC.
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影响因子：
50.3
作者：
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通讯作者：
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影响因子：
11.2
作者：
Hauer, Kristina;Calzada-Wack, Julia;Richter, Guenther H. S.
通讯作者：
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影响因子：
32.4
作者：
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通讯作者：
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作者：
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DOI：
10.1007/s10555-007-9094-7
发表时间：
2007-12
期刊：
Cancer metastasis reviews
影响因子：
--
作者：
Hillen F;Griffioen AW
通讯作者：
Griffioen AW