IDO is a nodal pathogenic driver of lung cancer and metastasis development.
IDO is a nodal pathogenic driver of lung cancer and metastasis development.
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DOI：
10.1158/2159-8290.cd-12-0014
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发表时间：
2012-08
期刊：
影响因子：
28.2
通讯作者：
Muller AJ
中科院分区：
文献类型：
--
作者：
Smith C;Chang MY;Parker KH;Beury DW;DuHadaway JB;Flick HE;Boulden J;Sutanto-Ward E;Soler AP;Laury-Kleintop LD;Mandik-Nayak L;Metz R;Ostrand-Rosenberg S;Prendergast GC;Muller AJ
基于临床前研究表明吲哚胺2,3 - 双加氧酶（IDO）酶抑制剂能够克服免疫逃逸并广泛增强其他治疗方式，它们已进入癌症治疗的临床试验。然而，在原发性或转移性疾病的生理模型中，缺乏IDO对肿瘤发生影响的明确遗传学证据。通过研究Ido1基因破坏在致癌KRAS诱导的肺癌以及乳腺癌衍生的肺转移小鼠模型中的影响，我们发现IDO缺乏导致两种模型中的肺部肿瘤负荷降低以及生存期延长。微型计算机断层扫描（Micro - CT）成像进一步显示，在Ido1基因纯合缺失小鼠中，基础肺血管的密度显著降低。在肺部肿瘤和转移瘤生长过程中，随着IDO的缺失，白细胞介素6（IL6）的诱导作用大幅减弱。从生物学角度来看，这导致了促肿瘤的髓源性抑制细胞（MDSCs）相应受损，因为在Ido1基因纯合缺失小鼠中，IL6的恢复使MDSC的抑制功能和转移易感性均得以恢复。总之，我们的研究结果将IDO定义为一种典型的整合调节剂，它连接炎症、血管生成和免疫逃逸，从而促进原发性和转移性肿瘤的生长。
IDO (indoleamine 2,3-dioxygenase) enzyme inhibitors have entered clinical trials for cancer treatment based on preclinical studies indicating that they can defeat immune escape and broadly enhance other therapeutic modalities. However, clear genetic evidence of IDO’s impact on tumorigenesis in physiologic models of primary or metastatic disease is lacking. Investigating the impact of Ido1 gene disruption in mouse models of oncogenic KRAS-induced lung carcinoma and breast carcinoma-derived pulmonary metastasis, we have found that IDO-deficiency resulted in reduced lung tumor burden and improved survival in both models. Micro-CT imaging further revealed that the density of the underlying pulmonary blood vessels was significantly reduced in Ido1-nullizygous mice. During lung tumor and metastasis outgrowth, IL6 induction was greatly attenuated in conjunction with the loss of IDO. Biologically, this resulted in a consequential impairment of pro-tumorigenic MDSCs (myeloid-derived suppressor cells), as restoration of IL6 recovered both MDSC suppressor function and metastasis susceptibility in Ido1-nullizygous mice. Together, our findings define IDO as a prototypical integrative modifier that bridges inflammation, vascularization and immune escape to license primary and metastatic tumor outgrowth.