Inhibition of indoleamine 2,3-dioxygenase 1 expression alters immune response in colon tumor microenvironment in mice.
Inhibition of indoleamine 2,3-dioxygenase 1 expression alters immune response in colon tumor microenvironment in mice.
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DOI：
10.1111/cas.12705
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发表时间：
2015-08
期刊：
影响因子：
5.7
通讯作者：
Hara A
中科院分区：
文献类型：
--
作者：
Takamatsu M;Hirata A;Ohtaki H;Hoshi M;Ando T;Ito H;Hatano Y;Tomita H;Kuno T;Saito K;Seishima M;Hara A
吲哚胺2,3-双加氧酶（IDO）是一种沿犬尿氨酸途径降解必需氨基酸l-色氨酸的酶，在许多疾病中发挥免疫调节作用。IDO在肿瘤组织和引流淋巴结中表达升高；这种增加被认为通过抑制免疫反应在肿瘤逃避中发挥作用。一种竞争性IDO抑制剂目前正在临床试验中用于治疗复发或难治性实体瘤，但IDO抑制剂在结直肠肿瘤中的疗效仍有待充分阐明。在本研究中，我们通过基因缺失和药物抑制来研究IDO缺乏对小鼠结肠肿瘤发生的影响。将ido1缺陷（−/−）小鼠与ApcMin/+小鼠杂交，或给予偶氮氧甲烷加或不加葡聚糖硫酸钠。Ido1缺乏并未导致结肠肿瘤大小和数量的显著差异。同样，使用1-甲基色氨酸（1-mT）对IDO的药理抑制也导致ApcMin/+小鼠肿瘤大小和数量没有显著差异。然而，Ido1缺失改变了肿瘤微环境中的免疫反应，显示出Ido1（−/−）小鼠结肠肿瘤中促炎细胞因子mRNA表达显著增加，foxp3阳性调节性T细胞数量显著减少。重要的是，1-mT治疗也显著改变了结肠肿瘤组织中细胞因子的表达。这些结果表明，尽管IDO在肿瘤微环境中具有免疫调节作用，但单独抑制IDO不能充分抑制小鼠结肠癌的发展。
Indoleamine 2,3-dioxygenase (IDO), an enzyme that degrades the essential amino acid l-tryptophan along the kynurenine pathway, exerts immunomodulatory effects in a number of diseases. IDO expression is increased in tumor tissue and in draining lymph nodes; this increase is thought to play a role in tumor evasion by suppressing the immune response. A competitive inhibitor of IDO is currently being tested in clinical trials for the treatment of relapsed or refractory solid tumors, but the efficacy of IDO inhibition in colorectal tumors remains to be fully elucidated. In this study, we investigated the effect of IDO deficiency on colon tumorigenesis in mice by genetic deletion and pharmacological inhibition. Ido1-deficient(−/−) mice were crossed with ApcMin/+ mice or were administered azoxymethane with or without dextran sodium sulfate. Ido1 deficiency did not lead to significant differences in the size and number of colon tumors. Similarly, the pharmacological inhibition of IDO using 1-methyltryptophan (1-mT) also resulted in no significant differences in tumor size and number in ApcMin/+ mice. However, Ido1 deficiency altered the immune response in the tumor microenvironment, showing a significant increase in mRNA expression of pro-inflammatory cytokines and a significant decrease in the number of Foxp3-positive regulatory T cells in the colon tumors of Ido1(−/−) mice. Importantly, 1-mT treatment also significantly altered cytokine expression in the colon tumor tissues. These results suggest that IDO inhibition alone cannot sufficiently suppress colon cancer development in mice despite its immunomodulatory activity in the tumor microenvironment.