miR-448 targets IDO1 and regulates CD8+ T cell response in human colon cancer
miR-448 targets IDO1 and regulates CD8+ T cell response in human colon cancer
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miR-448 通过靶向人结肠癌中的 IDO1 调节 CD8 T 细胞反应
DOI：
10.1186/s40425-019-0691-0
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发表时间：
2019-08-07
影响因子：
10.9
通讯作者：
Liu, Huanliang
中科院分区：
文献类型：
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作者：
Lou, Qiong;Liu, Ruixian;Liu, Huanliang
背景吲哚胺2，3-双加氧酶1（IDO 1）是T细胞功能的重要调节因子，有助于免疫耐受。IDO 1的上调已在许多癌症类型中发现;然而，IDO 1在结肠癌中的调节机制和临床意义仍不清楚。在这里，我们研究了靶向IDO 1的失调microRNA（miRNA）在结肠癌微环境中的作用。方法通过细胞实验和BALB/c小鼠和BALB/c裸鼠移植瘤模型的建立，阐明IDO 1的功能。我们在组织微阵列（TMA）中通过免疫组织化学（IHC）评估IDO 1蛋白表达，并使用癌症基因组图谱（TCGA）分析IDO 1 mRNA表达。我们通过使用双荧光素酶报告基因测定筛选靶向IDO 1的miRNA。我们通过Western印迹（WB）和荧光激活细胞分选（FACS）检测microRNA-448（miR-448）的功能。结果IDO 1稳定过表达可促进BALB/c小鼠移植瘤的生长，但对BALB/c裸鼠移植瘤的生长无明显影响。我们还通过观察IDO 1蛋白水平和mRNA水平揭示了IDO 1在结肠癌中的转录后调控。此外，miRNA模拟物的异位表达表明miR-448可显著下调IDO 1蛋白表达。值得注意的是，我们证明了miR-448通过抑制IDO 1酶功能来抑制CD 8（+）T细胞的凋亡。结论IDO 1抑制结肠癌患者的CD 8（+）T细胞反应。miR-448作为一种肿瘤抑制性miRNA，通过抑制IDO 1表达增强CD 8（+）T细胞应答。本研究结果为开发新的免疫疗法治疗结肠癌提供了理论依据。
Background Indoleamine 2,3-dioxygenase 1 (IDO1) is a critical regulator of T cell function, contributing to immune tolerance. Upregulation of IDO1 has been found in many cancer types; however, the regulatory mechanisms and clinical significance of IDO1 in colon cancer are still unclear. Here, we investigated the role of dysregulated microRNA (miRNA) targeting IDO1 in the colon cancer microenvironment. Methods We elucidated IDO1 function by performing cell-based assays and establishing transplanted tumor models in BALB/c mice and BALB/c nude mice. We evaluated IDO1 protein expression by immunohistochemistry (IHC) in a tissue microarray (TMA) and analyzed IDO1 mRNA expression with The Cancer Genome Atlas (TCGA). We screened miRNAs targeting IDO1 by using a dual luciferase reporter assay. We tested the function of microRNA-448 (miR-448) by using western blotting (WB) and fluorescence-activated cell sorting (FACS). Results We demonstrated that stable IDO1 overexpression enhanced xenograft tumor growth in BALB/c mice but not in BALB/c nude mice. We also revealed the involvement of posttranscriptional regulation of IDO1 in colon cancer by observing IDO1 protein levels and mRNA levels. Furthermore, ectopic expression of miRNA mimics suggested that miR-448 could significantly downregulate IDO1 protein expression. Notably, we proved that miR-448 suppressed the apoptosis of CD8(+) T cells by suppressing IDO1 enzyme function. Conclusion Our findings indicated that IDO1 suppressed the CD8(+) T cell response in colon cancer. miR-448, as a tumor-suppressive miRNA, enhanced the CD8(+) T cell response by inhibiting IDO1 expression. The results provide a theoretical basis for the development of new immunotherapy for the treatment of colon cancer.