PDF(Pubmed)
Abstract：
Although the antitumor efficacy of immune checkpoint blockade (ICB) has been proved in colorectal cancer (CRC), the results are unsatisfactory, presumably owing to the presence of tryptophan metabolism enzymes indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2). However, only a few dual inhibitors for IDO1 and TDO2 have been reported. Here, we discovered that sodium tanshinone IIA sulfonate (STS), a sulfonate derived from tanshinone IIA (TSN), reduced the enzymatic activities of IDO1 and TDO2 with a half inhibitory concentration (IC50) of less than 10 μM using enzymatic assays for natural product screening. In IDO1- or TDO2- overexpressing cell lines, STS decreased kynurenine (kyn) synthesis. STS also reduced the percentage of forkhead box P3 (FOXP3) T cells in lymphocytes from the mouse spleen cocultured with CT26. In vivo, STS suppressed tumor growth and enhanced the antitumor effect of the programmed cell death 1 (PD1) antibody. Compared with anti-PD1 (α-PD1) monotherapy, combined with STS had lower level of plasma kynurenine. Immunofluorescence assay suggested that STS decreased the number of FOXP3+ T cells and increased the number of CD8+ T cells in tumors. Flow cytometry analysis of immune cells in tumor tissues demonstrated an increase in the percentage of tumor-infiltrating CD8+ T cells. According to our findings, STS acts as an immunotherapy agent in CRC by inhibiting both IDO1 and TDO2.
摘要：
尽管免疫检查点阻断（ICB）的抗肿瘤功效已在结直肠癌（CRC）中得到证实，结果并不令人满意,可能是由于存在色氨酸代谢酶吲哚胺2,3-双加氧酶1（IDO1）和色氨酸2,3-双加氧酶2（TDO2）。然而,只有少数IDO1和TDO2的双重抑制剂被报道。这里,我们发现丹参酮IIA磺酸钠(STS)，来自丹参酮IIA（TSN）的磺酸盐，使用用于天然产物筛选的酶测定法，以小于10μM的半抑制浓度（IC50）降低了IDO1和TDO2的酶活性。在过表达IDO1-或TDO2-的细胞系中，STS降低犬尿氨酸（kyn）的合成。STS还降低了来自与CT26共培养的小鼠脾的淋巴细胞中叉头盒P3(FOXP3)T细胞的百分比。在体内,STS抑制肿瘤生长并增强程序性细胞死亡1（PD1）抗体的抗肿瘤作用。与抗PD1（α-PD1）单药治疗相比，合并STS的人血浆犬尿氨酸水平较低。免疫荧光分析表明STS减少了肿瘤中FOXP3T细胞的数量，增加了CD8T细胞的数量。肿瘤组织中免疫细胞的流式细胞术分析显示肿瘤浸润性CD8+T细胞的百分比增加。根据我们的发现,STS通过抑制IDO1和TDO2在CRC中充当免疫治疗剂。
