State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Ability of Biopharmaceuticals, Jiangsu Key Laboratory of Drug Screening, School of life science and Technology, China Pharmaceutical University, Nanjing, China.
Medical Laboratory department, Faculty of Medicine and Health Sciences, Hodeidah University, Al Hudaydah, Yemen.
Sci Rep. 2018 Jun 29;8(1):9869. doi: 10.1038/s41598-018-28238-8.
1-Methyl-D-tryptophan (1-MT) is extensively utilized in preclinical trials to deplete indoleamine 2,3-dioxigenase (IDO) activity and kynurenine pathway. Since IDO related signaling pathways aren't well understood, some clinical reports affirmed IDO inhibiting therapeutic significance. Therefore, we did use direct tumor autologous antigens vaccination and 1-MT without chemotherapy to explore biological mechanisms and immunomodulations of 1-MT that motivate antitumor responses. However, DCs antigen-uptake capability, anti-tumor efficiency, intra-tumor and intracellular cytokines were assessed. Besides, CD133+ cells viability and tumor biomarkers were investigated. Splenocytes responses and their signaling pathways such TLRs 2 to 9, NF-κβ1-2, Wnt/β-catenin and TGF-β were dissected. Results evinced that a regimen of 1-MT and TAAs significantly reduced CSC CD133 + viability inside tumor microenvironment, besides increasing tumor cells necrosis and apoptosis. Expression of TGF-β, IDO, RANTES, and PDL-1 was also significantly reduced. Interestingly, 1-MT enhanced lymphocytes TLR2, TLR7, TLR8, and TLR9 pathways. It motivated lymphocytes' NF-κβ2, STAT3, and STAT4 pathways, while reduced tumors' NF-κβp65 and Wnt/β-catenin signaling pathways. We found that periphery and intra-tumor Treg cells were significantly decreased. In conclusion, depletion of indoleamine 2,3-dioxigenase activity evidenced IDO relation with tumor stem cells proliferation pathways. Furthermore, 1-MT supports immunotherapeutic vaccines susceptibility and tumor specific targeting by reducing tumorgensis signaling pathways.
1-甲基-D-色氨酸（1-MT）在临床前试验中被广泛用于耗尽吲哚胺 2,3-双加氧酶（IDO）活性和犬尿氨酸途径。由于 IDO 相关信号通路尚未得到很好的理解，一些临床报告证实了 IDO 抑制治疗的意义。因此，我们确实使用直接肿瘤自体抗原疫苗接种和 1-MT 而不进行化疗来探索 1-MT 激发抗肿瘤反应的生物学机制和免疫调节作用。然而，我们评估了树突状细胞（DC）的抗原摄取能力、抗肿瘤效率、肿瘤内和细胞内细胞因子，此外，还研究了 CD133+细胞的活力和肿瘤标志物。还分析了脾细胞反应及其信号通路，如 TLRs 2 至 9、NF-κβ1-2、Wnt/β-catenin 和 TGF-β。结果表明，1-MT 和 TAAs 的方案显著降低了肿瘤微环境中 CSC CD133+细胞的活力，同时增加了肿瘤细胞的坏死和凋亡。TGF-β、IDO、RANTES 和 PDL-1 的表达也显著降低。有趣的是，1-MT 增强了淋巴细胞 TLR2、TLR7、TLR8 和 TLR9 途径。它激发了淋巴细胞的 NF-κβ2、STAT3 和 STAT4 途径，同时降低了肿瘤的 NF-κβp65 和 Wnt/β-catenin 信号通路。我们发现外周和肿瘤内 Treg 细胞显著减少。总之，耗尽吲哚胺 2,3-双加氧酶活性表明 IDO 与肿瘤干细胞增殖途径有关。此外，1-MT 通过降低肿瘤发生信号通路，支持免疫治疗疫苗的敏感性和肿瘤特异性靶向。
