Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
Int Immunopharmacol. 2024 Aug 20;137:112437. doi: 10.1016/j.intimp.2024.112437. Epub 2024 Jun 12.
The over-activation of tryptophan (Trp) metabolism to kynurenine (Kyn) catalyzed by Indoleamine 2,3-dioxygenase-1 (IDO1) enzyme, is one of the main metabolic pathways involved in tumor microenvironment (TME) immune escape and cancer treatment failure. The most efficient of IDO1 inhibitors is Epacadostat (EPA). Since monotherapy with single-agent IDO1 inhibitor regimen has led to an insufficient anti-tumor activity, we examined the efficacy of simultaneous treatment by Liposomal epacadostat (Lip-EPA) as a potent IDO inhibitor, in combination with docetaxel (DTX) as a complement immunogenic cell death (ICD) agent against B16F10 model. First, the in vitro combination index (CI) of epacadostat (EPA) and DTX was investigated by using the unified theory. Then, the in vivo efficacy of the combination therapy was assessed. Results indicated the synergestic cytotoxic effect of the combination on B16F10 compared to normal fibroblast cells (NIH). The immune profiling demonstrated a significant increase in the percentage of infiltrated T lymphocytes and IFN-γ release, a significant decrease in the percentage of regulatory T cells (Treg) population and the subsequent low levels of IL-10 generation in mice treated with Lip-EPA + DTX. Further, a significant tumor growth delay (TGD = 69.15 %) and an increased life span (ILS > 47.83 %) was observed with the combination strategy. Histopathology analysis revealed a remarkable increase in the Trp concentration following combination treatment, while Kyn levels significantly decreased. Results showed that the nano-liposomal form of IDO1 inhibitor in combination with chemotherapy could significantly improve the imunity response and dominate the tumor immuno-suppressive micro-environment, which merits further investigations.
色氨酸（Trp）代谢途径向犬尿氨酸（Kyn）的过度激活，由色氨酸 2,3-双加氧酶-1（IDO1）酶催化，是肿瘤微环境（TME）免疫逃逸和癌症治疗失败的主要代谢途径之一。IDO1 最有效的抑制剂是 Epacadostat（EPA）。由于单一药物 IDO1 抑制剂疗法导致抗肿瘤活性不足，我们研究了同时使用 Liposomal epacadostat（Lip-EPA）作为有效的 IDO 抑制剂，联合多西他赛（DTX）作为补充免疫原性细胞死亡（ICD）剂对 B16F10 模型的疗效。首先，通过统一理论研究了 Epacadostat（EPA）和 DTX 的体外组合指数（CI）。然后，评估了联合治疗的体内疗效。结果表明，与正常成纤维细胞（NIH）相比，组合对 B16F10 具有协同细胞毒性作用。免疫分析表明，用 Lip-EPA+DTX 治疗的小鼠中浸润 T 淋巴细胞的百分比显着增加，IFN-γ释放显着增加，调节性 T 细胞（Treg）群体的百分比显着减少，随后 IL-10 的产生水平降低。此外，观察到 Lip-EPA+DTX 联合治疗具有显着的肿瘤生长延迟（TGD=69.15%）和寿命延长（ILS>47.83%）。组织病理学分析显示，联合治疗后色氨酸浓度显着增加，而犬尿氨酸水平显着降低。结果表明，IDO1 抑制剂的纳米脂质体形式与化疗联合使用可以显着改善免疫反应并控制肿瘤免疫抑制微环境，值得进一步研究。
