Harvey Cushing Neurooncology Laboratories, Department of Neurosurgery, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Harvey Cushing Neurooncology Laboratories, Department of Neurosurgery, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Pathology and Laboratory Medicine, Department of Neurosurgery, Legorreta Cancer Center, Brown University, Providence, RI 02903, USA.
Cell Rep Med. 2023 May 16;4(5):101019. doi: 10.1016/j.xcrm.2023.101019. Epub 2023 Apr 14.
Derivatives of the Chinese traditional medicine indirubin have shown potential for the treatment of cancer through a range of mechanisms. This study investigates the impact of 6'-bromoindirubin-3'-acetoxime (BiA) on immunosuppressive mechanisms in glioblastoma (GBM) and evaluates the efficacy of a BiA nanoparticle formulation, PPRX-1701, in immunocompetent mouse GBM models. Transcriptomic studies reveal that BiA downregulates immune-related genes, including indoleamine 2,3-dioxygenase 1 (IDO1), a critical enzyme in the tryptophan-kynurenine-aryl hydrocarbon receptor (Trp-Kyn-AhR) immunosuppressive pathway in tumor cells. BiA blocks interferon-γ (IFNγ)-induced IDO1 protein expression in vitro and enhances T cell-mediated tumor cell killing in GBM stem-like cell co-culture models. PPRX-1701 reaches intracranial murine GBM and significantly improves survival in immunocompetent GBM models in vivo. Our results indicate that BiA improves survival in murine GBM models via effects on important immunotherapeutic targets in GBM and that it can be delivered efficiently via PPRX-1701, a nanoparticle injectable formulation of BiA.
中药靛玉红的衍生物已通过多种机制显示出治疗癌症的潜力。本研究探讨了 6'-溴靛玉红-3'-乙酰胺（BiA）对胶质母细胞瘤（GBM）中免疫抑制机制的影响，并评估了 BiA 纳米颗粒制剂 PPRX-1701 在免疫活性小鼠 GBM 模型中的疗效。转录组学研究表明，BiA 下调免疫相关基因，包括 IDO1，这是肿瘤细胞中色氨酸-犬尿氨酸-芳烃受体（Trp-Kyn-AhR）免疫抑制途径中的关键酶。BiA 在体外阻断干扰素-γ（IFNγ）诱导的 IDO1 蛋白表达，并增强 GBM 干细胞样细胞共培养模型中 T 细胞介导的肿瘤细胞杀伤。PPRX-1701 到达颅内小鼠 GBM，并显著提高免疫活性 GBM 模型的存活率。我们的结果表明，BiA 通过对 GBM 中重要的免疫治疗靶点的作用，改善了小鼠 GBM 模型的存活率，并且可以通过 PPRX-1701 高效递送至体内，PPRX-1701 是 BiA 的纳米颗粒注射制剂。
