Xing Zikang, Li Xuewen, He Zhen Ning Tony, Fang Xin, Liang Heng, Kuang Chunxiang, Li Aiying, Yang Qing
State Key Laboratory of Genetic Engineering, School of Life Sciences, MOE Engineering Research Center of Gene Technology, Shanghai Engineering Research Center of Industrial Microorganisms, Fudan University, Songhu Road 2005, Shanghai 200438, China.
Shanghai Key Lab of Chemical Assessment and Sustainability, School of Chemical Science and Engineering, Tongji University, Siping Road 1239, Shanghai 200092, China.
Pharmaceutics. 2024 Jun 28;16(7):870. doi: 10.3390/pharmaceutics16070870.
Glioma is characterized by strong immunosuppression and excessive angiogenesis. Based on existing reports, it can be speculated that the resistance to anti-angiogenic drug vascular endothelial growth factor A (VEGFA) antibody correlates to the induction of novel immune checkpoint indoleamine 2,3-dioxygenase 1 (IDO1), while IDO1 has also been suggested to be related to tumor angiogenesis. Herein, we aim to clarify the potential role of IDO1 in glioma angiogenesis and the mechanism behind it. Bioinformatic analyses showed that the expressions of IDO1 and angiogenesis markers VEGFA and CD34 were positively correlated and increased with pathological grade in glioma. IDO1-overexpression-derived-tryptophan depletion activated the general control nonderepressible 2 (GCN2) pathway and upregulated VEGFA in glioma cells. The tube formation ability of angiogenesis model cells could be inhibited by IDO1 inhibitors and influenced by the activity and expression of IDO1 in condition medium. A significant increase in serum VEGFA concentration and tumor CD34 expression was observed in IDO1-overexpressing GL261 subcutaneous glioma-bearing mice. IDO1 inhibitor RY103 showed positive anti-tumor efficacy, including the anti-angiogenesis effect and upregulation of natural killer cells in GL261 glioma-bearing mice. As expected, the combination of RY103 and anti-angiogenesis agent sunitinib was proved to be a better therapeutic strategy than either monotherapy.
胶质瘤的特征是强烈的免疫抑制和过度的血管生成。根据现有报道，可以推测抗血管生成药物血管内皮生长因子A（VEGFA）抗体的耐药性与新型免疫检查点吲哚胺2,3-双加氧酶1（IDO1）的诱导相关，而IDO1也被认为与肿瘤血管生成有关。在此，我们旨在阐明IDO1在胶质瘤血管生成中的潜在作用及其背后的机制。生物信息学分析表明，IDO1与血管生成标志物VEGFA和CD34的表达呈正相关，且在胶质瘤中随病理分级增加。IDO1过表达导致的色氨酸耗竭激活了一般控制非抑制性2（GCN2）途径，并上调了胶质瘤细胞中的VEGFA。血管生成模型细胞的管形成能力可被IDO1抑制剂抑制，并受条件培养基中IDO1的活性和表达影响。在IDO1过表达的GL261皮下荷瘤小鼠中，观察到血清VEGFA浓度和肿瘤CD34表达显著增加。IDO1抑制剂RY103显示出积极的抗肿瘤效果，包括在GL261荷瘤小鼠中的抗血管生成作用和自然杀伤细胞的上调。正如预期的那样，RY103与抗血管生成药物舒尼替尼联合使用被证明是比单一疗法更好的治疗策略。
