Division of Neurosurgery, Department of Clinical Sciences, The Rausing Laboratory, Lund University, Lund, Sweden.
Department of Clinical Sciences, Medical Radiation Physics, Lund University, Lund, Sweden.
PLoS One. 2020 May 29;15(5):e0233617. doi: 10.1371/journal.pone.0233617. eCollection 2020.
The aim of the study was to investigate therapeutic efficacy of single- or two-fraction radiotherapy in conjunction with IDO1-inhibition in a syngeneic rat glioblastoma model. IDO is known to cause immunosuppression through breakdown of tryptophan in the tumor microenvironment.
Gene expression analyses of IDO in glioblastoma were performed with data from publicly available datasets. Fractionation studies were done on animals to evaluate tumor size, immune cell infiltration of tumors and serum profile on day 18 after tumor inoculation. Survival analyses were done with animals carrying intracranial glioblastomas comparing two-fraction radiotherapy+IDO1-inhibition to controls. IDO inhibition was achieved by administration of 1-methyl tryptophan (1-MT), and radiotherapy (RT) was delivered in doses of 8Gy.
The expression of IDO1 was increased on gene level in glioblastoma stem cells. Tumor size was significantly reduced in animals treated with 1-MT+RTx 2 (both long and short intervals, i.e. 7 and 4 days between the treatments) as compared to control animals, animals treated with only 1-MT or animals treated with 1-MT+RTx1. Serum levels of IL-1A were significantly altered in all treated animals as compared to control animals. Survival was significantly increased in the animals treated with 1-MT+RTx2 (7-day interval) compared to control animals.
Addition of two-fraction RT to IDO1 inhibition with 1-MT significantly reduced tumor size in animals with glioblastoma. Survival was significantly increased in animals treated with two-fractioned RT+1-MT as compared to untreated controls increased significantly.
The currently used combination of only two fractions of radiotherapy and immune therapy is a promising area of research, increasing efficacy compared to single fraction irradiation, while potentially lowering radiation side effects compared to radiation in current clinical practice.
本研究旨在探讨在同种异体大鼠脑胶质瘤模型中，单次或两次分割放疗联合 IDO1 抑制的治疗效果。IDO 已知可通过分解肿瘤微环境中的色氨酸导致免疫抑制。
使用公开数据集的数据对脑胶质瘤中的 IDO 基因表达进行分析。对动物进行分割研究，以评估肿瘤大小、肿瘤内免疫细胞浸润和接种肿瘤后第 18 天的血清特征。对携带颅内脑胶质瘤的动物进行生存分析，比较两分割放疗+IDO1 抑制与对照组。IDO 抑制通过施用 1-甲基色氨酸（1-MT）实现，放疗（RT）剂量为 8Gy。
脑胶质瘤干细胞中 IDO1 的表达在基因水平上增加。与对照组、仅用 1-MT 治疗或用 1-MT+RTx1 治疗的动物相比，用 1-MT+RTx2（两次治疗之间的长、短间隔分别为 7 天和 4 天）治疗的动物的肿瘤体积明显减小。与对照组动物相比，所有治疗动物的血清白细胞介素 1A（IL-1A）水平均显著改变。与对照组动物相比，用 1-MT+RTx2（7 天间隔）治疗的动物的生存时间明显延长。
用 1-MT 联合 IDO1 抑制加两次分割 RT 治疗显著减小了脑胶质瘤动物的肿瘤体积。与未治疗的对照组相比，用两分割 RT+1-MT 治疗的动物的生存率显著增加。
目前仅使用两分割放疗和免疫治疗的联合治疗是一个很有前途的研究领域，与单次分割照射相比，其疗效提高，与目前临床实践中的放射治疗相比，放射副作用可能降低。
