Increased effect of two-fraction radiotherapy in conjunction with IDO1 inhibition in experimental glioblastoma

Abstract

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. MethodsGene 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 twofraction 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. ResultsThe 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. ConclusionsAddition 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 twofractioned RT+1-MT as compared to untreated controls increased significantly.

Immunomodulatory Effects of Tryptophan Metabolism in the Glioma Tumor Microenvironment

“…Radiotherapy response can be enhanced by GDC-0919, known as IDO1 inhibitor, with the ability to pass through BBB and reduces radiotherapy-induced immunosuppression (81). 1-MT, an IDO1 inhibitor, added with two-fraction radiotherapy significantly reduced tumor size and increased survival in bears with GBM compared to untreated controls (82). These findings provide novel insights to enhance the effect of radiotherapy in glioblastoma.…”

Comprehensive Analysis of Expression and Prognostic Value of MS4As in Glioma

“…Indoleamine 2,3-dioxygenase 1 ( IDO1 ) is known to cause immunosuppression through breakdown of tryptophan in the tumor microenvironment. A study showed the increased therapeutic efficacy of two-fraction radiotherapy in conjunction with IDO1 inhibition in a syngeneic rat glioblastoma model ( Ahlstedt et al, 2020 ). Meanwhile, two highly selective IDO1 inhibitors, PF-06840003 and BGB-5777, have demonstrated promising antitumor activity in pre-clinical models ( Gomes et al, 2018 ; Ladomersky et al, 2018 ).…”

The immunosuppressive role of indoleamine 2, 3-dioxygenase in glioblastoma: mechanism of action and immunotherapeutic strategies

“…Indoximod has received the most attention in clinical research because of its relatively potent antitumor properties and unique mechanisms of action. In contrast to direct IDO1 enzyme inhibitors, indoximod acts as a tryptophan mimic by reducing the inhibitory effects of IDO /TDO-mediated tryptophan deprivation on mTORC1 kinase [ 107 , 109 ]. Downregulation of mTORC1 in T cells promotes autophagy/tolerance while reducing T-cell antitumor efficacy, which is reversed by indoximod as a tryptophan substitute.…”