Abstract
ObjectivesThe 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 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.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 two-fractioned RT+1-MT as compared to untreated controls increased significantly.Advances in knowledgeThe 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.
Highlights
Immunotherapy has received much attention as a promising treatment for cancer of different types, and there is evidence of long-term therapeutic effects for some diagnoses
Tumor size was significantly reduced in animals treated with 1-methyl tryptophan (1-MT)+RTx 2 as compared to control animals, animals treated with only 1-MT or animals treated with 1-MT+RTx1
Survival was significantly increased in animals treated with twofractioned RT+1-MT as compared to untreated controls increased significantly
Summary
Immunotherapy has received much attention as a promising treatment for cancer of different types, and there is evidence of long-term therapeutic effects for some diagnoses. More than half of all cancer patients receive radiotherapy, and it is estimated to contribute to about 40% of all cancer cures world-wide. It is part of the current standard of care for glioblastoma. The immunomodulatory effects of radiation are very complex, potentially evoking both stimulatory and inhibitory actions on the immunological anti-tumor response [12,13,14,15,16,17]
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