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

Abstract

Glioblastoma multiforme (GBM) is a fatal brain tumor in adults with a bleak diagnosis. Expansion of immunosuppressive and malignant CD4 + FoxP3 + GITR + regulatory T cells is one of the hallmarks of GBM. Importantly, most of the patients with GBM expresses the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO). While IDO1 is generally not expressed at appreciable levels in the adult central nervous system, it is rapidly stimulated and highly expressed in response to ongoing immune surveillance in cancer. Increased levels of immune surveillance in cancer are thus related to higher intratumoral IDO expression levels and, as a result, a worse OS in GBM patients. Conversion of the important amino acid tryptophan into downstream catabolite known as kynurenines is the major function of IDO. Decreasing tryptophan and increasing the concentration of immunomodulatory tryptophan metabolites has been shown to induce T-cell apoptosis, increase immunosuppressive programming, and death of tumor antigen-presenting dendritic cells. This observation supported the immunotherapeutic strategy, and the targeted molecular therapy that suppresses IDO1 activity. We review the current understanding of the role of IDO1 in tumor immunological escape in brain tumors, the immunomodulatory effects of its primary catabolites, preclinical research targeting this enzymatic pathway, and various issues that need to be overcome to increase the prospective immunotherapeutic relevance in the treatment of GBM malignancy.

Discovery of novel serum biomarkers of gliomas by proximity extension assay

“…IDO1 targeting has emerged as a novel therapeutic opportunity in modern cancer immunotherapy (40). Interestingly, while IDO1 is not generally expressed in the adult central nervous system, most of GBM patients do express signi cant levels of IDO1 (41). Accumulating evidence highlight an important putative role for IDO1 in regulating tumor immunological escape in brain tumors.…”

TRIM8: a double-edged sword in glioblastoma with the power to heal or hurt

“…The importance of inflammation in gliomas is less evident than in other cancers, especially at the onset. The transcription factor NFKB induces the expression of genes involved in many aspects of the innate and adaptive immune system and is one of the most important molecules in triggering chronic inflammation as a hallmark and cause of cancer [ 121 , 122 ]. Constitutive NFKB activation is a common phenomenon in GBM, as in many other malignancies.…”

Probiotics: Protecting Our Health from the Gut

“…In addition, SCFAs promote the secretion of hormones from intestinal endocrine cells; due to these properties, they may regulate various functions at the CNS level and may even be involved in the development of neurological disorders [ 37 , 40 ]. Tryptophan metabolites, for their part, have been described as molecules with a high regulatory potential that send signals from the GM to various peripheral organs, including the brain, where they can regulate the development and activation of microglia and induce the production of molecules to modulate inflammation in the CNS [ 41 , 42 ]. Finally, microbial neurotransmitters include molecules such as γ-aminobutyric acid (GABA), a molecule that can modulate brain function and inflammatory processes associated with the CNS, and catecholamines, which can regulate cognitive abilities, mood, and gut motility [ 27 , 43 ].…”

“…Finally, microbial neurotransmitters include molecules such as γ-aminobutyric acid (GABA), a molecule that can modulate brain function and inflammatory processes associated with the CNS, and catecholamines, which can regulate cognitive abilities, mood, and gut motility [27,43]. 022, 10, x FOR PEER REVIEW 4 of 44 modulate inflammation in the CNS [41,42]. Finally, microbial neurotransmitters include molecules such as γ-aminobutyric acid (GABA), a molecule that can modulate brain function and inflammatory processes associated with the CNS, and catecholamines, which can regulate cognitive abilities, mood, and gut motility [27,43].…”