IDO has been implicated in immune modulation through its ability to limit T-cell function and engage mechanisms of immune tolerance.[2] Emerging evidence suggests that IDO becomes activated during tumor development, helping malignant cells escape eradication by the immune system.[3][4]
There are crystal structures for human IDO in complex with the inhibitor 4-phenylimidazole[5] and other inhibitors.[6][7]
Species, tissue, and subcellular distribution
Function
Indoleamine 2,3-dioxygenase is the first and rate-limiting enzyme of tryptophancatabolism through the kynurenine pathway, thus causing depletion of tryptophan, which can slow the growth of microbes as well as T cells. PGE2 is able to elevate the expression of indoleamine 2,3-dioxygenase in CD11C+dendritic cells and promotes the development of functional T-regulatory cells (Treg cells), which inhibit T-cell activity.
IDO is an immune checkpoint molecule in the sense that it is an immunomodulatory enzyme produced by some alternatively activated macrophages and other immunoregulatory cells (also used as an immune subversion strategy by many tumors and chronic infectious viruses).[8] IDO is known to suppress T and NK cells, generate and activate Tregs and myeloid-derived suppressor cells, and promote the growth of new blood cells to feed the tumor (angiogenesis).[3] IDO permits tumor cells to escape the immune system by depletion of L-tryptophan in the tumor microenvironment and by production of the catabolic product kynurenine, which selectively impairs the growth and survival of T-cells. A wide range of human cancers such as prostatic, colorectal, pancreatic, cervical, gastric, ovarian, head, lung, etc. overexpress human IDO (hIDO).[9]
It was originally thought that the mechanism of tryptophan oxidation occurred by base-catalysed abstraction, but it is now thought that the mechanism involves formation of a transient ferryl (i.e.high-valent iron) species.[10]
Interactions
Interferon-gamma has an antiproliferative effect on many tumor cells and inhibits intracellular pathogens such as Toxoplasma and Chlamydia, at least partly because of the induction of indoleamine 2,3-dioxygenase.
In tumor cells, IDO expression is normally controlled by the tumor suppressorBin1, which is widely disabled during cancer development.
By 2018 the function of IDO as a checkpoint used by tumors to escape immune surveillance was a focus of research and drug discovery efforts,[9] as well as efforts to understand if it could be used as a biomarker for prognosis.[11]
As of 2018, it appeared that overexpression of IDO in some tumors, such as ovarian, colorectal, and endometrial, and esophageal cancer, correlated with swifter death, while in kidney and liver cancers it appeared to correlate with better outcomes.[11] A 2018 meta-analysis found that it correlated with worse outcomes in all cancers, but the results were weak.[11]
Inhibitors
COX-2 inhibitors down-regulate indoleamine 2,3-dioxygenase, leading to a reduction in kynurenine levels as well as reducing proinflammatory cytokine activity.
1-Methyltryptophan is a racemic compound that weakly inhibits indoleamine dioxygenase, but is also a very slow substrate. The specific racemer 1-methyl-D-tryptophan (known as indoximod) is in clinical trials for various cancers.
Epacadostat (INCB24360) and navoximod (GDC-0919) are potent inhibitors of the indoleamine 2,3-dioxygenase enzyme and are in clinical trials for various cancers. BMS-986205 is also in clinical trials for cancer.
↑ 9.09.1Jiang T, Sun Y, Yin Z, Feng S, Sun L, Li Z (2015). "Research progress of indoleamine 2,3-dioxygenase inhibitors". Future Medicinal Chemistry. 7 (2): 185–201. doi:10.4155/fmc.14.151. PMID25686005.
↑ 11.011.111.211.3Yu CP, Fu SF, Chen X, Ye J, Ye Y, Kong LD, Zhu Z (2018). "The Clinicopathological and Prognostic Significance of IDO1 Expression in Human Solid Tumors: Evidence from a Systematic Review and Meta-Analysis". Cellular Physiology and Biochemistry. 49 (1): 134–143. doi:10.1159/000492849. PMID30134237.
