Investigating the Role of Indoleamine 2,3-Dioxygenase in Acute Myeloid Leukemia: A Systematic Review

Abstract

Background: The immunomodulatory enzyme, indoleamine 2,3-dioxygenase (IDO) facilitates tryptophan catabolism at the rate-limiting step of the kynurenine (Kyn) pathway. IDO expression and elevations in Kyn metabolites are associated with immunosuppressive tumor microenvironment including T cell proliferative arrest and generation of regulatory T cells (Tregs) which can favor tumor progression. However, the extent of the role of IDO in acute myeloid leukemia (AML) is currently ill-defined. This study reviews the role of IDO-driven Treg function in AML and evaluates the current body of evidence implicating IDO in AML pathogenesis.Method: Studies related to IDO in AML were identified through a systematic review of PubMed and Scopus. Data extracted described sample analysis, IDO expression, IDO in prognosis, techniques used in Treg phenotypic studies, and the effect of IDO inhibitors.Results: Twenty studies were included in the systematic review. Expression of IDO was identified in a range of cells in AML, both inducible and constitutive. Seven studies indicated an association between elevated expression and poor clinical prognosis. Six studies suggested a positive correlation between IDO expression and Treg induction, with FoxP3 being the prominent Treg phenotypic marker. Of eight studies investigating IDO inhibition, some reported reductions in Treg frequency and enhanced effector T cell proliferation.Conclusion: This review highlights that IDO expression in AML is associated with poor prognosis and measurement of IDO and its Kyn metabolites may offer utility as prospective prognostic markers. Pharmacological inhibition of IDO using novel drugs may hold promise for the treatment of AML.

Adipocyte-derived kynurenine promotes obesity and insulin resistance by activating the AhR/STAT3/IL-6 signaling

“…Given that Kyn has been recognized as an immunosuppressive factor 14 , 15 , the above results prompted us to assume that the increased circulating Kyn could be a compensatory effect against chronic inflammation in individuals with obesity. We thus injected the mice subcutaneously with Kyn (20 mg kg −1 d −1 ) or PBS for 30 consecutive days starting from the eighth weeks of a 12-week period of HFD challenge.…”

“…Overexpressed IDO1 exhausts circulating Trp and competitively inhibits the production of other Trp metabolites such as serotonin, which involves in satiety generation and appetite suppression 12 , 13 . Kyn is generally recognized as an immunosuppressive factor 14 , 15 , while obesity is always accompanied by the low-grade chronic inflammation. Therefore, the increase of circulating Kyn has been considered as a compensatory effect 16 , 17 .…”

Plasmacytoid Dendritic Cells, a Novel Target in Myeloid Neoplasms

“…In AML and myelodysplastic syndromes, IDO1 expression has been identified as an independent adverse prognostic factor [ 111 ], able to impair immune response by Treg induction [ 140 ]. Using IDO1 inhibitor is promising in AML [ 141 ] and may be interesting in pDC-AML. T-cells from the AML BM microenvironment also express several immune checkpoint molecules such as PD1, CTLA-4, LAG3, TIM3, GITR, OX40, 4-1BB and ICOS, whereas AML blasts express 4-1BBL, CD80, CD86, ICOSL, PD-L1, PD-L2 and OX40L.…”

Insights on Metabolic Reprogramming and Its Therapeutic Potential in Acute Leukemia

“…Importantly, repopulating tumor cells can escape immune surveillance by transferring to adjacent CD8+ T cells the KYN metabolite, which in turn activates the aryl hydrocarbon receptor (AhR) and increases PD-1 expression [129]. The expression levels of IDO1 and KYN and the activity of KP have also been investigated in the context of hematological malignancies, in particular in AML, where an extensive review of the literature has been recently performed [130,131]. Briefly, an initial study found that the KYN/Trp ratio was higher in the serum of AML patients compared to healthy controls, suggesting that increased IDO activity is associated with lower survival [132].…”