IDO Expression in Cancer: Different Compartment, Different Functionality?

Abstract

Indoleamine 2,3-dioxygenase 1 (IDO1) is a cytosolic haem-containing enzyme involved in the degradation of tryptophan to kynurenine. Although initially thought to be solely implicated in the modulation of innate immune responses during infection, subsequent discoveries demonstrated IDO1 as a mechanism of acquired immune tolerance. In cancer, IDO1 expression/activity has been observed in tumor cells as well as in the tumor-surrounding stroma, which is composed of endothelial cells, immune cells, fibroblasts, and mesenchymal cells. IDO1 expression/activity has also been reported in the peripheral blood. This manuscript reviews available data on IDO1 expression, mechanisms of its induction, and its function in cancer for each of these compartments. In-depth study of the biological function of IDO1 according to the expressing (tumor) cell can help to understand if and when IDO1 inhibition can play a role in cancer therapy.

Keywords: IDO; cancer; indoleamine (2,3)-dioxygenase; kynurenine; tryptophan; tumor immunity.

Figure 1

Schematic representation of IDO expression in different compartments of the immune system during cancer. IDO is expressed by multiple cell types in the tumor microenvironment (A), the tumor-draining lymph node (B) and the peripheral blood (C). (A) Bin1 attenuation results in STAT1- and NFκB-dependent constitutive expression of IDO in cancer cells. In addition, COX2 overexpression facilitates constitutive IDO expression via PGE2-mediated activation of the PKC/PI3K pathways. IFNγ is recognized as a highly potent inducer of IDO expression. Binding of IFNγ to its receptor (IFNγR) leads to (i) tyrosine phosphorylation of STAT-1, triggering its dimerization and binding to the GAS sequence in IDO1 and (ii) NF-κB and STAT-1 dependent synthesis of IFNγ-regulated factor 1 (IRF1), which binds to the ISRE sequences in IDO1. Tumor IDO expression activates the cytosolic transcription factor aryl hydrocarbon receptor (AhR) by kynurenine (Kyn), stimulating an autocrine positive feedback loop via IL-6 dependent STAT-3 signaling which maintains IDO expression. In addition to IFNγ, IDO expression can be induced by other proinflammatory cytokines such as tumor necrosis factor α (TNFα) and IL-1 who enhance the expression of IFNγR on cancer cells. IFNγ and TNFα can also induce IDO expression in endothelial cells of venules in the tumor microenvironment. In the tumor-surrounding stroma, IDO is expressed by cancer associated-fibroblasts, pericytes, and infiltrating immune cells. (B) Regulatory T-cells (Tregs) induce IDO expression by antigen-presenting cells (APCs) via CTLA-4/B7 ligation in the tumor-draining lymph node. In addition, cancer cells are involved in the upregulation of IDO expression in plasmacytoid dendritic cells (pDCs) by shedding of the extracellular domain of the type III TGF-B receptor (sTGFBR3). IDO expression in myeloid DCs (mDCs) can be induced by cancer cell-secreted Wnt5a, which triggers binding of β-catenin to its responsive elements. IDO⁺ APCs inhibit T-cell responses and polarize naïve CD4⁺ T-cell differentiation toward the phenotype of suppressive Tregs via TGFβ-mediated FoxP3 upregulation. Myeloid derived suppressor cells (MDSCs) upregulate IDO via IL-6 triggered STAT-3 activation. (C) IDO⁺ APCs and IDO⁺ MDSCs infiltrate the tumor microenvironment and the peripheral blood, contributing to local and systemic immune escape.