The Role of Indoleamine 2, 3-Dioxygenase 1 in Regulating Tumor Microenvironment

Abstract

Indoleamine 2, 3-dioxygenase 1 (IDO1) is a rate-limiting enzyme that metabolizes an essential amino acid tryptophan (Trp) into kynurenine (Kyn), and it promotes the occurrence of immunosuppressive effects by regulating the consumption of Trp and the accumulation of Kyn in the tumor microenvironment (TME). Recent studies have shown that the main cellular components of TME interact with each other through this pathway to promote the formation of tumor immunosuppressive microenvironment. Here, we review the role of the immunosuppression mechanisms mediated by the IDO1 pathway in tumor growth. We discuss obstacles encountered in using IDO1 as a new tumor immunotherapy target, as well as the current clinical research progress.

Keywords: dendritic cell; indoleamine 2,3-dioxygenase 1; interferon-γ; myeloid-derived suppressor cell; regulatory T cell; tumor microenvironment.

Figure 1

Regulation of activating IDO1 transcription. IFN-γ promotes STAT1 phosphorylation by JAK, then STAT1 dimerization binding to GAS-2 and GAS-3 sites upstream of the IDO1 coding region to activate IDO1 transcription and induce IRF-1 synthesis. IRF-1 binds to ISRE-1 and ISRE-2 sites in concert with STAT1 to promote IDO expression. IFN-β upregulates IDO1 expression via activating JAK1/TyK2 and STAT1/STAT2. Another regulatory pathway, activation of IKKα by NF-κB-inducing kinase (NIK) results in the formation of p52-REL-B dimers, which promotes NF-κB translocation and attaches to the IDO1 coding region. TNF-α synergistically enhancing the IDO1 induction effect of IFN-γ.

Figure 2

Immunosuppression network mechanism of TADCs, Tregs, and MDSCs in TME. iDCs activate IDO1 expression through CTLA-4 ligation with B7, then are transformed into tDCs lacking the function of activating CD8 + T-cell upon induction of IFN-γ from TME. IDO1 of tDCs can be strongly induced by the Kyn metabolite 3-HAA and the Wnt3a and Wnt5a receptors accumulated in TME. Kyn produced by tDCs metabolism binds to AhR of T cells, stimulating their differentiation into Foxp3 + Tregs. In response to depleted Trp, the GCN2 pathway of Foxp3 + Tregs is activated to suppress tumor immune responses. Tumor-derived IL-6 promotes STAT3 phosphorylation, which upregulates NF-κB-driven IDO1 expression and activates immunosuppressive functions of MDSCs. On the other hand, high expression of CARD9 in MDSCs inhibits immunosuppressive function via the NF-κB pathway. Foxp3 + Tregs and MDSCs interact to influence each other’s ability to migrate to tumors. Moreover, IDO1-activated Tregs cause proliferation of TAMs.

Figure 3

Immunosuppression mechanism of other TME-related cells in TME. IDO1 metabolism in tumors produces an overaccumulation of Kyn. Kyn binds and activates AhR of TAMs, drives TAMs to secrete adenosine to interfere with T cells’ immune function in TME. CD155 expression on TAMs also is upregulated to promote tumor immunosuppression. Kyn binds and activates AhR of NK cells and downregulates NKp46 and NKG2D receptor expression. The significant reduction of these natural cytotoxic receptors inhibits the function of NK cells to kill tumor cells. The major tumor stromal cells CAFs secrete IL-6, which educates iDCs to acquire a tolerogenic phenotype, and further promotes tumor immunosuppression. IFN-γ/IFN-β from tumor induce TRCs into dormancy by activating IDO1 expression. Increased IDO1 expression in B cells drives their conversion to iBregs. iBregs are involved in regulating the immune function of T cells and Tregs in TME.