The Role of Indoleamine-2,3-Dioxygenase in Cancer Development, Diagnostics, and Therapy

Abstract

Tumors are composed of abnormally transformed cell types and tissues that differ from normal tissues in their genetic and epigenetic makeup, metabolism, and immunology. Molecular compounds that modulate the immune response against neoplasms offer promising new strategies to combat cancer. Inhibitors targeting the indoleamine-2,3-dioxygenase 1 enzyme (IDO1) represent one of the most potent therapeutic opportunities to inhibit tumor growth. Herein, we assess the biochemical role of IDO1 in tumor metabolism and immune surveillance, and review current diagnostic and therapeutic approaches that are intended to increase the effectiveness of immunotherapies against highly aggressive and difficult-to-treat IDO-expressing cancers.

Keywords: cancer diagnostics; clinical trial; gene expression; immune surveillance; immunotherapy; indoleamine-2,3-dioxygenase; metabolism.

Figure 1

The biochemical function and regulation of indolamine-2,3-dioxygenase 1 (IDO1). (A) The kynurenine (Kyn) pathway of tryptophan (Trp) catabolism. l-Trp is metabolized in three separate biochemical pathways (indicated by arrows). In the Kyn pathway, IDO1/IDO2 and tryptophan-2,3-dioxygenase (TDO) catalyze the first and rate-limiting step of Trp degradation that gives rise to N-formylkynurenine. N-formylkynurenine is then transformed into l-Kyn and formic acid by kynurenine formamidase. l-Kyn is converted to anthranilic acid by kynureninase or l-hydroxykynurenine by kynurenine hydroxylase. Non-specific hydroxylation of anthranilic acid results in l-hydroxykynurenine. Kynureninase converts l-hydroxykynurenine to 3-hydroxyanthranilic acid that is further metabolized by hydroxyanthranilate dioxygenase to aminocarboxymuconic semialdehyde. The semialdehyde spontaneously forms quinolinic acid that is a precursor of NAD⁺ synthesis, or a decarboxylase enzyme converts it to aminomuconic semialdehyde. Aminomuconic semialdehyde is then converted to picolinic acid or glutaryl-CoA that is metabolized in the tricarbonic acid cycle and terminal oxidation. Metabolites that are highlighted in red have been directly implicated in immunosuppressive mechanisms and cancer development. (B) The structure of the IDO1 gene. IDO1 is located on chromosome 8 [39771328–39786309 forward (+) strand; 14,982 base pairs] comprising 10 exonic region (red bars). The promoter region (green section upstream the transcription start site) contains several transcription factor-binding sites that have been identified by ChIP sequencing. ChIP peaks were collected from the GTRD database of transcription binding sites (3). Only normal (non-transformed) cell types were considered. (C) The role of IDO1 in cancer immunoediting. In the first phase of immunoediting (“elimination”), sporadically arising transformed cells are destroyed by the innate and adaptive immune systems. Activated B cells produce tumor reactive antibodies to eradicate most transformed cells. Natural killer (NK) cells and effector T cells release inflammatory cytokines, such as IFN-γ, which activate dendritic cells (DCs) that secrete low levels of IDO1. IDO1 depletes the essential amino acid Trp from the tumor microenvironment that inhibits tumor growth. In the “equilibrium” phase, surviving tumor cells are still controlled by the immune system; however, they rapidly accumulate mutations. When the immune system can no longer block the abnormal and autonomous growth of “edited” cells, the tumor becomes clinically manifested (“escape”). The escape phase is associated with high IDO1 level that is primarily produced by tumor cells and tolerogenic immune cells [e.g., tolerogenic DCs, myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs)]. Trp depletion and Kyn accumulation lead to immunosuppression and tolerogenicity by inhibiting effector T cell and NK cell functions and stimulating regulatory T cells. IDO1 also promotes the expansion and activation of MDSCs and induces polarization of macrophages to a tolerogenic phenotype. Increased Kyn levels activate the aryl hydrocarbon receptor (AhR) that switch the activity of DCs from immunogenic to tolerogenic. Elevated CTLA4 expression of regulatory T cells results in further increase of IDO1 secretion by DCs. IDO1-induced expansion and activation of regulatory T cells, tolerogenic DCs, and MDSCs suppress the activity of antitumor effector T cells. Other immunosuppressive agents (e.g., PD-L1/PD-1, CTLA4) also inhibit effector T cell functions. Oncological immunotherapy aims to reverse immunoediting (backward arrow) by inhibiting and activating local immunosuppressive and tumor eradication mechanisms, respectively.