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.

IDO and intra‐tumoral neutrophils were independent prognostic factors for overall survival for hepatocellular carcinoma

“…There are three Trp‐catabolic enzymes (IDO1, IDO2, and TDO) in mammals which catalyze conversion of the essential amino acid tryptophan (Trp) to kynurenine (Kyn). In humans, IDO1 shows a high protein expression in the peripheral lymph organs, while IDO2 and TDO show high tissue specificity and much lower expression level than IDO1 that significantly restrict their activity . The “IDO” we discussed in this study was IDO1.…”

“…In humans, IDO1 shows a high protein expression in the peripheral lymph organs, while IDO2 and TDO show high tissue specificity and much lower expression level than IDO1 that significantly restrict their activity. 6,17 The "IDO" we discussed in this study was IDO1. In patients with solid tumors, such as colorectal cancer, small cell lung cancer, melanoma, and ovarian cancer, high IDO expression is correlated with a poor prognosis and shorter overall survival.…”

Inflammation-Induced Tryptophan Breakdown is Related With Anemia, Fatigue, and Depression in Cancer

“…IDO1 can be expressed by many different cells, including antigenpresenting cells (APCs) like monocyte-derived macrophages, dendritic cells (DCs) and fibroblasts. Its expression is mainly induced by inflammatory stimuli such as IFN-γ, tumor necrosis factor alpha (TNF-α), IL-1, and IL-2 secreted by Th1 type cells, inflammatory cytokines of innate immune cells as well as TGF-β, IL-10, and adenosine secreted by regulatory T cells (T reg ) (118). IDO1 expression is further stimulated by its own product Kyn via the aryl hydrocarbon receptor (AhR) (119)(120)(121) as well as by the cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) (122).…”

“…An enhanced Trp catabolism via Kyn pathway seems to be involved in immune paralysis against tumor cells. This may be primarily mediated by increased IDO1 expression and subsequent accumulation of Trp metabolites, since IDO1 is either expressed by many tumor cells themselves (see Table 1) or by tumor associated cells such as DCs or endothelial cells (ECs) (118).…”

Heterogeneity and targeted therapy-induced adaptations in lung cancer revealed by longitudinal single-cell RNA sequencing

“…Our data indicate that cancer cells within PD tumors may inhibit the activity of the immune system during targeted therapy. The identification of this pathway as a mediator of immune suppression within PD tumors has important potential therapeutic implications, as IDO1 is known to be upregulated in many cancers (Cheong and Sun, 2018;Hornyák et al, 2018;. Multiple clinical trials have attempted to block this pathway using IDO1 inhibitors as a monotherapy as well as in combination with immune checkpoint inhibitors or hormone therapy (Ricciuti et al, 2019), albeit with limited success.…”