Indoleamine 2,3-Dioxygenase and Its Therapeutic Inhibition in Cancer

Abstract

The tryptophan catabolic enzyme indoleamine 2,3-dioxygenase-1 (IDO1) has attracted enormous attention in driving cancer immunosuppression, neovascularization and metastasis. IDO1 suppresses local CD8+ T effector cells and natural killer cells and induces CD4+ T regulatory cells (iTreg) and myeloid-derived suppressor cells (MDSC). The structurally distinct enzyme tryptophan dioxygenase (TDO) also has been implicated recently in immune escape and metastatic progression. Lastly, emerging evidence suggests that the IDO1-related enzyme IDO2 may support IDO1-mediated iTreg and contribute to B-cell inflammed states in certain cancers. IDO1 and TDO are upregulated widely in neoplastic cells but also variably in stromal, endothelial and innate immune cells of the tumor microenviroment and in tumor-draining lymph nodes. Pharmacological and genetic proofs in preclinical models of cancer have validated IDO1 as a cancer therapeutic target. IDO1 inhibitors have limited activity on their own but greatly enhance ‘immunogenic’ chemotherapy or immune checkpoint drugs. IDO/TDO function is rooted in inflammatory programming, thereby influencing tumor neovascularization, MDSC generation and metastasis beyond effects on adaptive immune tolerance. Discovery and development of small molecule enzyme inhibitors of IDO1 derived from the hydroxylamidine and phenylimidazole chemotypes have advanced furthest to date in Phase II/III human trials (epacadastat and GDC-0919/navoximod, respectively). Second generation combined IDO/TDO inhibitors may broaden impact in cancer treatment, for example, in addressing IDO1 bypass (inherent resistance) or acquired resistance to IDO1 inhibitors. This review surveys knowledge about IDO1 function and how IDO1 inhibitors reprogram inflammation to heighten therapeutic responses in cancer.

HLA‐G, HLA‐E, and IDO overexpression predicts a worse survival of Tunisian patients with vulvar squamous cell carcinoma

“…This increase of IDO might have effects on CTL and NK cells by the decrease of tryptophan level and the increase of kynurenine in the vulvar microenvironment, reducing their activation or inducing their apoptosis, and on LT regulators by their activation (Figure ). Consistent with this hypothesis, we found, as for Sznurkowski et al study, a worse survival rate for patients expressing highly IDO.…”

“…IDO is an immunosuppressive enzyme that initiates the tryptophan catabolism . Recent studies proposed that tryptophan degradation by tumor cells may be proposed as a strategy for immune escape .…”

“…IDO can also induce HLA‐G expression on other immune cell like dendritic cells . Overexpression of IDO in VSCC is thought to be active as described by de Jong et al conducing to the degradation of the tryptophan and the generation of kynurenines, that modulates immune responses of LT, NK cells and LT regulators …”

“…Thereby, IDO expression correlates with poor clinical outcome in some cancer types including endometrial, ovary, colorectal, and lung cancers and malignant melanoma . Thus, IDO is actually revealed as a promising novel therapeutic target cancer …”

“…14 Indoleamine 2,3-dioxygenase (IDO) is a tryptophan catabolic enzyme that catalyzes the degradation of tryptophan into kynurenine and other toxic metabolites. 15 IDO plays a key role in T-and NK cells function and activating regulatory T-cells [16][17][18][19] and the subsequent tumor cells. Thereby, IDO expression correlates with poor clinical outcome in some cancer types including endometrial, ovary, colorectal, and lung cancers and malignant melanoma.…”