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Review
. 2018 Aug 2;11(1):100.
doi: 10.1186/s13045-018-0644-y.

Targeting the IDO1 pathway in cancer: from bench to bedside

Ming Liu  1   2 , Xu Wang  3 , Lei Wang  3   4 , Xiaodong Ma  4 , Zhaojian Gong  3   5 , Shanshan Zhang  3   6 , Yong Li  7
Affiliations
Review

Targeting the IDO1 pathway in cancer: from bench to bedside

VSports在线直播 - Ming Liu et al. J Hematol Oncol. .

Abstract

Indoleamine 2, 3-dioxygenases (IDO1 and IDO2) and tryptophan 2, 3-dioxygenase (TDO) are tryptophan catabolic enzymes that catalyze the conversion of tryptophan into kynurenine. The depletion of tryptophan and the increase in kynurenine exert important immunosuppressive functions by activating T regulatory cells and myeloid-derived suppressor cells, suppressing the functions of effector T and natural killer cells, and promoting neovascularization of solid tumors. Targeting IDO1 represents a therapeutic opportunity in cancer immunotherapy beyond checkpoint blockade or adoptive transfer of chimeric antigen receptor T cells. In this review, we discuss the function of the IDO1 pathway in tumor progression and immune surveillance VSports手机版. We highlight recent preclinical and clinical progress in targeting the IDO1 pathway in cancer therapeutics, including peptide vaccines, expression inhibitors, enzymatic inhibitors, and effector inhibitors. .

Keywords: 3-dioxygenases; Clinical trial; IDO1; Immunosuppression; Immunotherapy; Indoleamine 2 V体育安卓版. .

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Figures

Fig. 1
Fig. 1
Overview of the IDO metabolic pathway. Approximately 95% of L-tryptophan (Trp) is catabolized into kynurenine (Kyn) through three rate-limiting enzymes: tryptophan 2,3-dioxygenase (TDO) in the liver and indoleamine 2, 3-dioxygenase 1/2 (IDO1/2) in peripheral tissues. Kyn is converted to 3-hydroxykynurenine (3-HK) by kynurenine 3-monooxygenase (KMO), to anthranilic acid (AA) by kynureninase (KYNase), or to kynurenic acid (KYNA) by kynurenine aminotransferase (KAT). Next, catalyzed by KYNase, 3-HK is converted to 3-hydroxyanthranilic acid (3-HAA), which is further converted to quinolinic acid (QA), picolinic acid, nicotinamide adenine dinucleotide (NAD+), and other molecules
Fig. 2
Fig. 2
The IDO1 gene transcripts across tumor samples and paired normal tissues. Data are summarized from The Cancer Genome Atlas, https://cancergenome.nih.gov/. The Y axis denotes the number of IDO1 transcripts per million of total RNA reads. Abbreviations: ACC, adrenocortical carcinoma; BLCA, bladder urothelial carcinoma; BRCA, breast invasive carcinoma; CESC, cervical squamous cell carcinoma and endocervical adenocarcinoma; CHOL, cholangiocarcinoma; COAD, colon adenocarcinoma; DLBC, lymphoid neoplasm diffuse large B-cell lymphoma; ESCA, esophageal carcinoma; GBM, glioblastoma multiforme; HNSC, head and neck squamous cell carcinoma; KICH, kidney chromophobe; KIRC, kidney renal clear cell carcinoma; KIRP, kidney renal papillary cell carcinoma; LAML, acute myeloid leukemia; LGG, brain lower grade glioma; LIHC, liver hepatocellular carcinoma; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; OV, ovarian serous cystadenocarcinoma; PAAD, pancreatic adenocarcinoma; PCPG, pheochromocytoma and paraganglioma; PRAD, prostate adenocarcinoma; READ, rectum adenocarcinoma; SARC, sarcoma; SKCM, skin cutaneous melanoma; STAD, stomach adenocarcinoma; TGCT, testicular germ cell tumors; THCA, thyroid carcinoma; THYM, thymoma; UCS, uterine carcinosarcoma; UCEC, uterine corpus endometrial carcinoma
Fig. 3
Fig. 3
Regulation, function, and targeting of IDO1 in cancer. a The upstream regulators of IDO1. IDO1 is expressed in cancer cells, endothelial cells, antigen-presenting cells, and stromal cells. IDO1 expression is regulated by IFNs, PD-1, oncogene activation (KIT or RAS), PAMPs, and DAMPs through relevant signaling pathways like IFN-γ/JAK/STAT, PI3K/PKC, and NF-κB. b The downstream effectors of IDO1 and IDO1 targeting. Three effector pathways (mTOR, GCN2, and AhR) mediate the effects of IDO1 activities in various types of cells in regard to immunosuppression, neovascularization, interactions with the gut microbiome, and the tumor microenvironment. Four strategies have been developed to target the IDO1 pathway in preclinical and clinical studies. IDO1, indoleamine 2, 3-dioxygenase 1; Trp, tryptophan; Kyn, kynurenine; IFN, interferon; PD-1, programmed death receptor 1; PAMP, pathogen-associated molecular pattern; DAMP, damage-associated molecular pattern; GCN2, general control over nonderepressible 2; mTOR, mammalian target of rapamycin; AhR, aryl hydrocarbon receptor; NK, natural killer cell; Treg, regulatory T cell; MDSC, myeloid-derived suppressor cell; EC, endothelial cell; DC, dendritic cell
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