Indoleamine 2,3-dioxygenase (IDO) inhibitors and cancer immunotherapy

Abstract

Strategies for unlocking immunosuppression in the tumor microenvironment have been investigated to overcome resistance to first-generation immune checkpoint blockade with anti- programmed cell death protein 1 (PD-1)/ programmed death-ligand 1 (PD-L1) and anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4) agents. Indoleamine 2,3-dioxygenase (IDO) 1, an enzyme catabolizing tryptophan to kynurenine, creates an immunosuppressive environment in preclinical studies. Early phase clinical trials investigating inhibition of IDO1, especially together with checkpoint blockade, provided promising results. Unfortunately, the phase 3 trial of the IDO1 inhibitor epacadostat combined with the PD-1 inhibitor pembrolizumab did not show clinical benefit when compared with pembrolizumab monotherapy in patients with advanced malignant melanoma, which dampened enthusiasm for IDO inhibitors. Even so, several molecules, such as the aryl hydrocarbon receptor and tryptophan 2,3-dioxygenase, were reported as additional potential targets for the modulation of the tryptophan pathway, which might enhance clinical effectiveness. Furthermore, the combination of IDO pathway blockade with agents inhibiting other signals, such as those generated by PIK3CA mutations that may accompany IDO1 upregulation, may be a novel way to enhance activity. Importantly, IDO1 expression level varies by tumor type and among patients with the same tumor type, suggesting that patient selection based on expression levels of IDO1 may be warranted in clinical trials.

Keywords: 3-dioxygenase; Aryl hydrocarbon receptor; Immune checkpoint inhibitor; Immuno-oncology; Immunotherapy; Indoleamine 2; Precision medicine.

Fig. 1.

Objective response rate (ORR) in selected randomized controlled trials evaluating epacadostat and indoximod. ORR was available from nine randomized controlled trials evaluating either epacadostat or indoximod. No study revealed significant differences in ORR. The vertical axis of the graph shows the National Clinical Trial number and cancer types. The horizontal axis of the graph shows the response rate (0–1). The blue bar illustrates the response rate of IDO inhibitors. The orange bar shows the response rate of the control treatment. The gray bar indicates the response rate of the additional control treatment if the study contains more than two treatment arms. Abbreviations: HNSCC, head and neck squamous cell carcinoma; IDO, indoleamine 2,3-dioxygenase: NSCLC, non-small cell lung carcinoma; OFP, ovarian, fallopian tube, and peritoneal; ORR, objective response rate; RCC, renal cell carcinoma; UC, urothelial carcinoma.

Fig. 2.

Role of IDO in the tumor microenvironment. The expression of IDO is regulated by signaling pathways such as: (1) the PI3K-AKT-mTOR pathway; (2) the JAK-STAT pathway, which is typically upregulated by inflammatory molecules including PGE2, IFN γ, and IL-6; (3) tryptophan metabolites, which are catabolized from tryptophan by IDO or TDO activate the AhR pathway, leading to accumulation of TAM and Treg, and an increase in tolerogenicity of MDSCs around the tumor cells, making the tumor microenvironment immunosuppressive; (4) tryptophan catabolites, which also increase the expression of PD-1 on the surface of T cells and inhibit the cell signaling inside cytotoxic T cells, resulting in suppression of T cell function towards cancer cells. Abbreviations: AhR, aryl hydrocarbon receptor; AKT, protein kinase B; ATP, adenosine triphosphate; CoA, coenzyme A; COX2, cyclooxygenase 2; ERK, extracellular signal-regulated kinase 1/2; ETV4, ETS variant transcription factor 4; GSK3β, glycogen synthase kinase 3 beta; IDO, indoleamine 2,3-dioxygenase; IFN γ, interferon gamma; IFN γR, interferon gamma receptor; IL-1, interleukin 1; IL-6, interleukin 6; IL-6R, interleukin 6 receptor; IL-R, interleukin receptor; Kyn, kynurenine; MDSC, myeloid-derived-suppressor cell; MHC1, major histocompatibility complex 1; mTORC1, mammalian target of rapamycin complex 1; NAD+, nicotinamide adenine dinucleotide; NFkB, nuclear factor kappa B; PD-1, programed cell death 1; PD-L1, programmed death-ligand 1; PGE2, prostaglandin E2; PGE2R, prostaglandin E2 receptor; PI3K, phosphoinositide 3-kinase; PKC, protein kinase C; PTGS2, prostaglandin-endoperoxide synthase 2;STAT1, signal transducer and activator of transcription 1; STAT3, signal transducer and activator of transcription 3; TAM, tumor-associated macrophage; TCR, T-cell receptor; TDO, tryptophan-2,3-dioxygenase; TNFα, tumor necrosis factor alpha; Treg, regulatory T cell; Trp, tryptophan.

Fig. 3.

High IDO1 RNA (≥75 percentile rank) expression rate across cancer types. Different patterns of IDO1 RNA expression based on the primary site of cancer are shown (n = 514). Transcriptomic sequencing was used to evaluate the expression of IDO1 based on RNA transcript abundance normalized to internal housekeeping gene profiles and ranked (0–100 percentile) in a standardized manner to a reference population of 735 tumors spanning 35 histologies. The expression profiles were stratified by rank values into “Low” (0–74), and “High” (75–100) as previously described [63]. The percentage of the population with high expression is shown in this graph. Among diverse types of cancer, RNA expression of IDO1 was highest in patients with uterine cancer (52.2 %, 12/23 patients) followed by ovarian cancer (37.2 %, 16/43), lung cancer (25 %, 5/20), and esophageal cancer (17.6 %, 3/17). Abbreviations: IDO1, Indoleamine 2,3-dioxygenase 1; RNA, Ribonucleic acid.