Inflammatory programming and immune modulation in cancer by IDO

Inflammatory programming and immune modulation in cancer by IDO


Courtney Smith1, George C Prendergast1, 2, †

1 Lankenau Institute for Medical Research (LIMR), Wynnewood PA USA;
2 Department of Pathology, Anatomy and Cell Biology, Jefferson Medical School and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia PA USA;

Corresponding author : Lankenau Institute for Medical Research, 100 Lancaster Avenue, Wynnewood PA 19096 USA.
Phone +1-617-699 5419. E-mail


June 2013




Immune dysregulation is one of the hallmarks of tumor growth and progression, a key event that allows for tumor evasion of the host immune system. More recent cancer modalities are embracing combinations incorporating immunotherapy with more traditional chemotherapy and radiotherapy. Traditional approaches are difficult to tolerate for the patient and become less effective as tumors evolve to survive these treatments. Immunotherapy has the benefit of reduced toxicity as it utilizes the patient's own immune system to identify and eliminate tumor cells. One mechanism manipulated by tumors is upregulation of the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO). In this review, we focus on the mechanism by which tumors use IDO to evade detection by T cell immunity, as well as on novel small molecules that inhibit it as a cancer therapeutic strategy.

Diversity of IDO-related immunoregulatory enzymes

Identification of the non-hepatic tryptophan catabolizing enzyme, indoleamine 2,3-deoxygenase (IDO; EC; originally D-tryptophan pyrrolase) was first reported in 1963 (Higuchi and Hayaishi, 1967; Higuchi et al., 1963). IDO, also known as IDO1, catalyzes the first and rate-limiting step that converts tryptophan to N-formyl-kynurenine, a process that utilizes oxidative cleavage of the 2,3 double bond in the indole ring resulting in the biosynthesis of nicotinamide adenine dinucleotide (NAD) (Takikawa, 2005). The catabolism of tryptophan can also occur through the enzyme tryptophan 2,3-dioxygenase (TDO2), though studies have shown that the enzymes are not redundant. While both IDO1 and TDO2 catalyze this same reaction, beyond that the two enzymes are structurally distinct and do not share any significant sequence similarity. Structurally, IDO1 exists as a 41kD monomeric enzyme whereas TDO2 is a 320kD homotetramer (Watanabe et al., 1981). Furthermore, TDO2 and IDO1 are differentially localized. Unlike TDO2, IDO1 is not involved in the dietary homeostasis of tryptophan degradation. Instead IDO1 is found in various cells including immune cells, endothelial cells, fibroblast and some tumor cells (Serafini, et al., 2006; Friberg et al., 2002; Uyttenhove et al., 2003; Munn et al., 2004).

IDO1 is relatively well conserved between species suggesting evolutionary importance. The primary sequence of IDO1 is 63% identical between mouse and human. The crystal structure of IDO1 and the resulting site-directed mutagenesis show that both substrate binding and the precise relationship between the substrate and iron-bound dioxygen are necessary for activity (Sugimoto et al., 2006). More recently, a homolog to IDO1, termed IDO2, has been identified. Initially, a missannotation in the human genome database prevented the identification of IDO2. The correction of this error revealed the 420 amino acid open-reading frame that shares 44% sequence homology with IDO1 (Ball et al., 2007; Metz et al., 2007). Importantly, IDO2 contains the conserved residues that are identified as critical for tryptophan binding and catabolism (Sugimoto et al., 2006). Between mouse and human, IDO2 is 73% identical at the primary sequence. Due to the recent discovery of IDO2, there is still much to learn about this enzyme. While both human and murine IDO2 enzyme have been shown to catabolize tryptophan to kynurenine, IDO2 has a distinct pattern of expression that differs from both IDO1 and TDO2 (Metz et al., 2012). Using total RNAs from human tissues, full-length IDO2 was found expressed in the placenta and brain. Interestingly, primers located in exon 10 showed IDO2 mRNA in a greater number of tissues including liver, small intestine, spleen, placental, thymus, lung, brain, kidney and colon supporting the possible existence of additional splice isoforms and perhaps transcriptional start or polyadenylation sites. To further complicate its study, transcripts of IDO2 in murine tissues are localized to liver and kidney which differs from human tissues somewhat. Interestingly, IDO2 mRNA is expressed in murine pre-dendritic cells and following stimulation with IFNγ, IL-10 or lipopolysaccharide (LPS), IDO2 protein can be detected (Metz et al., 2012), suggesting in these specialized antigen-presenting cells of the immune system.

IDO in the immune system

The first evidence for a role of IDO in immune regulation was observed when IDO expression was induced following viral infection or treatment with interferon (IFNγ), an important inflammatory cytokine (Yoshida et al., 1979; Yoshida et al., 1981). A prior observation that IDO is present in the urine of cancer patients then re-surfaced and its importance re-evaluated (Rose, 1967). A groundbreaking study from Munn and Mellor in 1999 directly established IDO as an important immune regulator (Munn et al., 1998). This study showed that pregnant female mice treated with 1-methyl-tryptophan (1MT), an IDO inhibitor, caused rejection of allogeneic concepti but not syngeneic concepti. Further studies showed that this occurs through an MHC-restricted T cell-mediated rejection of the allogeneic mouse concepti (Mellor et al., 2001). These findings have been widely interpreted to mean that the normally high levels of IDO in the placenta are important in preventing the maternal immune system from attacking the "foreign" fetus.

Once IDO was established as an immune modulator, studies have focused on its role both in disease states as well as in normal immune surveillance. The immunosuppressive function of IDO1 manifests in several manners. Collectively, IDO1 and its metabolites can directly suppress T cells (Fallarino et al., 2002; Frumento et al., 2002; Terness et al., 2002; Weber et al., 2006) and NK cells (Della Chiesa et al., 2006) as well as enhance local Tregs (Fallarino et al., 2003). The protumorigenic capabilities of myeloid derived suppressor cells (MDSCs) (Smith et al., 2012) suggest that this population is also affected by IDO1. Furthermore, IDO1 is produced in response to IFN-γ in endothelial cells, fibroblasts and the immune cells including dendritic cells and myeloid derived cells (Taylor and Feng, 1991; Burke et al., 1995; Varga et al., 1996; Munn et al., 1999; Hwu et al., 2000). It has therefore been hypothesized that IDO1 not only regulates immunity at the level of T cells but is regulated by or and regulated by cytokine production in the host that is associated with the generation of a pro-tumorigenic microenvironment. A role for IDO1 in cancer is further suggested by the fact that many human tumor cells themselves express IDO1 (Uyttenhove et al., 2003; Taylor and Feng, 1991).

IDO in cancer

Treatment of cancer commonly entails surgical resection followed by chemotherapy and radiotherapy. The standard regimens show highly variable degrees of success in the longer term, because of the ability of tumor cells to escape these treatments to regenerate primary tumor growth and more importantly seed distant metastasis. The production of IDO in the tumor microenvironment appears to aid in tumor growth and metastasis. It is logical then to target IDO as a means of slowing tumor progression. This has been the premise of several recent studies.

Studies have revealed a pathophysiological link between IDO1 and cancer, with increased levels of IDO1 activity associated with a variety of different tumors (Brandacher et al., 2006; Okamoto et al., 2005). In a case study of ovarian cancer, overexpression of IDO correlated with poorer survival. Immunohistochemical staining on tumor sections were categorized as negative or positive, with the latter further defined as sporadic, focal or diffusely staining. While patients with no IDO expression had greater than 5-year survival following surgery, the three subcategories of positive IDO staining showed a 50% survival of patients to 41, 17 and 11 months, inversely correlated with the amount of staining (Okamoto et al., 2005). Two mechanisms by which IDO suppresses the local immune system are inhibition of effector T cells or activation of Tregs (Fallarino et al., 2006; Munn and Mellor, 2007). In the colorectal study, high IDO expression was associated with few tumor infiltrating CD3+ T cells. In addition to affecting the local environment, tumor biopsies with high expression of IDO in both colorectal and hepatocellular carcinomas have shown greater metastasis in patients (Brandacher et al., 2006; Pan et al., 2008). While these studies showed IDO expressed by the tumor itself, other clinical studies have found both stromal cells and surrounding immune cells to be the source of IDO overexpression. Poor survival correlated with IDO-positive eosinophils in small cell lung cancer (Astigiano et al., 2005) while a study of melanoma patients showed poor prognosis in patients with detectable IDO in the dendritic cells (DC) from the tumor draining lymph nodes (Lee et al., 2003; Munn et al., 2004).

These clinical cancer studies are supported and enhanced by studies in the mouse model. As shown in the clinical studies, tumors may induce IDO1 production in neighboring cells such as antigen presenting dendritic cells located in the tumor-draining lymph nodes (TDLNs). 4T1 is a highly malignant breast carcinoma-derived cell line that, following orthotopic engraftment into the murine mammary fatpad, forms tumors of the latter variety in which no IDO1 expression is detectable in the primary tumor but is found expressed at high levels in the TDLNs. The IDO1-expressing cells in the TDLNs appear morphologically to be plasmacytoid dendritic cells. A similar pattern of IDO1 expression has previously been observed in a mouse model of melanoma (Munn et al., 2004). Importantly D-1MT treatment of 4T1-tumor bearing mice cooperated with chemotherapy to suppress primary tumor growth, ascribing an immunosuppressive role of IDO1 in the TDLNs (Hou et al., 2007).

The use of an immunogenic tumor cell line transfected to overexpress IDO demonstrated that IDO prevents immune surveillance from rejecting these tumors in preimmunized mice. There was also a reduction in tumor associated T cells. Furthermore the use of 1MT resulted in a slowed progression of the tumor, further implicating IDO as a tumor evasion mechanism (Uyttenhove et al., 2003). In the MMTV-neu mouse model of breast cancer, the synergistic benefit of combining chemotherapy with the indoleamine-2,3-dioxygenase (IDO1) inhibitor 1-methyl-D-tryptophan was observed (Muller et al., 2005). It was shown that the effects of D-1MT were greatly enhanced when given in conjunction with the commonly used chemotherapeutic agent paclitaxel. Depletion of either CD4+ or CD8+ T-cells in these mice abolished the benefit provided by D-1MT, indicating the importance of T cell immunity to the antitumor response. These studies have all led to the initiation of phase I clinical trials testing the efficacy of 1-MT as a cancer vaccine adjuvant.

Signaling mechanisms upstream and downstream of IDO

The NF-κB signaling pathway has been implicated in IDO1 signaling through the initial observation that INDO can be induced by interferon-γ (IFN-γ) treatment (Ozaki et al., 1988). A more detailed report showed that BAR adapter proteins encoded by the Bin1 gene are important mediators of NF-κB signaling to IDO. Bin1 is a suppressor of tumor growth that is poorly expressed in tumor cells (Ge et al., 1999; Ge et al., 2000; Tajiri et al., 2003). Using a knockout mouse for Bin1 it was shown that there was an increase in STAT1 and NF-κB signaling leading to increased IDO (Muller et al., 2005; Muller et al., 2004). This suggested that under normal conditions, Bin1 acts to suppress tumor growth by keeping levels of IDO under control. However, loss of this regulatory gene led to increased tumor growth as Bin1 supported T-cell mediated immune surveillance was impaired (Muller et al., 2005). The engraftment of c-myc+ras-transformed skin epithelial cells in syngeneic mice resulted in limited tumor growth if Bin1 was present than if it was deleted, mimicking the effects of Bin1 attenuation in human tumor cells. Notably, the beneficial effects of Bin1 deletion to tumor growth were lost in immune deficient or T-cell depleted mice, revealing the importance of the immune system in mediating the primary effects of Bin1 on tumor growth. Studies in Bin1-deficient cells established that IDO expression was upregulated and that the inhibitor 1MT could phenocopy the effect of Bin1 competency. This work also indicated that Bin1 limits IDO transcription by limiting the activity of NF-κB and STAT which are sufficient to support IDO expression (Muller et al., 2004; Bild et al., 2002).

GCN2 signaling is another mechanism by which IDO may regulate immune cell function. GCN2 is a kinase that acts as a sensor for amino acid starvation. The depletion of tryptophan from the microenvironment can trip GCN2 signaling resulting in apoptosis, cell cycle arrest and differentiation. GCN2 rapidly responds to amino acid deprivation through the phosphorylation of eIF-2α resulting in inhibition of translation (Bild et al., 2006). GCN2 is activated by IDO as a result of the tryptophan deprivation it creates. GCN2 is also a signaling component of T cells which may be a mechanism by which IDO regulates the immune system and produces biological effects. Notably, GCN2-deficient T cells are resistant to the immune suppressive effects of IDO (Munn and Mellor, 2007; Munn et al., 2005). GCN2 signaling switches on the expression of stress-activated proteins that trigger growth arrest and apoptosis as well as differentiation. ATF4, ATF3 and CHOP/GADD153 (Harding et al., 2000; Jiang et al., 2004; Vattem and Wek, 2004; Lu et al., 2004; Hai et al., 1999; Wang et al., 1996; Fan et al.,2002) have been implicated as three critical targets of GCN2 in responding to amino acid deprivation.

Cytokines are critical for immune recognition of tumor cells, but when they are hijacked by the tumor they may provide a mechanism of immune escape for both the primary tumor and distant metastases. This was seen in Ido1-nullizygous mice that exhibited both reduced lung tumor burden in the oncogenic KRAS-induced model as well as in the metastatic 4T1 orthotopic breast cancer model. Both models showed reduction of lung tumor burden that was directly correlated with improved survival of Ido1-/- mice (Smith et al., 2012). Further investigation into the immune regulatory role revealed a reduction in the levels of the inflammatory cytokine IL-6 in IDO-deficient mice. However, when IL-6 was restored in these mice, the rate of metastasis was also restored to levels of wild-type mice. Ex vivo studies of myeloid derived suppressor cells (MDSC) from IDO-deficient mice with 4T1 primary tumors showed an impairment in the ability of MDSC to suppress T cell function, compared to MDSC derived from 4T1 tumor-bearing wild-type mice. The attenuation of IL-6 levels in IDO-deficient mice was associated with an impairment in MDSC function, and as before restoring IL-6 overcame the MDSC defect, allowed metastatic disease to progress at the rate observed in wild-type mice (Smith et al., 2012). The implication of these results was that IL-6 serves as a key regulator of tumor growth downstream of IDO, a connection of potential therapeutic value since IL-6 levels are increased in patients with recurring tumors (Kita et al., 2011).

The mechanisms through which IDO affects tumor growth remain only partly elucidated. One intriguing effector pathway appears to involve the aryl hydrocarbon receptor (AHR), discovered to be a target receptor for kynurenine (Opitz et al., 2011). AHR was discovered originally as the receptor for dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD]). Upon binding to AHR in dendritic cell cultures, TCDD can induce expression of both IDO1 and IDO2 suggesting the presence of a feed-forward regulatory loop (Vogel et al., 2008). It is postulated that induction of IDO1 through TCDD requires a combination of signaling by AHR and RelB, the non-canonical NF-κB signaling molecule that may work through IL-8 and AHR following CD40 ligation (Vogel et al., 2007a; Tas et al., 2007; Vogel et al., 2007b). Furthermore, it was shown that TCDD treatment of mouse splenic T-cells resulted in increased levels of FoxP3, an effect that was abrogated in Ahr-null mice signifying that Ahr is important in the development of Tregs (Vogel et al., 2008). Further mechanistic connections are suggested by observations that kynurenic acid, a byproduct of tryptophan catabolism, also induces AHR activity and results in IL-6 signaling (DiNatale et al., 2010). Interestingly, IDO1-nullizygous mice show a diminished IL-6 levels in primary lung tumors and pulmonary metastases (Smith et al., 2012). Taken together, studies identify AHR and IL-6 (a target of the GCN2 pathway activated by IDO (Metz et al., 2007)) as key players in IDO signaling in cancer.

Clinical trials of IDO inhibitors

IDO is an appealing therapeutic target for cancer treatment for several reasons. Structurally, it is well-defined, allowing for easier discovery of molecular inhibitors. Furthermore, it is both structurally and spatially distinct from the tryptophan catabolic enzymes IDO2 and TDO2. From a clinical viewpoint, pharmodynamic evaluations are eased by measuring serum tryptophan and kynurenine levels. Additionally, while immunotherapies are gaining clinical use, they are often restricted by being either tailored to each patient or expensive. An enzymatic inhibitor provides a more generic and less expensive method to alter immune recognition and elimination of tumor cells. The potential value of targeting IDO in cancer was further given credence by the addition of 1MT onto a select list of the 12 immunotherapeutic agents identified by an NCI workshop panel as having high potential for use in cancer therapy (Koblish et al., 2008). 1MT is a tryptophan analog that entered early stage clinical trials in 2008 and results are expected by the conclusion of 2013. While 1MT may provide antitumor effects, recent preclinical studies in mice have suggested that 1MT does not act directly on IDO but rather downstream in an effector pathway leading to mTOR control (Metz et al., 2012).

An enzymatic inhibitor of IDO termed INCB024360 has entered clinical trials. INCB024360 is a hydrozyamidine that competitively blocks the degradation of tryptophan to kynurenine through IDO with an IC50 of approximately 72 nM (Liu et al., 2010). Similarly to 1MT, treatment with INCB024360 showed attenuated tumor growth in wild-type mice but not in immune-deficient mice (Liu et al., 2010; Koblish et al., 2010). In both mice and dogs, INCB024360 was given orally, resulting in a reduction of kynurenine in the tumors, tumor draining lymph nodes and also plasma (Koblish et al., 2010). There was no apparent maximum tolerated dose determined in the Phase I trials allowing it to move into Phase II trials, where it will be tested as a monotherapy in ovarian cancer and as a combination therapy with ipilimumab for metastatic melanoma.

One interesting aspect of IDO inhibition is that it may already be occurring with other cancer drugs. For example, the paradigm targeted cancer drug Gleevec has been found to suppress IDO expression in GIST cells as a result of Kit inhibition (Balachandran et al., 2011). Another recent study has revealed that the cytotoxic agent β-lapachone is a direct inhibitor of IDO, postulating that this cytotoxic agent may benefit from the additional immunological effects that derive from its potent uncompetitive inhibitory effects on IDO1 activity. Other drugs in use include NSAIDs that indirectly block IDO activity as a result of COX2 inhibition (Sayama et al., 1981). Another effective IDO inhibitor in mouse studies is the anti-inflammatory ethyl pyruvate, which by inhibiting NF-kB activity blocks IDO expression and produces robust anti-tumor responses that are both T cell and IDO dependent (Muller et al., 2010). Taken together, these findings point to a promising future for IDO inhibitors as new tools for immunotherapy and immunochemotherapy of cancer.


Enzymatic formation of D-kynurenine.
Higuchi K, Kuno S, Hayaishi O.
Federation Proc. 1963; 22:243.
Enzymic formation of D-kynurenine from D-tryptophan.
Higuchi K, Hayaishi O.
Arch Biochem Biophys. 1967 May;120(2):397-403.
PMID 4291827
Tryptophan metabolism in carcinoma of the breast.
Rose DP.
Lancet. 1967 Feb 4;1(7484):239-41.
PMID 4163145
Induction of indoleamine 2,3-dioxygenase in mouse lung during virus infection.
Yoshida R, Urade Y, Tokuda M, Hayaishi O.
Proc Natl Acad Sci U S A. 1979 Aug;76(8):4084-6.
PMID 291064
Inhibition of interferon-mediated induction of indoleamine 2,3-dioxygenase in mouse lung by inhibitors of prostaglandin biosynthesis.
Sayama S, Yoshida R, Oku T, Imanishi J, Kishida T, Hayaishi O.
Proc Natl Acad Sci U S A. 1981 Dec;78(12):7327-30.
PMID 6174971
Immunohistochemical localization of indoleamine 2,3-dioxygenase in the argyrophilic cells of rabbit duodenum and thyroid gland.
Watanabe Y, Yoshida R, Sono M, Hayaishi O.
J Histochem Cytochem. 1981 May;29(5):623-32.
PMID 6788834
Induction of pulmonary indoleamine 2,3-dioxygenase by interferon.
Yoshida R, Imanishi J, Oku T, Kishida T, Hayaishi O.
Proc Natl Acad Sci U S A. 1981 Jan;78(1):129-32.
PMID 6165986
Induction of indoleamine 2,3-dioxygenase: a mechanism of the antitumor activity of interferon gamma.
Ozaki Y, Edelstein MP, Duch DS.
Proc Natl Acad Sci U S A. 1988 Feb;85(4):1242-6.
PMID 3124115
Relationship between interferon-gamma, indoleamine 2,3-dioxygenase, and tryptophan catabolism.
Taylor MW, Feng GS.
FASEB J. 1991 Aug;5(11):2516-22. (REVIEW)
PMID 1907934
The role of indoleamine 2,3-dioxygenase in the anti-tumour activity of human interferon-gamma in vivo.
Burke F, Knowles RG, East N, Balkwill FR.
Int J Cancer. 1995 Jan 3;60(1):115-22.
PMID 7814143
Control of extracellular matrix degradation by interferon-gamma. The tryptophan connection.
Varga J, Yufit T, Hitraya E, Brown RR.
Adv Exp Med Biol. 1996;398:143-8.
PMID 8906257
Stress-induced phosphorylation and activation of the transcription factor CHOP (GADD153) by p38 MAP Kinase.
Wang XZ, Ron D.
Science. 1996 May 31;272(5266):1347-9.
PMID 8650547
Prevention of allogeneic fetal rejection by tryptophan catabolism.
Munn DH, Zhou M, Attwood JT, Bondarev I, Conway SJ, Marshall B, Brown C, Mellor AL.
Science. 1998 Aug 21;281(5380):1191-3.
PMID 9712583
Mechanism for elimination of a tumor suppressor: aberrant splicing of a brain-specific exon causes loss of function of Bin1 in melanoma.
Ge K, DuHadaway J, Du W, Herlyn M, Rodeck U, Prendergast GC.
Proc Natl Acad Sci U S A. 1999 Aug 17;96(17):9689-94.
PMID 10449755
ATF3 and stress responses.
Hai T, Wolfgang CD, Marsee DK, Allen AE, Sivaprasad U.
Gene Expr. 1999;7(4-6):321-35. (REVIEW)
PMID 10440233
Inhibition of T cell proliferation by macrophage tryptophan catabolism.
Munn DH, Shafizadeh E, Attwood JT, Bondarev I, Pashine A, Mellor AL.
J Exp Med. 1999 May 3;189(9):1363-72.
PMID 10224276
Loss of heterozygosity and tumor suppressor activity of Bin1 in prostate carcinoma.
Ge K, Minhas F, Duhadaway J, Mao NC, Wilson D, Buccafusca R, Sakamuro D, Nelson P, Malkowicz SB, Tomaszewski J, Prendergast GC.
Int J Cancer. 2000 Apr 15;86(2):155-61.
PMID 10738240
Regulated translation initiation controls stress-induced gene expression in mammalian cells.
Harding HP, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M, Ron D.
Mol Cell. 2000 Nov;6(5):1099-108.
PMID 11106749
Indoleamine 2,3-dioxygenase production by human dendritic cells results in the inhibition of T cell proliferation.
Hwu P, Du MX, Lapointe R, Do M, Taylor MW, Young HA.
J Immunol. 2000 Apr 1;164(7):3596-9.
PMID 10725715
Prevention of T cell-driven complement activation and inflammation by tryptophan catabolism during pregnancy.
Mellor AL, Sivakumar J, Chandler P, Smith K, Molina H, Mao D, Munn DH.
Nat Immunol. 2001 Jan;2(1):64-8.
PMID 11135580
Cytoplasmic transport of Stat3 by receptor-mediated endocytosis.
Bild AH, Turkson J, Jove R.
EMBO J. 2002 Jul 1;21(13):3255-63.
PMID 12093727
T cell apoptosis by tryptophan catabolism.
Fallarino F, Grohmann U, Vacca C, Bianchi R, Orabona C, Spreca A, Fioretti MC, Puccetti P.
Cell Death Differ. 2002 Oct;9(10):1069-77.
PMID 12232795
ATF3 induction following DNA damage is regulated by distinct signaling pathways and over-expression of ATF3 protein suppresses cells growth.
Fan F, Jin S, Amundson SA, Tong T, Fan W, Zhao H, Zhu X, Mazzacurati L, Li X, Petrik KL, Fornace AJ Jr, Rajasekaran B, Zhan Q.
Oncogene. 2002 Oct 24;21(49):7488-96.
PMID 12386811
Indoleamine 2,3-dioxygenase contributes to tumor cell evasion of T cell-mediated rejection.
Friberg M, Jennings R, Alsarraj M, Dessureault S, Cantor A, Extermann M, Mellor AL, Munn DH, Antonia SJ.
Int J Cancer. 2002 Sep 10;101(2):151-5.
PMID 12209992
Tryptophan-derived catabolites are responsible for inhibition of T and natural killer cell proliferation induced by indoleamine 2,3-dioxygenase.
Frumento G, Rotondo R, Tonetti M, Damonte G, Benatti U, Ferrara GB.
J Exp Med. 2002 Aug 19;196(4):459-68.
PMID 12186838
Inhibition of allogeneic T cell proliferation by indoleamine 2,3-dioxygenase-expressing dendritic cells: mediation of suppression by tryptophan metabolites.
Terness P, Bauer TM, Rose L, Dufter C, Watzlik A, Simon H, Opelz G.
J Exp Med. 2002 Aug 19;196(4):447-57.
PMID 12186837
Modulation of tryptophan catabolism by regulatory T cells.
Fallarino F, Grohmann U, Hwang KW, Orabona C, Vacca C, Bianchi R, Belladonna ML, Fioretti MC, Alegre ML, Puccetti P.
Nat Immunol. 2003 Dec;4(12):1206-12. Epub 2003 Oct 26.
PMID 14578884
Pattern of recruitment of immunoregulatory antigen-presenting cells in malignant melanoma.
Lee JR, Dalton RR, Messina JL, Sharma MD, Smith DM, Burgess RE, Mazzella F, Antonia SJ, Mellor AL, Munn DH.
Lab Invest. 2003 Oct;83(10):1457-66.
PMID 14563947
Expression of a MYCN-interacting isoform of the tumor suppressor BIN1 is reduced in neuroblastomas with unfavorable biological features.
Tajiri T, Liu X, Thompson PM, Tanaka S, Suita S, Zhao H, Maris JM, Prendergast GC, Hogarty MD.
Clin Cancer Res. 2003 Aug 15;9(9):3345-55.
PMID 12960121
Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase.
Uyttenhove C, Pilotte L, Theate I, Stroobant V, Colau D, Parmentier N, Boon T, Van den Eynde BJ.
Nat Med. 2003 Oct;9(10):1269-74. Epub 2003 Sep 21.
PMID 14502282
Activating transcription factor 3 is integral to the eukaryotic initiation factor 2 kinase stress response.
Jiang HY, Wek SA, McGrath BC, Lu D, Hai T, Harding HP, Wang X, Ron D, Cavener DR, Wek RC.
Mol Cell Biol. 2004 Feb;24(3):1365-77.
PMID 14729979
Translation reinitiation at alternative open reading frames regulates gene expression in an integrated stress response.
Lu PD, Harding HP, Ron D.
J Cell Biol. 2004 Oct 11;167(1):27-33.
PMID 15479734
Targeted deletion of the suppressor gene bin1/amphiphysin2 accentuates the neoplastic character of transformed mouse fibroblasts.
Muller AJ, DuHadaway JB, Donover PS, Sutanto-Ward E, Prendergast GC.
Cancer Biol Ther. 2004 Dec;3(12):1236-42. Epub 2004 Dec 14.
PMID 15611650
Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes.
Munn DH, Sharma MD, Hou D, Baban B, Lee JR, Antonia SJ, Messina JL, Chandler P, Koni PA, Mellor AL.
J Clin Invest. 2004 Jul;114(2):280-90.
PMID 15254595
Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells.
Vattem KM, Wek RC.
Proc Natl Acad Sci U S A. 2004 Aug 3;101(31):11269-74. Epub 2004 Jul 26.
PMID 15277680
Eosinophil granulocytes account for indoleamine 2,3-dioxygenase-mediated immune escape in human non-small cell lung cancer.
Astigiano S, Morandi B, Costa R, Mastracci L, D'Agostino A, Ratto GB, Melioli G, Frumento G.
Neoplasia. 2005 Apr;7(4):390-6.
PMID 15967116
Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy.
Muller AJ, DuHadaway JB, Donover PS, Sutanto-Ward E, Prendergast GC.
Nat Med. 2005 Mar;11(3):312-9. Epub 2005 Feb 13.
PMID 15711557
GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase.
Munn DH, Sharma MD, Baban B, Harding HP, Zhang Y, Ron D, Mellor AL.
Immunity. 2005 May;22(5):633-42.
PMID 15894280
Indoleamine 2,3-dioxygenase serves as a marker of poor prognosis in gene expression profiles of serous ovarian cancer cells.
Okamoto A, Nikaido T, Ochiai K, Takakura S, Saito M, Aoki Y, Ishii N, Yanaihara N, Yamada K, Takikawa O, Kawaguchi R, Isonishi S, Tanaka T, Urashima M.
Clin Cancer Res. 2005 Aug 15;11(16):6030-9.
PMID 16115948
Biochemical and medical aspects of the indoleamine 2,3-dioxygenase-initiated L-tryptophan metabolism.
Takikawa O.
Biochem Biophys Res Commun. 2005 Dec 9;338(1):12-9. Epub 2005 Sep 15. (REVIEW)
PMID 16176799
The tryptophan catabolite L-kynurenine inhibits the surface expression of NKp46- and NKG2D-activating receptors and regulates NK-cell function.
Della Chiesa M, Carlomagno S, Frumento G, Balsamo M, Cantoni C, Conte R, Moretta L, Moretta A, Vitale M.
Blood. 2006 Dec 15;108(13):4118-25. Epub 2006 Aug 10.
PMID 16902152
The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor zeta-chain and induce a regulatory phenotype in naive T cells.
Fallarino F, Grohmann U, You S, McGrath BC, Cavener DR, Vacca C, Orabona C, Bianchi R, Belladonna ML, Volpi C, Santamaria P, Fioretti MC, Puccetti P.
J Immunol. 2006 Jun 1;176(11):6752-61.
PMID 16709834
Myeloid suppressor cells in cancer: recruitment, phenotype, properties, and mechanisms of immune suppression.
Serafini P, Borrello I, Bronte V.
Semin Cancer Biol. 2006 Feb;16(1):53-65. Epub 2005 Sep 15. (REVIEW)
PMID 16168663
Differential effects of the tryptophan metabolite 3-hydroxyanthranilic acid on the proliferation of human CD8+ T cells induced by TCR triggering or homeostatic cytokines.
Weber WP, Feder-Mengus C, Chiarugi A, Rosenthal R, Reschner A, Schumacher R, Zajac P, Misteli H, Frey DM, Oertli D, Heberer M, Spagnoli GC.
Eur J Immunol. 2006 Feb;36(2):296-304.
PMID 16385630
Prognostic value of indoleamine 2,3-dioxygenase expression in colorectal cancer: effect on tumor-infiltrating T cells.
Brandacher G, Perathoner A, Ladurner R, Schneeberger S, Obrist P, Winkler C, Werner ER, Werner-Felmayer G, Weiss HG, Gobel G, Margreiter R, Konigsrainer A, Fuchs D, Amberger A.
Clin Cancer Res. 2006 Feb 15;12(4):1144-51.
PMID 16489067
Coping with stress: eIF2 kinases and translational control.
Wek RC, Jiang HY, Anthony TG.
Biochem Soc Trans. 2006 Feb;34(Pt 1):7-11. (REVIEW)
PMID 16246168
Characterization of an indoleamine 2,3-dioxygenase-like protein found in humans and mice.
Ball HJ, Sanchez-Perez A, Weiser S, Austin CJ, Astelbauer F, Miu J, McQuillan JA, Stocker R, Jermiin LS, Hunt NH.
Gene. 2007 Jul 1;396(1):203-13. Epub 2007 Apr 18.
PMID 17499941
Inhibition of indoleamine 2,3-dioxygenase in dendritic cells by stereoisomers of 1-methyl-tryptophan correlates with antitumor responses.
Hou DY, Muller AJ, Sharma MD, DuHadaway J, Banerjee T, Johnson M, Mellor AL, Prendergast GC, Munn DH.
Cancer Res. 2007 Jan 15;67(2):792-801.
PMID 17234791
Novel tryptophan catabolic enzyme IDO2 is the preferred biochemical target of the antitumor indoleamine 2,3-dioxygenase inhibitory compound D-1-methyl-tryptophan.
Metz R, Duhadaway JB, Kamasani U, Laury-Kleintop L, Muller AJ, Prendergast GC.
Cancer Res. 2007 Aug 1;67(15):7082-7.
PMID 17671174
Indoleamine 2,3-dioxygenase and tumor-induced tolerance.
Munn DH, Mellor AL.
J Clin Invest. 2007 May;117(5):1147-54. (REVIEW)
PMID 17476344
Noncanonical NF-kappaB signaling in dendritic cells is required for indoleamine 2,3-dioxygenase (IDO) induction and immune regulation.
Tas SW, Vervoordeldonk MJ, Hajji N, Schuitemaker JH, van der Sluijs KF, May MJ, Ghosh S, Kapsenberg ML, Tak PP, de Jong EC.
Blood. 2007 Sep 1;110(5):1540-9. Epub 2007 May 4.
PMID 17483297
RelB, a new partner of aryl hydrocarbon receptor-mediated transcription.
Vogel CF, Sciullo E, Li W, Wong P, Lazennec G, Matsumura F.
Mol Endocrinol. 2007a Dec;21(12):2941-55. Epub 2007 Sep 6.
PMID 17823304
Involvement of RelB in aryl hydrocarbon receptor-mediated induction of chemokines.
Vogel CF, Sciullo E, Matsumura F.
Biochem Biophys Res Commun. 2007b Nov 23;363(3):722-6. Epub 2007 Sep 19.
PMID 17900530
Twelve immunotherapy drugs that could cure cancers.
Cheever MA.
Immunol Rev. 2008 Apr;222:357-68. doi: 10.1111/j.1600-065X.2008.00604.x. (REVIEW)
PMID 18364014
Expression and prognosis role of indoleamine 2,3-dioxygenase in hepatocellular carcinoma.
Pan K, Wang H, Chen MS, Zhang HK, Weng DS, Zhou J, Huang W, Li JJ, Song HF, Xia JC.
J Cancer Res Clin Oncol. 2008 Nov;134(11):1247-53. doi: 10.1007/s00432-008-0395-1. Epub 2008 Apr 26.
PMID 18438685
Aryl hydrocarbon receptor signaling mediates expression of indoleamine 2,3-dioxygenase.
Vogel CF, Goth SR, Dong B, Pessah IN, Matsumura F.
Biochem Biophys Res Commun. 2008 Oct 24;375(3):331-5. doi: 10.1016/j.bbrc.2008.07.156. Epub 2008 Aug 9.
PMID 18694728
Kynurenic acid is a potent endogenous aryl hydrocarbon receptor ligand that synergistically induces interleukin-6 in the presence of inflammatory signaling.
DiNatale BC, Murray IA, Schroeder JC, Flaveny CA, Lahoti TS, Laurenzana EM, Omiecinski CJ, Perdew GH.
Toxicol Sci. 2010 May;115(1):89-97. doi: 10.1093/toxsci/kfq024. Epub 2010 Jan 27.
PMID 20106948
Hydroxyamidine inhibitors of indoleamine-2,3-dioxygenase potently suppress systemic tryptophan catabolism and the growth of IDO-expressing tumors.
Koblish HK, Hansbury MJ, Bowman KJ, Yang G, Neilan CL, Haley PJ, Burn TC, Waeltz P, Sparks RB, Yue EW, Combs AP, Scherle PA, Vaddi K, Fridman JS.
Mol Cancer Ther. 2010 Feb;9(2):489-98. doi: 10.1158/1535-7163.MCT-09-0628. Epub 2010 Feb 2.
PMID 20124451
Selective inhibition of IDO1 effectively regulates mediators of antitumor immunity.
Liu X, Shin N, Koblish HK, Yang G, Wang Q, Wang K, Leffet L, Hansbury MJ, Thomas B, Rupar M, Waeltz P, Bowman KJ, Polam P, Sparks RB, Yue EW, Li Y, Wynn R, Fridman JS, Burn TC, Combs AP, Newton RC, Scherle PA.
Blood. 2010 Apr 29;115(17):3520-30. doi: 10.1182/blood-2009-09-246124. Epub 2010 Mar 2.
PMID 20197554
Non-hematopoietic expression of IDO is integrally required for inflammatory tumor promotion.
Muller AJ, DuHadaway JB, Chang MY, Ramalingam A, Sutanto-Ward E, Boulden J, Soler AP, Mandik-Nayak L, Gilmour SK, Prendergast GC.
Cancer Immunol Immunother. 2010 Nov;59(11):1655-63. doi: 10.1007/s00262-010-0891-4. Epub 2010 Jul 17.
PMID 20640572
Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido.
Balachandran VP, Cavnar MJ, Zeng S, Bamboat ZM, Ocuin LM, Obaid H, Sorenson EC, Popow R, Ariyan C, Rossi F, Besmer P, Guo T, Antonescu CR, Taguchi T, Yuan J, Wolchok JD, Allison JP, DeMatteo RP.
Nat Med. 2011 Aug 28;17(9):1094-100. doi: 10.1038/nm.2438.
PMID 21873989
Does postoperative serum interleukin-6 influence early recurrence after curative pulmonary resection of lung cancer?
Kita H, Shiraishi Y, Watanabe K, Suda K, Ohtsuka K, Koshiishi Y, Goya T.
Ann Thorac Cardiovasc Surg. 2011;17(5):454-60. Epub 2011 Jul 13.
PMID 21881374
An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor.
Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, Trump S, Schumacher T, Jestaedt L, Schrenk D, Weller M, Jugold M, Guillemin GJ, Miller CL, Lutz C, Radlwimmer B, Lehmann I, von Deimling A, Wick W, Platten M.
Nature. 2011 Oct 5;478(7368):197-203. doi: 10.1038/nature10491.
PMID 21976023
IDO inhibits a tryptophan sufficiency signal that stimulates mTOR: A novel IDO effector pathway targeted by D-1-methyl-tryptophan.
Metz R, Rust S, Duhadaway JB, Mautino MR, Munn DH, Vahanian NN, Link CJ, Prendergast GC.
Oncoimmunology. 2012 Dec 1;1(9):1460-1468.
PMID 23264892
IDO is a nodal pathogenic driver of lung cancer and metastasis development.
Smith C, Chang MY, Parker KH, Beury DW, DuHadaway JB, Flick HE, Boulden J, Sutanto-Ward E, Soler AP, Laury-Kleintop LD, Mandik-Nayak L, Metz R, Ostrand-Rosenberg S, Prendergast GC, Muller AJ.
Cancer Discov. 2012 Aug;2(8):722-35. doi: 10.1158/2159-8290.CD-12-0014. Epub 2012 Jul 19.
PMID 22822050
Written2013-06Courtney Smith, George C Prendergast
Institute for Medical Research (LIMR), Wynnewood PA USA (CS); Department of Pathology, Anatomy, Cell Biology, Jefferson Medical School, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia PA USA (GCP)


This paper should be referenced as such :
Smith, C ; Prendergast, GC
Inflammatory programming, immune modulation in cancer by IDO
Atlas Genet Cytogenet Oncol Haematol. 2013;17(12):856-862.
Free journal version : [ pdf ]   [ DOI ]
On line version :