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Deep Insight Section
Inflammatory programming and immune
modulation in cancer by IDO
Courtney Smith, George C Prendergast
Lankenau Institute for Medical Research (LIMR), Wynnewood PA USA (CS), Department of Pathology,
Anatomy and Cell Biology, Jefferson Medical School and Kimmel Cancer Center, Thomas Jefferson
University, Philadelphia PA USA (GCP)
Published in Atlas Database: June 2013
Online updated version : http://AtlasGeneticsOncology.org/Deep/IDOandCancerID20121.html
DOI: 10.4267/2042/51878
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2013 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Abstract
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.
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
Diversity of IDO-related
immunoregulatory enzymes
Identification of the non-hepatic tryptophan
catabolizing enzyme, indoleamine 2,3-deoxygenase
(IDO; EC 1.13.11.42; 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
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(12)
856
Inflammatory programming and immune modulation in cancer by IDO
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 protumorigenic 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).
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 antigenpresenting cells of the immune system.
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 IDOpositive 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
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 reevaluated (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
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(12)
Smith C, Prendergast GC
857
Inflammatory programming and immune modulation in cancer by IDO
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 NFκB 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 KRASinduced 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 IDOdeficient 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 IDOdeficient mice was associated with an impairment in
MDSC function, and as before restoring IL-6 overcame
the MDSC defect, allowed metastatic disease to
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-2,3dioxygenase (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,
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(12)
Smith C, Prendergast GC
858
Inflammatory programming and immune modulation in cancer by IDO
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.
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.
Clinical trials of IDO inhibitors
IDO is an appealing therapeutic target for cancer
treatment for several reasons. Structurally, it is welldefined, 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
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(12)
Smith C, Prendergast GC
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This article should be referenced as such:
Smith C, Prendergast GC. Inflammatory programming and
immune modulation in cancer by IDO. Atlas Genet Cytogenet
Oncol Haematol. 2013; 17(12):856-862.
862