I. Introduction
The immune system protects from pathogens that have
the potential to be lethal. In the case of tumors, they usually grow despite an
intact immune system; seemingly with apparent disregard for immune system
control. It is intuitive to think that the immune system would recognize tumor
cells as foreign and destroy them. Unfortunately this is not always the case.
In 1909, Paul Ehrlich proposed the cancer immunosurveillance hypothesis and
predicted that the immune system repressed the growth of cancers that would
otherwise occur with greater frequency (Ehrlich, 1909). This hypothesis was
embraced by tumor immunologists until the 1970s when Stutman showed no
increased frequency of cancers in nude mice (Stutman, 1974). For many decades
thereafter, immunologists focused on immunologic roles in organ transplantation
and pregnancy (Thomas, 1959). Nobel Prize winners F. Macfarlane Burnet and
Peter Brian Metawar focused on immunologic tolerance and its role in allograft
rejection, and ultimately resurrected the concept of natural immune defense
against cancer. Recently, there has been a resurgence in the concept of cancer
immunosurveillance, and it is more appropriately named “cancer immunoediting”
(Dunn et al, 2004). Cancer immunoediting holds that the immune system not only
protects us from tumor development, but also sculpts the tumor phenotype (Dunn et al, 2004).
The final phase of
cancer immunoediting is immune escape from the forces of immunologic control,
and supports the notion that tumor cell-specific neo-antigens could cause
regression of developing cancers (Burnet, 1957; 1964). This concept of immune
tolerance emerged and was described as a state of specific unresponsiveness that
is antigen specific. There is an overall lack of attack on self antigens that
is a normal part of the immune response. Since failure of self-tolerance leads
to autoimmune disease, a delicate balance is imperative for normal immune
function.
It is to be expected that no single mechanism can
completely explain the discrimination of the immune system and regulation of
immune surveillance in circumstances such as pregnancy, auto immune disease,
carcinogenesis and cancer progression. One aspect of the immunoregulatory
process that has gained much attention in tumor immunology over the last
several years is the role of the enzyme indolamine 2, 3- dioxygenase in
modulating T cell responses through the essential amino acid catabolism of
tryptophan. In this review article, we will discuss the mechanism and
consequence of tryptophan metabolism in T-cell-mediated immune response, and
the effect it has on cancer initiation and progression. We have summarized the
evidence supporting this role in immune tolerance including the role of
regulatory T cells. Lastly, we discuss the clinical implications of IDO
inhibition as an adjuvant to potentiate cancer vaccine therapy.
II. What is IDO?
Tryptophan is an amino acid required for protein
synthesis and other metabolic functions. Tryptophan is synthesized from
molecules such as phosphoenolpyruvate in bacteria, fungi and plants, and these
organisms fuel the tryptophan flux through the food chain (Moffett and Namboodiri,
2003). Animals are incapable of synthesizing tryptophan, so they ingest it in
protein form, which is then hydrolyzed into the constituted amino acids. It is
delivered through the hepatic portal system, and that portion which is not used
for protein synthesis in the liver can either be distributed through the blood
stream for protein synthesis or it can be degraded in the liver by the
kynurenine pathway (Moffett and Namboodiri, 2003). There is a clear association
between tryptophan catabolism and inflammatory reactions, which may be
occurring in the immune system rather than in the liver (Moffett and Namboodiri,
2003).
Indoleamine 2, 3-dioxygenase (IDO) is a
heme-containing enzyme that catabolizes the first and rate-limiting step in
oxidative degradation of tryptophan. IDO is encoded by a single gene and is
transcribed in response to inflammatory mediators such as interferon-g (Taylor and Feng, 1991). In the late 1970s, Hayashi et al
discovered that de novo synthesis of
IDO was induced by immune stimulating agents such as lipopolysaccharide
(Hayaishi and
Yoshida, 1978; Yoshida and
Hayaishi, 1978); and later
interferon was found to be one of the primary inducers of IDO synthesis
(Yoshida et al, 1986). Tryptophan depletion by IDO was then thought to be limited to
areas of inflammation where leukocytes were actively producing inflammatory
mediators. In 1984, it was shown that growth of Toxoplasmosis gondii could be inhibited by IFN-mediated IDO
induction, and could be controlled by the amount of tryptophan concentrations
in the culture media (Pfefferkorn, 1984). Tryptophan depletion by IDO was the
principal mechanism responsible for inhibiting parasitic growth. Numerous human
cell lines express IDO when exposed to interferon-g while it is scarcely detected in freshly isolated
tissues (Burke et al, 1995; Varga et al, 1996; Munn et al, 1999; Hwu et al, 2000). Other cytokines such as LPS, TNFa and IL1 act in a synergistic fashion with interferon-g to further increase IDO expression in human dendritic
cells (Babcock and
Carlin, 2000; Hwu et al, 2000).
Anti-inflammatory cytokines such as IL4, IL10 and TGFb inhibit IDO expression (Yuan et al, 1998; MacKenzie et al, 1999).
III. How does Tryptophan deprivation
thwart immune response?
We know that IDO is released by stimuli such as
interferon-g. Tryptophanyl tRNA synthetase is the only amino-acyl
tRNA synthetase whose expression is enhanced by inflammatory mediators such as
interferon-g (Yuan et al, 1998; Munn et al, 1999). Human and murine T cells enter the cell
cycle, but progression terminates midway through the G1 phase before the
commencement of S phase when tryptophan is withheld from the culture media
(Munn et al, 1999). Growth arrested T cells fail to acquire cytolytic effector
functions. This may imply that T cells possess a tryptophan sensitive
checkpoint in the cell cycle that determines whether or not they proliferate
(Mellor et al, 2001). Thus, tryptophan is important for T cell proliferation, as in
its absence T cells arrest in G1 phase of the cell cycle (Mellor et al, 2003). This
enzyme is expressed by human macrophages. When present in the tumor
microenvironment, it suppress T cell responses locally by limiting tryptophan
availability (Mellor and
Munn, 2003).
IDO is important in maintaining maternal tolerance toward the fetus during pregnancy, as well as in suppressing T cell response to MHC-mismatched allografts (Mellor and Munn, 2004). Dendritic cells are key regulators of immune outcomes as they are the most efficient antigen presenting cells in the body. They are capable of promoting or suppressing T cell responses depending on the circumstances (Moser, 2003). They function as the foreman of the immune system, whereby they integrate incoming signals and direct and appropriate T cell response: immune activation or tolerance (Mosmann and Livingstone, 2004).
IV. Regulation of IDO gene expression
The IDO enzyme is encoded by a single gene with 10
exons spread over approximately 15 kb of DNA located in a syntenic region of
human and mouse chromosome 8 (Mellor and Munn, 2004). Transcription is controlled by
responding to inflammatory mediators like IFN-ab and IFN-g interferons (Dai and Gupta, 1990; Taylor and Feng, 1991; Hassanain et al, 1993; Mellor
and Munn, 1999).
Myeloid-lineage cells such as Dendritic cells and macrophages, fibroblasts,
endothelial cells and tumor-cell lines express IDO after exposure to IFN-g (Taylor and Feng, 1991; Burke et al, 1995; Varga et al, 1996; Munn et al, 1999; Hwu et al, 2000).
Signal transducer and activator of transcription and IFN-regulatory factor 1
function cooperatively to mediate the induction of IDO expression by IFN-g, and mice that lack either IFN-g or IRF1 are deficient in IDO expression during
infection (Silva et al, 2002).
Due to the synergistic actions of lipopolysaccharide
(LPS) and the inflammatory cytokine IL-1 and tumor necrosis factor (TNF), they
enhance IDO expression in vitro (Babcock and Carlin, 2000; Robinson et al, 2003). However, in vivo, responsiveness to LPS
depends on TNF, but does not require IFN-g indicating an IFN-g
independent pathway for IDO expression (Fujigaki et al, 2001). There may be some cell
specific inflammatory mediators of transcription, further modulating IDO
expression (Yuan et al, 1998; MacKenzie et al, 1999).
IDO is functionally an intracellular enzyme. This enzyme is known to be found constitutively at the maternal-fetal interface by human extra-villous trophoblast cells (Kudo and Boyd, 2000; Kudo et al, 2001, 2004; Honig et al, 2004). Also at this interface, trophoblast giant cells of fetal origin also express IDO (Baban et al, 2004). Functional IDO expression can be seen in lymphoid organs such as epididymis, colon and ileum, lymph nodes, spleen and thymus (Takikawa et al, 1986). Protein expression may be present without functional activity. Although human DCs constitutively express immunoreactive IDO protein, it does not have enzymatic activity until IFN-g and CD80/CD86 cells activate (Munn et al, 2004). Incorporation of the heme group into the active site is required for IDO activity, and inhibitors of heme biosynthesis inhibit functional activity without affecting protein levels (Thomas et al, 2001).
V. Why doesn’t a mother reject her
fetus?
The immunologic paradox of fetal survival was
investigated by Medawar in 1953. The phenomenon allowing allogenic mammalian
fetus to survive in the maternal circulation contradicted the recent concepts
involved in organ transplantation and rejection. Fetuses have paternally
encoded genes that are foreign to the maternal immune system. The three
possible mechanisms explored were: anatomic separation, antigenic immature
fetus, immunologic inertness of the mother. Since the maternal T cells are
aware of the paternally inherited major histocompatibility complex (MHC) class
I alloantigens during pregnancy (Tafuri et al, 1995; Munn et al, 1998; Jiang and Vacchio, 1998), only the latter seemed plausible. The
enzyme IDO was found in syncytiotrophoblasts (Kamimura et al, 1991), thus in a mouse model,
they exposed syngeneic or allogeneic fetuses to 1-methyl-tryptophan that
competitively inhibits the IDO enzyme activity. PCR product specific for IDO
was found in both syngeneic and allogeneic conceptuses by post conception day
7.5, and by day 9.5, all the allogenic fetuses were deteriorating. When the
experiment was repeated using female mice carrying a defective RAG-1 gene thus preventing lymphocyte
development, the conceptuses were normal. The data demonstrated that inhibition of tryptophan catabolism during
pregnancy allows maternal lymphocytes to mediate fetal rejection (Munn et al, 1998). Also, IDO protected the fetus by suppressing T cell
driven local inflammatory response to fetal alloantigens. Thus, IDO did not act
alone in fetal tolerance.
Another interesting question about the catabolism of
tryptophan by IDO is that tryptophan is an essential amino acid required to
nurture fetal growth. It has been shown that cultured human IDO+ macrophages
express an inducible high affinity tryptophan transporter activity (Munn et al, 1999). This
particular positioning of a tryptophan transporter at the point of contact
between T cells and APCs would provide an effective way for APCs to remove free
tryptophan from T cells rapidly without necessarily depleting tryptophan from
the surrounding tissue milieu (Mellor and Munn, 2001).
Recently, it has been discovered that fetal tissues deplete tryptophan at the maternal-fetal interface, thus inhibiting T cell proliferation (Munn et al, 1998; Mellor et al, 2001). When the fetal trophoblasts invade the uterine tissue at the site of implantation with human leukocyte antigen G, it inhibits maternal natural killer cell activation (Aluvihare et al, 2004). This produces an anatomic barrier, thereby insulating the fetus from maternal immune system (Mellor and Munn, 2000). This may support one of Medawar’s initial three hypotheses for preventing fetal rejection that was later rebuked: anatomic separation.
VI. The role of IDO in the anti-tumor
immune response
Indolamine 2,3 dioxygenase has been detected in
various tumors, including gynecological malignancies (Sedlmayr et al, 2002;
Schroecksnadel et al, 2005) and in tumor draining lymph nodes (Mellor and Munn, 2004). Recent evidence
suggests that IDO plays an important role in suppressing anti-tumor immunity
(Uyttenhove et al, 2003). Mellor and Munn propose that one mechanism by which IDO exerts
suppressive activity involves the generation of regulatory T cells (Mellor and Munn, 2004).
Specifically, they suggest that IDO-arrested T cells can adopt a regulatory T
cell phonotype. Thus, individuals with higher IDO activity might also have
greater regulatory T cells activity; due to the acquired regulatory T cell
phenotype of IDO arrested cells. These regulatory T cells have the
ability to induce expression of IDO by dendritic cells and thus mediate the
inhibitory effects of regulatory T cells. This concept of IDO competent
dendritic cells is combined with concept of immunogenic versus tolerogenic
signal integration (Mellor and Munn, 2004). The IDO
mediated immune regulation would require an immature dendritic cell that would
express IDO and perhaps during maturation, the IDO competent cell can receive
conditioning signal that lead to different signals. For instance, the
tolerogenic signals such as CD80/CD86 ligation by CTLA4+ regulatory T cells
would induce IDO expression, thereby eliciting the functionally suppressive
regulatory T cell phenotype (Mellor and Munn, 2004). Conversely, immunogenic signals such as
CD40 ligation by T helper cells would promote a non-suppressive phenotype and
down regulate IDO expression (Grohmann et al, 2000). It is
believed that both pathways lead to competent and mature APCs, specialized for
opposing functions.
Several studies have demonstrated that IDO expressing
dendritic cells can suppress potent T cell responses in vivo and promote
systemic tolerance (Grohmann et al, 2001a, b) One mechanism by which this may occur is
by recruitment of regulatory T cell development. When mice are exposed to
immunomodulatory agent CTLA4-Ig, IDO may serve as a downstream suppressor
mechanism used by certain Tregs (Mellor et al, 2003), these cells may promote
acquired regulatory T cells that arise extra-thymically and are responsible for
acquired peripheral tolerance and antigen-specific anergy (Bluestone and Abbas, 2003).
Research in tumor immunology has clarified that tumors
can induce tolerance to their own antigens, and thereby evade immune
destruction despite the presence of cytotoxic T cells in the circulation
(Pardoll, 2003). IDO may be involved in this process by preventing T cell
proliferation at the tumor microenvironment. Transfecting tumor cells with IDO rendered a normally immunogenic
tumor cell line resistant to immune rejection in primed hosts that were fully
protected against their untransfected tumors (Uyttenhove et al, 2003). Tumor cells have been
shown to express IDO in vivo (Curiel et al, 2004; Schroecksnadel et al, 2005). This may be a mechanism
at which tumor cells exert their anti-proliferative effect on T cells, thus
enhancing increased tumor survival.
Ubiquitous expression of IDO has been observed in a
population of host APCs in tumor-draining lymph nodes of both humans and mice
(Munn et al, 2004). In this scenario, presentation of tumor antigens by host APCs
allows naďve T cells to be familiarized with tumor derived antigens (Munn et al, 2004).
Dendritic cells either can be activating or tolerizing. Expression by certain
cells of the immune system allows them to inhibit T cell proliferation (Munn et
al, 1999, 2002; Hwu et al, 2000). In recent publications, the downstream
molecular mechanisms that IDO utilizes to regulate T cell function have been
explored. Using a mouse model, IDO expressing plasmacytoid DCs were shown to
activate the GCN2 kinase pathway in responding T cells. In GCN2-knockout T
cells were not inhibited by IDO expressing DCs from tumor-draining lymph nodes,
thus indicating that GCN2 acts as a molecular sensor in T cells that promotes
proliferative arrest and anergy induction in response to IDO (Munn et al, 2004). This mechanism indicates the role of IDO in
stress-related immune response such as malignancy.
IDO expression has been demonstrated in many tumors
and cell lines including hepatocellular carcinoma (Ishio et al, 2004), gynecologic cancer cell
lines such as cervical, vulva, breast and ovarian (Leung et al, 1992). IDO may be exploited by
tumor cells as a mechanism of tumor evasion (Munn and Mellor, 2004). Transfection of IDO in tumor cell lines confers the
ability to inhibit antigen-specific T cell responses in vitro (Mellor et al, 2002). These
tumors are able to grow as a result of local immunosuppression within the tumor
microenvironment. If this is true, in order for APCs to present the tumor
antigens, it must take place at tumor draining lymph nodes (TDLN) (Munn et al, 2004). In a
murine model, TDLN had more IDO+ cells versus few in the lymph nodes that were
negative for tumor (Munn et al, 2004). These same TDLNs had a population of
suppressive DCs, whereas the negative lymph nodes had excellent stimulatory DCs
(Munn et al, 2004). Thus, the population of immunoregulatory DCs in TDLN is
capable of mediating active immunosuppression in vivo, rather than their having
a defective ability to stimulate T cells (Almand et al, 2000; Vicari et al, 2002; Yang et al, 2003
Furumoto et al, 2004). This underscores the localized nature of the immune
suppression that lends support to the cell type specific function of IDO.
One critical barrier of cancer therapy is mechanisms
of drug resistance in tumor cells. Although much is still unknown, multi-drug
resistance genes have been identified in many tumors. The mechanisms of
chemoresistance may not be ubiquitous for all malignancies, and thus tumor
specific identification is necessary. Recently, IDO has been identified as a
mechanism of chemoresistance in ovarian cancer (Okamoto et al, 2005). IDO was identified as
one of 17 genes responsible for chemoresistance in ovarian cancer using gene
chip analysis. Real-time quantitative PCR was performed on chemoresistant cell
lines and tumor from refractory patients, but not in those that were
chemosensitive (Okamoto et al, 2005). Immunohistochemical analysis of IDO protein
showed differences in those tumors with poor versus good prognosis. All
patients without relapse had tumors negative for IDO This single, small study
demonstrates another tumor specific mechanism of tumor survival (Okamoto et al, 2005).
Malignant tumors may exploit the mechanism of T-cell response inhibition by recruiting IDO-expressing APCs to the tumor-draining lymph nodes. Abnormal accumulations of IDO-positive cells with a monocytoid or plasmacytoid morphology were identified in the perisinusoidal regions of draining lymph nodes in 45% of nodes studied (Lee et al, 2003). Recruitment of IDO-positive cells was seen in nodes with and without malignancy. It is possible that these IDO-positive APCs may contribute mechanistically to acquired tolerance to tumor antigens. Immunostaining of tumor-draining lymph nodes for abnormal accumulation of IDO-expressing cells might thus constitute an adverse prognostic factor (Lee et al, 2003).
VII. Cancer vaccines
Vaccinations against cancer aim to induce tumor
specific effector T cells that can reduce the tumor mass, as well as tumor
specific memory T cells that can control tumor relapse (Banchereau and Palucka, 2005). Dendritic
cells are often used as adjuvants for vaccination because of their ability to
regulate T cell immunity by antigen presentation. Dendritic cells can induce
and maintain immune tolerance (Steinman et al, 2003). Central tolerance depends on mature thymic
DCs, which are essential for the deletion of newly generated T cells that have
a receptor that recognizes self components (Brocker, 1999). This may not be
sufficient for all antigens, and those antigens expressed locally will not have
access to them. Thus, peripheral tolerance, which occurs in lymphoid organs,
may be important for antigen presentation. Peripheral tolerance requires
immature DCs to present tissue antigens to T cells in the absence of
appropriate co-stimulation leading to T cell anergy or deletion (Brocker,
1999), or to the development of IL-10 secreting inducible regulatory T cells
(Jonuleit et al, 2000; Dhodapkar et al, 2001). Mature DCs may contribute to peripheral
tolerance by promoting the clonal expansion of naturally occurring regulatory T
cells (Banchereau and
Palucka, 2005).
In order to make the antigen presentation stimulate a more robust immune
response, these mechanisms of T cell activation, regulatory T cell function
provides a basis for a potential revolution in cancer immunotherapy. By
administering an IDO inhibitor such as 1-methyl tryptophan, it may be possible
to break one barrier that allows tumor escape and improve the anti-tumor immune
response.
VII. Preclinical studies of IDO
inhibition and tumor immunity
The mechanism by which IDO interferes with anti-tumor
immunity is of interest. Preclinical studied of IDO inhibition in efforts to
improve anti-tumor immune responses have been done in mouse models. IDO is
under genetic control of Bin1, which is attenuated in many human malignancies
(Muller et al, 2005; Schroecksnadel et al, 2005). Mouse knockout studies indicate that Bin1
loss elevates the STAT1- and NF-kB-dependent expression of IDO, driving escape of oncogenically
transformed cells from T cell-dependent anti-tumor immunity (Muller et al, 2005). In an
established breast cancer mouse model, small-molecule inhibitors of IDO
cooperate with cytotoxic agents to elicit regression of established tumors
refractory to single-agent therapy. This finding suggests that Bin1 loss
promotes immune escape in cancer by deregulating IDO and that IDO inhibitors
may improve responses to cancer chemotherapy. In melanoma studies, when mice
were injected with IDO inhibitor 1-methy-dl-tryptophan, the cytotoxic activity
of the mice NK cells was reduced in a dose dependent fashion (Kai et al, 2003).
IDO acts as an immunosuppressive enzyme, and when expressed by mononuclear cells that invade tumors and tumor-draining lymph nodes, is one mechanism that may account for this function. Lewis lung carcinoma (LLC) cells stimulated a more robust allogeneic T cell response in vitro in the presence of a competitive inhibitor of IDO, 1-methyl tryptophan (Friberg et al, 2002). When administered in vivo this inhibitor also resulted in delayed LLC tumor growth in syngeneic mice. The function of IDO as an inhibitor of cytotoxic activity of NK cells in melanoma has been demonstrated in a dose-dependent manner when an 1-methyltryptophan is given (Kai et al, 2003). In conclusion, these results indicated that IDO plays an important role in anti-tumor immunity by regulating cytotoxic activity of NK cells.
VIII. Conclusions and future directions
The
mechanism by which the immune system of a tumor-bearing host acquires tolerance
toward tumor antigens is still elusive. Antigen-presenting cells (APCs) are
critical regulators of the decision between immune response and tolerance.
Recent evidence suggests that the immunosuppressive effect of IDO may allow tumors
to escape immune surveillance. To date, there are no human clinical studies
utilizing IDO inhibitors to counteract the tolerogenic effects of IDO in the
tumor microenvironment. The manipulation of this enzyme and the modification of
its effects may enhance the efficacy of immunotherapeutic strategies designed
to generate durable anti-tumor immunity.
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