[Frontiers in Bioscience E4, 734-745, January 1, 2012]
Blocking IDO activity to enhance anti-tumor immunity
David H. Munn1
1
TABLE OF CONTENTS
1. Abstract
Tumors express potentially immunogenic antigens, yet the immune response to these antigens is typically profoundly suppressed. Patients with established tumors behave as if they were functionally tolerant to any antigens associated with the tumor. This tolerance reflects a process of active immune suppression elicited by the tumor, and represents a critical barrier to successful anti-tumor immunotherapy. Indoleamine 2,3-dioxygenase (IDO) is a natural immunoregulatory mechanism contributes to immune suppression and tolerance in a variety of settings. In tumor-bearing hosts, animal models suggest that tumor-induced IDO helps create a tolerogenic milieu within the tumor and the associated tumor-draining lymph nodes. IDO directly suppresses the proliferation and differentiation of effector T cells, and markedly enhances the suppressor activity of regulatory T cells (Tregs). Together, these effects contribute to the inability of the immune system to respond effectively to tumor antigens. Treatment of tumor-bearing animals with IDO-inhibitor drugs enhances anti-tumor immune responses, and IDO-inhibitors are synergistic with a variety of chemotherapeutic drugs, anti-tumor vaccines and other immunotherapy. Strategies to pharmacologically inhibit IDO may thus enhance immune-mediated responses following conventional chemotherapy, and may be synergistic with other forms of immunotherapy.
2. TUMOR-INDUCED TOLERANCE
Tumors express a variety of potentially immunogenic antigens (1), and there are many T cells in tumor-bearing hosts that are specific for tumor-associated antigens (2, 3). Despite this antigenicity, once tumors become established they are not spontaneously rejected by the immune system. Functionally, the immune system behaves as if it were tolerant to all antigens associated with an established tumor.
This state of functional tolerance applies not only to self antigens shared by the tumor, but also to authentically foreign antigens (tumor-specific neo-antigens) as well. In some cases the immune system seems unaware of antigens on tumors (immunologic "ignorance") (4, 5); but in many cases the tumor-associated antigens are clearly detected by the immune system, yet there is no effective immune response (tolerance). In the case of autochthonous tumors, this state of acquired tolerance has been shown to be created very early during tumor development (6). During development, the immune system may transiently retard the growth of the developing tumor for a time (7), but all clinically-apparent tumors have evolved mechanisms to escape this immune surveillance.
The molecular mechanisms by which tumors create functional tolerance to themselves are not yet fully defined, but they clearly represent an active process. This is readily seen in the case of transplantable tumors engineered to express a known, immunogenic foreign antigen: when they are implanted, these tumors rapidly create tolerance to the new antigen (8-10). Of critical importance for understanding this process, tolerization appears driven by the host immune system, involving the active participation of host antigen-presenting cells (8), Tregs (11) and other endogenous suppressive mechanisms. The tumor releases factors that recruit the initial tolerizing milieu (12), but the actual mechanisms of suppression that function in this milieu are generated by the immune system itself.
This represents both a challenge and an opportunity for anti-tumor immunotherapy. The challenge is that the immune system in a tumor-bearing host will actively suppress any attempt to generate a therapeutic immune response against the tumor. But the opportunity is that the molecular mechanisms underlying this pathologic suppression are likely to be the same endogenous tolerogenic mechanisms employed by the immune system in other contexts. Thus, the goal for immunotherapy is to identify these endogenous immunosuppressive mechanisms that have been "hijacked" by the tumor, and develop strategies to circumvent them.
3. IDO IS AN ENDOGENOUS MECHANISM OF IMMUNE TOLERANCE
3.1. Natural biologic role of IDO
Indoleamine 2,3-dioxygenase (IDO) is an evolutionarily ancient enzyme that degrades the amino acid tryptophan. In mammals, it is highly inducible by inflammatory stimuli (13). Initially, the role of IDO was assumed to lie in host defense against infection (by starving the microbes of tryptophan), and in certain types of infection this may be true (14, 15). However, IDO is also an endogenous mechanism of immunoregulation and tolerance in the immune system, and it is in this role that it appears to have been co-opted by tumors. In the immune system, the normal role of IDO is to promote certain specific forms of acquired peripheral tolerance, and to control excessive inflammation (reviewed in (16) and (17)). In tissues, local expression of IDO controls innate immunity and excessive inflammation from chronic infection (18, 19), including direct suppression of pro-inflammatory TH17 cytokines IL-6 and IL-17 (20). IDO also can induce antigen-specific tolerance in T cells. IDO is not required for constitutive tolerance to self, as shown by the fact that mice lacking IDO, or treated with IDO inhibitors, do not develop spontaneous autoimmune disorders. However, in the case of acquired peripheral tolerance (i.e., tolerance to new antigens encountered in the periphery), the effects of IDO can be dramatic. IDO is expressed in the placenta, and mice treated with IDO-inhibitor drug during pregnancy spontaneously reject their allogeneic fetuses (21, 22). IDO is also expressed in antigen-presenting cells of the gut, and IDO activity is required for acquired mucosal tolerance (23, 24). In other models, inhibition of IDO markedly exacerbates graft-versus-host disease (25) and autoimmune disorders (26). In tissue-transplantation models, blocking IDO renders the host refractory to a variety of strategies to induce tolerance toward the new graft (27-29). Conversely, tissue allografts that are engineered to overexpress IDO can spontaneously create tolerance to themselves, and are not rejected even across a fully mismatched MHC barrier (29-31). Thus, in certain settings, IDO functions as a potent natural mechanism for creating acquired tolerance and suppressing T cell responses. This natural role can become pathologic when abnormal IDO expression is driven by tumors.
3.2. Biochemical characteristics of IDO
The system historically referred to as "IDO" comprises two related genes, IDO1 and IDO2. These share sequence homology but differ in their regulation and pattern of expression (32, 33). IDO2 was only recently cloned (32, 34), and IDO1 is the more extensively studied of the two. Genetic polymorphisms exist in both genes, and these polymorphisms can affect functional activity (35). The regulation of IDO gene expression is complex. Both IDO1 and IDO2 mRNAs show multiple splice isoforms, and gene expression and enzyme activity are regulated by SOCS3, NF-kB, DAP12 and IRF8 (36-38). The protein is also post-translationally regulated by ubiquitination and protein nitration via iNOS (37, 39).
Given this complexity, it is not surprising that IDO regulation can differ markedly between different cell types. Even in the same cell type (dendritic cells, for example) IDO may be regulated differently depending on the maturation or activation state of the cell. In vivo, IDO is inducible in macrophages and dendritic cells by interferons and other pro-inflammatory signals, and can also be expressed by endothelial cells and other cell types under certain conditions (reviewed in ref. (16)).
IDO1 is a monomeric enzyme with a heme prosthetic group that catalyzes the oxidative cleavage of tryptophan to N-formylkynurenine. (An analogous reaction is catalyzed by the housekeeping enzyme tryptophan oxygenase in liver, but TDO is not known to have any immunoregulatory role.) For its oxidase function, IDO1 can utilize either molecular oxygen or reactive oxygen species (e.g., as supplied by cytochrome P450 or other sources) (40). Historically, enzymology studies of IDO have relied on in vitro systems that use ascorbate and methylene blue as reducing agents to maintain the heme center in the active redox state. This catalase/methylene blue system is not physiologic, but the real reducing system (or systems) that support IDO in vivo are at present unknown. As a caveat, however, it has recently been shown that the conditions of the in vitro assay system can markedly affect the kinetics and substrate specificity of the IDO enzyme (40). Thus, extrapolation from in vitro systems to in vivo enzyme characteristics should be undertaken with a certain caution, since IDO expressed under physiologic conditions may be subject to different reducing systems, cofactors, splice variants and post-translational modifications, depending on the cell type.
3.3. Mechanism of action of IDO
Cells that express IDO create two effects in the milieu around them: depletion of the essential amino acid tryptophan, and production of a series of kynurenine-pathway metabolites. Both of these effects have immunoregulatory properties. Several kynurenine metabolites have been shown to have immunomodulatory effects (41), in particular 3-hydroxyanthranylic acid (42). In certain models, local production of these kynurenine metabolites by IDO is required to control excessive inflammation in tissues (18). The molecular mechanism of action of kynurenines has not been fully elucidated, but may involve inhibition of PDK1® NFkB signaling (43) and/or signaling through the aryl-hydrocarbon receptor (44).
In addition, IDO reduces the local concentration of tryptophan. Tryptophan is an essential amino acid, and low levels have the dual effect of inhibiting the mTOR kinase pathway (an effect analogous to rapamycin), and activating the amino-acid sensitive GCN2 kinase pathway (45). mTOR kinase is a known regulator of immune responses (46). The GCN2 pathway responds to cellular deficiency of one or more amino acids (47), and cells of the immune system appear highly sensitive to regulation by GCN2 (48, 49). GCN2 activation by IDO affects gene expression in both the cell that expresses IDO (50), and in adjacent T cells to which the IDO+ cell presents antigen (45, 51, 52). The effects of local amino-acid depletion on mTOR and GCN2 are not confined only to tryptophan; immunoregulatory enzymes such as arginase can produce analogous affects in other contexts (53). Thus, it has been proposed that amino-acid based regulation may represent a generalized mechanism of control in the immune system (54).
3.4. IDO and Tregs
As described above, kynurenine production and tryptophan depletion can directly inhibit the activation, proliferation and survival of effector T cells. In addition, IDO can create potent indirect suppression by activating the regulatory T cell (Treg) system. Naive CD4+ T cells exposed to IDO during activation are biased to become Foxp3+ inducible Tregs (55-58). IDO can also directly activate mature, pre-existing Tregs for markedly enhanced suppressor function (51). In addition, IDO stabilizes the suppressive phenotype of Tregs under inflammatory conditions, and prevents inflammation-induced reprogramming of Tregs into T-helper-like cells (52, 59, 60). IDO-activated Tregs are found in tumor-draining lymph nodes in mice, where they may contribute to tumor-induced immunosuppression and tolerance (51).
3.5. IDO expression by human cell types
Most mechanistic studies of IDO have been performed in mouse models, but IDO can also be expressed by a variety of human cell types. Cultured human monocyte-derived (myeloid) dendritic cells can express high levels of IDO under certain conditions, although (like mouse dendritic cells) the lineage, maturation state and activating stimulus determines whether IDO is expressed or not. In the case of cultured human dendritic cells, a variety of stimuli and conditions have been reported to lead to IDO expression (36, 58, 61-68). Under other conditions, IDO may be expressed at the protein level but without enzymatic activity (62, 69); while under other conditions dendritic cells may not express IDO at all (70). Human macrophages and plasmacytoid dendritic cells can also express IDO (56-58, 71-73). Functionally, IDO expression by dendritic cells or macrophages can inhibit proliferation of human T cells in vitro (62, 63, 65, 71-73), and can promote the differentiation of Foxp3+ regulatory T cells from human CD4+ T cells (56-58, 74).
4. IDO AFTER HEMATOPOIETIC STEM CELL TRANSPLANTATION
In mouse models of acute graft-versus-host disease, IDO plays a protective role against lethal inflammation and end-organ damage. One key target appears to be the gastrointestinal tract, since mice lacking IDO suffer severe gut damage in graft-versus-host disease (25, 75). This is reasonable, since IDO is naturally expressed in gut, and has been implicated in mucosal tolerance (24) and control of inflammation during colitis (26). In other models, histone deacetylase inhibitor drugs are immunosuppressive and can ameliorate experimental graft-versus-host disease; it has recently been shown that this effect requires induction of host IDO (76). In humans, monocytes from patients following hematopoietic stem cell transplantation showed elevated levels of IDO, and increased IDO-mediated suppression of T cells in vitro (77). The degree to which IDO participates in controlling graft-versus-host disease in humans (and perhaps also contributing to post-transplant immunosuppression (78)) remains to be elucidated; however, based on the results in mouse models, IDO seems likely to play a significant role.
5. IDO AND TUMORS
5.1. IDO and tolerance to tumors
Studies suggest that resting T cells initially become aware of tumor antigens primarily through cross-presentation on host antigen-presenting cells (8, 79, 80). The tumor actively modifies the local milieu (i.e., the tumor microenvironment and draining lymph nodes) so that antigen presentation that occurs in this milieu become anergizing and and tolerogenic (12, 16, 81). Analysis of lymph nodes draining sites of established tumors often show abnormal over-expression of IDO. This can be seen in sentinel lymph nodes of human cancers (62, 82-84), and in experimental tumors in mice (85-87). IDO has also been demonstrated in host stromal cells that are actively recruited by growing mouse tumors, and which appear important for tolerance induction (12) (although the mechanistic contribution of IDO these cells is not yet known).
In mice, IDO-expressing dendritic cells isolated from tumor-draining lymph nodes actively suppress T cell proliferation and create antigen-specific anergy in vitro and in vivo (45, 85). These IDO+ dendritic cells also activate Foxp3+ Tregs in vitro to become markedly more suppressive (51). The phenotype of IDO+ cells in mouse tumor-draining lymph nodes is consistent with plasmacytoid dendritic cells, but with additional co-expression of the B cell-lineage marker CD19 (85, 88). Similar CD19+ plasmacytoid dendritic cells expressing IDO are found in other, non-tumor models of inflammation and tolerance (89, 90). One important point to note is that, in these mouse models, the tumor cells themselves often do not express IDO. The relevant site of IDO expression is thus the host immune cells, and these are often cryptically located in the tumor-draining lymph nodes or in the surrounding stroma at the margins of the tumor (12, 85, 87). This has relevant implications for human studies, because simply biopsying the tumor itself would not have revealed the presence and biological importance of IDO.
5.2. IDO expression in patients with malignancy
In humans, the IDO+ cells found in tumor-draining lymph nodes are less well characterized, but they often display a "plasmacytoid" morphology (82). Studies of melanoma sentinel lymph nodes showed co-expression of the plasmacytoid-dendritic cell marker BDCA2 on IDO+ cells (91), and a study of ovarian cancer suggested that the IDO+ cells co-express CD123 (92). These markers would be consistent with plasmacytoid dendritic cells, although other cell types such as macrophages and endothelial cells in tumors may also express IDO in tumors (72, 93).
IDO has been demonstrated by immunohistochemistry in a wide spectrum of human cancers (94). IDO has been studied in patients with malignant melanoma (85, 95, 96); pancreatic cancer (97, 98); colorectal cancer (99, 100); prostate cancer (93); ovarian cancer (92); acute myelogenous leukemia (74, 101, 102); endometrial cancer (103, 104); and ovarian cancer (105). In several malignancies, the presence of IDO was an independent predictor of a worse clinical outcome (sometimes dramatically worse) (85, 99, 101, 102, 104, 105). In many of these studies, IDO was expressed by the tumor cells themselves (although in most cases the tumor-draining lymph nodes were not studied).
6. CHEMO-IMMUNOTHERAPY WITH IDO-INHIBITOR DRUGS
6.1. Immunologic effects of chemotherapy
An important recent advance in cancer immunotherapy has been the realization that standard chemotherapy drugs can in some cases be combined with anti-tumor immunotherapy to produce synergistic effects (106). Mechanistically, chemotherapy induces a combination of antigen release from dying tumor cells, depletion of suppressor cells, and an immune-activating period of lymphopenia; which together can generate a beneficial (though transient) anti-tumor immune response (107). Indeed, the effects of even standard chemotherapy may be more dependent on this transient immune activation than previously appreciated (108, 109). Unfortunately, the immune response is limited (the tumor invariably re-establishes tolerance); nevertheless, conventional chemotherapy may create a useful window of opportunity in which active immunotherapy can be added to enhance and sustain the immune activation. Clinically, this synergy between chemotherapy and immunotherapy could have profound implications, because patients would no longer need to fail all conventional therapy before becoming candidates for immunotherapy.
6.2. 1MT plus chemotherapy in mouse models
Preclinical studies in mouse tumor models have demonstrated that the IDO inhibitor 1-methyl-tryptophan displays synergy when combined with a variety of chemotherapeutic drugs (22, 110). Active agents included cyclophosphamide, doxorubicin, paclitaxel, cisplatin and gemcitabine. The synergy between 1MT and chemotherapy was immune-mediated, since the effect required an intact immune system. Importantly, this synergy was also demonstrated a model of autochthonous breast tumors, in which each tumor arises through its own unique series of mutations following the initial oncogenic transformation (111). Even though each tumor thus had to develop its own strategy to evade the immune system, all of the tumors responded to the combination of 1MT plus chemotherapy (22). Thus, the fact that 1MT was synergistic with multiple classes of chemotherapy, in multiple different tumor types and genetic mutations, suggests that IDO plays a fundamental and broadly-applicable biologic role in helping suppress the host anti-tumor immune response following chemotherapy.
7. IDO-INHIBITOR DRUGS COMBINED WITH VACCINES AND IMMUNOTHERAPY
Hosts with established tumors respond poorly to therapeutic anti-tumor vaccines (112). In the mouse B16 melanoma model, response to therapeutic vaccination could be significantly enhanced by administration of D-1MT at the time of immunization (52, 60). In part, this appeared to result from the fact that blocking IDO allowed some of the host Tregs to be converted ("re-programmed") into a polyfunctional TH17-like helper phenotype, resulting in enhanced vaccine-induced CD8+ T cell responses (60).
In other studies, administration of D-1MT enhanced the anti-tumor effects of immunotherapy with IL-12 in a 4T1 breast-cancer model (86). Of note, in this latter study the high levels of immunosuppressive IDO were actually created as an unwanted byproduct of the therapy itself (via IFNγ secreted in response to IL-12). This brings up the important point that IDO is frequently induced as a physiologic counter-regulatory mechanism in response to a variety of intense inflammatory stimuli. Thus, for example, IDO is induced by acute graft-versus-host disease (25), excessive lung inflammation (18), high-dose systemic CpG (90) or mycobacterial infection (20, 113). In physiologic settings this counter-regulatory IDO is beneficial, since it prevents mice from dying of uncontrolled inflammation (18, 25). However, in the case of cancer immunotherapy, collateral IDO induction - whether by adjuvants, immune stimulants or activated T cells - would be highly undesirable. Unfortunately, tumor-bearing hosts may be particularly prone to unwanted IDO induction in response to inflammation, especially in the tumor microenvironment and tumor-draining lymph nodes (where IDO is already increased). This could explain why a variety of different mouse models of vaccination and immunotherapy, with diverse mechanisms of action, all benefit from combination with an IDO-inhibitor drug. The common factor may be that any successful anti-tumor inflammatory response, regardless of how it is generated, is liable to trigger unwanted collateral induction of IDO.
8. PRECLINICAL AND CLINICAL STUDIES OF IDO-INHIBITOR DRUGS
8.1. 1-methyl-tryptophan: D and L isomers
The first pharmacologic inhibitor of IDO to be described in vivo was 1-methyl-tryptophan (1MT) (21). A number of additional inhibitors of IDO have been reported in the literature (see refs. (22, 114, 115) and further reviewed in ref. (116)). The most extensively studied inhibitor is 1MT, and this is the first compound to reach clinical trials. 1MT exists as D and L stereoisomers, each with somewhat different properties. L-1MT is far more potent at inhibiting purified IDO in cell-free systems (with the caveat mentioned above that stereoselectivity of the enzyme may be influenced by the choice of in vitro assay conditions (40)). L-1MT is also superior at inhibiting IDO expressed in tumor cell lines (110). However, using assays based on primary human or mouse dendritic cells, D-1MT appears somewhat better at reversing inhibition of T cell proliferation by IDO (110). In vivo, murine studies directly comparing D-1MT vs. L-1MT showed the D isomer to be superior in combination chemo-immunotherapy (86, 110).
The molecular basis for the difference in biological properties of D-1MT and L-1MT is not yet fully elucidated. It has been suggested that the IDO1 and IDO2 enzymes might be differentially sensitive to D-1MT vs. L-1MT (32), although this has not yet been tested in vivo. Perhaps more importantly, as mentioned above the cofactors and reducing system that interact with IDO appear to exert a significant influence on the stereo-selectivity of the enzyme (40). Hence, the relative potency of the D and L isomers of 1MT may differ between different cell types depending on which cofactors, redox systems, and other intracellular conditions predominate in that cell. IDO is also clearly subject to regulation by allosteric effects (40, 117), as well as to transcriptional and post-translational regulation, so some of the inhibitory effects of 1MT may occur in a non-competitive fashion. (For all of these reasons, it may therefore be more accurate to refer to "inhibitors of the IDO pathway", rather than assuming that all inhibitors are competitive.) Finally, it is relevant to consider the possibility of off-target effects, since the L isomer of 1MT is accepted by IDO as a substrate and metabolized (albeit more slowly than authentic tryptophan) into methylated downstream products (117, 118). All of these possibilities will need to be clarified by additional investigation.
That said, both D and L isomers of 1MT have been shown to inhibit functional IDO enzymatic activity (kynurenine production) in vitro, when assays are based on physiologically-relevant IDO-expressing cells. The D isomer of 1MT, which is the isomer in clinical trials, has good biological activity in mouse studies, and inhibits functional IDO activity in human cells in multiple models (56, 62, 68, 72, 73, 110, 119). In all of these models, IDO was physiologically expressed by dendritic cells or macrophages. It is possible that the forms of IDO aberrantly expressed by tumor cells may behave differently (92). However, the preponderance of mouse preclinical studies suggest that the relevant IDO-expressing cells are usually those of the host immune system. Thus, while the topic remains the subject of some debate (120), the on-going clinical trials of D-1MT should soon help clarify the issue of biologic activity.
8.2. Phase I clinical trials of D-1MT
The first IDO-inhibitor drug to reach the clinic, D-1MT, is now in Phase I trials. Preclinical pharmacology/toxicology studies showed D-1MT to have good oral bioavailability and a long half-life (compatible with once- or twice-daily administration), with no dose-limiting toxicity in mice, rats or dogs (121). A first-in-humans clinical trial of D-1MT is ongoing, and only interim results have been reported (122). No efficacy data are yet available, but D-1MT appeared well tolerated. Two patients who had previously received immunotherapy with other agents developed Grade 2 hypophysitis while receiving 1MT. This may represent a recall toxicity, because subsequent patients without prior immunotherapy have not shown hypophysitis. The study is ongoing.
9. SUMMARY AND PERSPECTIVE
In patients with established tumors, the immune system actively suppresses anti-tumor immune responses (tumor-induced tolerance). In order for anti-tumor vaccines and immunomodulators to be optimally effective, strategies must be developed to overcome this tumor-induced suppression. IDO is positioned at the intersection of three key immunosuppressive pathways: inhibition of effector T cells, activation of Tregs, and suppression of inflammation. Abnormal levels of IDO are induced in host cells by the presence of tumor, and IDO can also be expressed by the tumor itself. In addition, IDO can be collaterally induced as a counter-regulatory pathway by a variety of pro-inflammatory stimuli, which may act to antagonize the efficacy of vaccine adjuvants and other immunotherapy approaches. Thus, pharmacologic inhibition of IDO may be synergistic with existing strategies of active immunotherapy, particularly if administered in the window of opportunity following conventional chemotherapy.
10. ACKNOWLEDGEMENTS
Conflict of Interest: The author holds intellectual property in the therapeutic use of IDO and IDO inhibitors, and receives consulting income and research support from NewLink Genetics, Inc.
11. REFERENCES
1. T. Boon and P. van der Bruggen: Human tumor antigens recognized by T lymphocytes. J Exp Med, 183, 725-729 (1996)
doi:10.1084/jem.183.3.725
PMid:8642276
2. C. Lurquin, B. Lethe, E. De Plaen, V. Corbiere, I. Theate, N. van Baren, P. G. Coulie and T. Boon: Contrasting frequencies of antitumor and anti-vaccine T cells in metastases of a melanoma patient vaccinated with a MAGE tumor antigen. J Exp Med, 201, 249-57 (2005)
doi:10.1084/jem.20041378
PMid:15657294 PMCid:2212799
3. A. M. Ercolini, B. H. Ladle, E. A. Manning, L. W. Pfannenstiel, T. D. Armstrong, J. P. Machiels, J. G. Bieler, L. A. Emens, R. T. Reilly and E. M. Jaffee: Recruitment of latent pools of high-avidity CD8(+) T cells to the antitumor immune response. J Exp Med, 201, 1591-1602 (2005)
doi:10.1084/jem.20042167
PMid:15883172 PMCid:2212915
4. A. F. Ochsenbein, P. Klenerman, U. Karrer, B. Ludewig, M. Pericin, H. Hengartner and R. M. Zinkernagel: Immune surveillance against a solid tumor fails because of immunological ignorance. Immunol, 96, 2233-2238 (1999)
PMID: 10051624
5. M. T. Spiotto, P. Yu, D. A. Rowley, M. I. Nishimura, S. C. Meredith, T. F. Gajewski, Y. X. Fu and H. Schreiber: Increasing tumor antigen expression overcomes "ignorance" to solid tumors via crosspresentation by bone marrow-derived stromal cells. Immunity, 17, 737-747 (2002)
doi:10.1016/S1074-7613(02)00480-6
6. G. Willimsky, M. Czeh, C. Loddenkemper, J. Gellermann, K. Schmidt, P. Wust, H. Stein and T. Blankenstein: Immunogenicity of premalignant lesions is the primary cause of general cytotoxic T lymphocyte unresponsiveness. J Exp Med, 205, 1687-700 (2008)
doi:10.1084/jem.20072016
PMid:18573907 PMCid:2442645
7. C. M. Koebel, W. Vermi, J. B. Swann, N. Zerafa, S. J. Rodig, L. J. Old, M. J. Smyth and R. D. Schreiber: Adaptive immunity maintains occult cancer in an equilibrium state. Nature, 450, 903-7 (2007)
doi:10.1038/nature06309
PMid:18026089
8. E. M. Sotomayor, I. Borrello, F. M. Rattis, A. G. Cuenca, J. Abrams, K. Staveley-O'Carroll and H. I. Levitsky: Cross-presentation of tumor antigens by bone marrow-derived antigen-presenting cells is the dominant mechanism in the induction of T-cell tolerance during B-cell lymphoma progression. Blood, 98, 1070-1077. (2001)
doi:10.1182/blood.V98.4.1070
PMid:11493453
9. P. Yu, Y. Lee, W. Liu, T. Krausz, A. Chong, H. Schreiber and Y. X. Fu: Intratumor depletion of CD4+ cells unmasks tumor immunogenicity leading to the rejection of late-stage tumors. J Exp Med, 201, 779-791 (2005)
doi:10.1084/jem.20041684
PMid:15753211 PMCid:2212829
10. A. Cuenca, F. Cheng, H. Wang, J. Brayer, P. Horna, L. Gu, H. Bien, I. M. Borrello, H. I. Levitsky and E. M. Sotomayor: Extra-lymphatic solid tumor growth is not immunologically ignored and results in early induction of antigen-specific T-cell anergy: Dominant role of cross-tolerance to tumor antigens. Cancer Res, 63, 9007-9015 (2003)
PMid:14695219
11. G. Darrasse-Jeze, A. S. Bergot, A. Durgeau, F. Billiard, B. L. Salomon, J. L. Cohen, B. Bellier, K. Podsypanina and D. Klatzmann: Tumor emergence is sensed by self-specific CD44hi memory Tregs that create a dominant tolerogenic environment for tumors in mice. J Clin Invest (2009)
PMID: 19652360
12. J. D. Shields, I. C. Kourtis, A. A. Tomei, J. M. Roberts and M. A. Swartz: Induction of Lymphoidlike Stroma and Immune Escape by Tumors That Express the Chemokine CCL21. Science, 328, 749-752 (2010)
doi:10.1126/science.1185837
PMid:20339029
13. M. W. Taylor and G. Feng: Relationship between interferon-g, indoleamine 2,3-dioxygenase, and tryptophan catabolism. FASEB J, 5, 2516-2522 (1991)
PMid:1907934
14. A. Popov, Z. Abdullah, C. Wickenhauser, T. Saric, J. Driesen, F. G. Hanisch, E. Domann, E. L. Raven, O. Dehus, C. Hermann, D. Eggle, S. Debey, T. Chakraborty, M. Kronke, O. Utermohlen and J. L. Schultze: Indoleamine 2,3-dioxygenase-expressing dendritic cells form suppurative granulomas following Listeria monocytogenes infection. J Clin Invest, 116, 3160-3170 (2006)
doi:10.1172/JCI28996
PMid:17111046 PMCid:1636691
15. A. Muller, K. Heseler, S. K. Schmidt, K. Spekker, C. R. Mackenzie and W. Daubener: The missing link between indoleamine 2,3-dioxygenase mediated antibacterial and immunoregulatory effects. Journal of cellular and molecular medicine, 13, 1125-35 (2009)
doi:10.1111/j.1582-4934.2008.00542.x
PMid:19602041
16. A. L. Mellor and D. H. Munn: Creating immune privilege: active local suppression that benefits friends, but protects foes. Nat Rev Immunol, 8, 74-80 (2008)
doi:10.1038/nri2233
PMid:18064049
17. D. H. Munn and A. L. Mellor: Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J Clin Invest, 117, 1147-1154 (2007)
doi:10.1172/JCI31178
PMid:17476344 PMCid:1857253
18. L. Romani, F. Fallarino, A. De Luca, C. Montagnoli, C. D'Angelo, T. Zelante, C. Vacca, F. Bistoni, M. C. Fioretti, U. Grohmann, B. H. Segal and P. Puccetti: Defective tryptophan catabolism underlies inflammation in mouse chronic granulomatous disease. Nature, 451, 211-5 (2008)
doi:10.1038/nature06471
PMid:18185592
19. U. Grohmann, C. Volpi, F. Fallarino, S. Bozza, R. Bianchi, C. Vacca, C. Orabona, M. L. Belladonna, E. Ayroldi, G. Nocentini, L. Boon, F. Bistoni, M. C. Fioretti, L. Romani, C. Riccardi and P. Puccetti: Reverse signaling through GITR ligand enables dexamethasone to activate IDO in allergy. Nat Med, 13, 579-86 (2007)
doi:10.1038/nm1563
PMid:17417651
20. L. Desvignes and J. D. Ernst: Interferon-gamma-responsive nonhematopoietic cells regulate the immune response to Mycobacterium tuberculosis. Immunity, 31, 974-85 (2009)
doi:10.1016/j.immuni.2009.10.007
PMid:20064452 PMCid:2807991
21. D. H. Munn, M. Zhou, J. T. Attwood, I. Bondarev, S. J. Conway, B. Marshall, C. Brown and A. L. Mellor: Prevention of allogeneic fetal rejection by tryptophan catabolism. Science, 281, 1191-1193 (1998)
doi:10.1126/science.281.5380.1191
PMid:9712583
22. A. J. Muller, J. B. Duhadaway, P. S. Donover, E. Sutanto-Ward and G. C. Prendergast: Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Nat Med, 11, 312-319 (2005)
doi:10.1038/nm1196
PMid:15711557
23. A. P. van der Marel, J. N. Samsom, M. Greuter, L. A. van Berkel, T. O'Toole, G. Kraal and R. E. Mebius: Blockade of IDO inhibits nasal tolerance induction. J Immunol, 179, 894-900 (2007)
PMid:17617580
24. G. Matteoli, E. Mazzini, I. D. Iliev, E. Mileti, F. Fallarino, P. Puccetti, M. Chieppa and M. Rescigno: Gut CD103+ dendritic cells express indoleamine 2,3-dioxygenase which influences T regulatory/T effector cell balance and oral tolerance induction. Gut, 59, 595-604 (2010)
doi:10.1136/gut.2009.185108
PMid:20427394
25. L. K. Jasperson, C. Bucher, A. Panoskaltsis-Mortari, P. A. Taylor, A. L. Mellor, D. H. Munn and B. R. Blazar: Indoleamine 2,3-dioxygenase is a critical regulator of acute GVHD lethality. Blood, 111, 3257-3265 (2008)
doi:10.1182/blood-2007-06-096081
PMid:18077788 PMCid:2265461
26. G. J. Gurtner, R. D. Newberry, S. R. Schloemann, K. G. McDonald and W. F. Stenson: Inhibition of indoleamine 2,3-dioxygenase augments trinitrobenzene sulfonic acid colitis in mice. Gastroenterology, 125, 1762-1773 (2003)
doi:10.1053/j.gastro.2003.08.031
PMid:14724829
27. U. Grohmann, C. Orabona, F. Fallarino, C. Vacca, F. Calcinaro, A. Falorni, P. Candeloro, M. L. Belladonna, R. Bianchi, M. C. Fioretti and P. Puccetti: CTLA-4-Ig regulates tryptophan catabolism in vivo. Nat Immunol, 3, 1097-1101 (2002)
doi:10.1038/ni846
PMid:12368911
28. A. L. Mellor, B. Baban, P. Chandler, B. Marshall, K. Jhaver, A. Hansen, P. A. Koni, M. Iwashima and D. H. Munn: Cutting Edge: Induced indoleamine 2,3 dioxygenase expression in dendritic cell subsets suppresses T cell clonal expansion. J Immunol, 171, 1652-1655 (2003)
PMid:12902462
29. C. Guillonneau, M. Hill, F. X. Hubert, E. Chiffoleau, C. Herve, X. L. Li, M. Heslan, C. Usal, L. Tesson, S. Menoret, A. Saoudi, B. Le Mauff, R. Josien, M. C. Cuturi and I. Anegon: CD40Ig treatment results in allograft acceptance mediated by CD8CD45RC T cells, IFN-gamma, and indoleamine 2,3-dioxygenase. J Clin Invest, 117, 1096-106 (2007)
doi:10.1172/JCI28801
PMid:17404623 PMCid:1839240
30. K. A. Swanson, Y. Zheng, K. M. Heidler, T. Mizobuchi and D. S. Wilkes: CDllc+ cells modulate pulmonary immune responses by production of indoleamine 2,3-dioxygenase. Am J Respir Cell Mol Biol, 30, 311-318 (2004)
doi:10.1165/rcmb.2003-0268OC
PMid:12959949
31. H. Liu, L. Liu, B. S. Fletcher and G. A. Visner: Novel action of indoleamine 2,3-dioxygenase attenuating acute lung allograft injury. Am J Respir Crit Care Med, 173, 566-572 (2006)
doi:10.1164/rccm.200509-1413OC
PMid:16293800
32. R. Metz, J. B. Duhadaway, U. Kamasani, L. Laury-Kleintop, A. J. Muller and G. C. Prendergast: Novel tryptophan catabolic enzyme IDO2 is the preferred biochemical target of the antitumor indoleamine 2,3-dioxygenase inhibitory compound D-1-methyl-tryptophan. Cancer Res, 67, 7082-7 (2007)
doi:10.1158/0008-5472.CAN-07-1872
PMid:17671174
33. H. J. Ball, H. J. Yuasa, C. J. Austin, S. Weiser and N. H. Hunt: Indoleamine 2,3-dioxygenase-2; a new enzyme in the kynurenine pathway. Int J Biochem Cell Biol, 41, 467-71 (2009)
doi:10.1016/j.biocel.2008.01.005
34. H. J. Ball, A. Sanchez-Perez, S. Weiser, C. J. Austin, F. Astelbauer, J. Miu, J. A. McQuillan, R. Stocker, L. S. Jermiin and N. H. Hunt: Characterization of an indoleamine 2,3-dioxygenase-like protein found in humans and mice. Gene, 396, 203-13 (2007)
doi:10.1016/j.gene.2007.04.010
PMid:17499941
35. M. Arefayene, S. Philips, D. Cao, S. Mamidipalli, Z. Desta, D. A. Flockhart, D. S. Wilkes and T. C. Skaar: Identification of genetic variants in the human indoleamine 2,3-dioxygenase (IDO1) gene, which have altered enzyme activity. Pharmacogenet Genomics, 19, 464-76 (2009)
doi:10.1097/FPC.0b013e32832c005a
PMid:19514129
36. C. Orabona, P. Puccetti, C. Vacca, S. Bicciato, A. Luchini, F. Fallarino, R. Bianchi, E. Velardi, K. Perruccio, A. Velardi, V. Bronte, M. C. Fioretti and U. Grohmann: Toward the identification of a tolerogenic signature in IDO-competent dendritic cells. Blood, 107, 2846-2854 (2006)
doi:10.1182/blood-2005-10-4077
PMid:16339401
37. C. Orabona, M. T. Pallotta, C. Volpi, F. Fallarino, C. Vacca, R. Bianchi, M. L. Belladonna, M. C. Fioretti, U. Grohmann and P. Puccetti: SOCS3 drives proteasomal degradation of indoleamine 2,3-dioxygenase (IDO) and antagonizes IDO-dependent tolerogenesis. Proc Natl Acad Sci USA, 105, 20828-33 (2008)
doi:10.1073/pnas.0810278105
PMid:19088199 PMCid:2634889
38. S. W. Tas, M. J. Vervoordeldonk, N. Hajji, J. H. Schuitemaker, K. F. van der Sluijs, M. J. May, S. Ghosh, M. L. Kapsenberg, P. P. Tak and E. C. de Jong: Noncanonical NF-kappaB signaling in dendritic cells is required for indoleamine 2,3-dioxygenase (IDO) induction and immune regulation. Blood, 110, 1540-9 (2007)
doi:10.1182/blood-2006-11-056010
PMid:17483297
39. H. Fujigaki, K. Saito, F. Lin, S. Fujigaki, K. Takahashi, B. M. Martin, C. Y. Chen, J. Masuda, J. Kowalak, O. Takikawa, M. Seishima and S. P. Markey: Nitration and inactivation of IDO by peroxynitrite. J Immunol, 176, 372-9 (2006)
PMid:16365430
40. J. T. Pearson, S. Siu, D. P. Meininger, L. C. Wienkers and D. A. Rock: In vitro modulation of cytochrome P450 reductase supported indoleamine 2,3-dioxygenase activity by allosteric effectors cytochrome b(5) and methylene blue. Biochemistry, 49, 2647-56 (2010)
doi:10.1021/bi100022c
PMid:20178337
41. M. L. Belladonna, C. Orabona, U. Grohmann and P. Puccetti: TGF-beta and kynurenines as the key to infectious tolerance. Trends Mol Med, 15, 41-9 (2009)
doi:10.1016/j.molmed.2008.11.006
PMid:19162548
42. D. Favre, J. Mold, P. W. Hunt, B. Kanwar, P. Loke, L. Seu, J. D. Barbour, M. M. Lowe, A. Jayawardene, F. Aweeka, Y. Huang, D. C. Douek, J. M. Brenchley, J. N. Martin, F. M. Hecht, S. G. Deeks and J. M. McCune: Tryptophan catabolism by indoleamine 2,3-dioxygenase 1 alters the balance of TH17 to regulatory T cells in HIV disease. Sci Transl Med, 2, 32ra36 (2010)
PMID: 20484731
43. T. Hayashi, J. H. Mo, X. Gong, C. Rossetto, A. Jang, L. Beck, G. I. Elliott, I. Kufareva, R. Abagyan, D. H. Broide, J. Lee and E. Raz: 3-Hydroxyanthranilic acid inhibits PDK1 activation and suppresses experimental asthma by inducing T cell apoptosis. Proc Natl Acad Sci U S A, 104, 18619-24 (2007)
doi:10.1073/pnas.0709261104
PMid:18003900 PMCid:2141826
44. J. D. Mezrich, J. H. Fechner, X. Zhang, B. P. Johnson, W. J. Burlingham and C. A. Bradfield: An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J Immunol, 185, 3190-8 (2010)
doi:10.4049/jimmunol.0903670
PMid:20720200
45. D. H. Munn, M. D. Sharma, B. Baban, H. P. Harding, Y. Zhang, D. Ron and A. L. Mellor: GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. Immunity, 22, 633-642 (2005)
doi:10.1016/j.immuni.2005.03.013
PMid:15894280
46. J. D. Powell and G. M. Delgoffe: The mammalian target of rapamycin: linking T cell differentiation, function, and metabolism. Immunity, 33, 301-11 (2010)
doi:10.1016/j.immuni.2010.09.002
PMid:20870173
47. R. C. Wek, H. Y. Jiang and T. G. Anthony: Coping with stress: eIF2 kinases and translational control. Biochem Soc Trans, 34, 7-11 (2006)
doi:10.1042/BST0340007
PMid:16246168
48. M. S. Sundrud, S. B. Koralov, M. Feuerer, D. P. Calado, A. E. Kozhaya, A. Rhule-Smith, R. E. Lefebvre, D. Unutmaz, R. Mazitschek, H. Waldner, M. Whitman, T. Keller and A. Rao: Halofuginone inhibits TH17 cell differentiation by activating the amino acid starvation response. Science, 324, 1334-8 (2009)
doi:10.1126/science.1172638
PMid:19498172 PMCid:2803727
49. R. B. Jalili, F. Forouzandeh, A. Moeenrezakhanlou, G. R. Rayat, R. V. Rajotte, H. Uludag and A. Ghahary: Mouse pancreatic islets are resistant to indoleamine 2,3 dioxygenase-induced general control nonderepressible-2 kinase stress pathway and maintain normal viability and function. Am J Pathol, 174, 196-205 (2009)
doi:10.2353/ajpath.2009.080539
PMid:19074614 PMCid:2631332
50. A. K. Manlapat, D. J. Kahler, P. R. Chandler, D. H. Munn and A. L. Mellor: Cell-autonomous control of interferon type I expression by indoleamine 2,3-dioxygenase in regulatory CD19(+) dendritic cells. Eur J Immunol, 37, 1064-1071 (2007)
doi:10.1002/eji.200636690
PMid:17343295
51. M. D. Sharma, B. Baban, P. Chandler, D. Y. Hou, N. Singh, H. Yagita, M. Azuma, B. R. Blazar, A. L. Mellor and D. H. Munn: Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase. J Clin Invest, 117, 2570-2582 (2007)
doi:10.1172/JCI31911
PMid:17710230 PMCid:1940240
52. M. D. Sharma, D. Y. Hou, Y. Liu, P. A. Koni, R. Metz, P. Chandler, A. L. Mellor, Y. He and D. H. Munn: Indoleamine 2,3-dioxygenase controls conversion of Foxp3+ Tregs to TH17-like cells in tumor-draining lymph nodes. Blood, 113, 6102-6111 (2009)
doi:10.1182/blood-2008-12-195354
PMid:19366986 PMCid:2699232
53. P. C. Rodriguez, D. G. Quiceno and A. C. Ochoa: L-arginine availability regulates T-lymphocyte cell-cycle progression. Blood, 109, 1568-73 (2007)
doi:10.1182/blood-2006-06-031856
PMid:17023580 PMCid:1794048
54. S. P. Cobbold, E. Adams, C. A. Farquhar, K. F. Nolan, D. Howie, K. O. Lui, P. J. Fairchild, A. L. Mellor, D. Ron and H. Waldmann: Infectious tolerance via the consumption of essential amino acids and mTOR signaling. Proc Natl Acad Sci USA, 106, 12055-60 (2009)
doi:10.1073/pnas.0903919106
PMid:19567830 PMCid:2704109
55. F. Fallarino, U. Grohmann, S. You, B. C. McGrath, D. R. Cavener, C. Vacca, C. Orabona, R. Bianchi, M. L. Belladonna, C. Volpi, P. Santamaria, M. C. Fioretti and P. Puccetti: 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. J Immunol, 176, 6752-6761 (2006)
PMid:16709834
56. W. Chen, X. Liang, A. J. Peterson, D. H. Munn and B. R. Blazar: The indoleamine 2,3-dioxygenase pathway is essential for human plasmacytoid dendritic cell-induced adaptive T regulatory cell generation. J Immunol, 181, 5396-5404 (2008)
PMid:18832696 PMCid:2614675
57. O. Manches, D. Munn, A. Fallahi, J. Lifson, L. Chaperot, J. Plumas and N. Bhardwaj: HIV-activated human plasmacytoid DCs induce Tregs through an indoleamine 2,3-dioxygenase-dependent mechanism. J Clin Invest, 118, 3431-3439 (2008)
doi:10.1172/JCI34823
PMid:18776940 PMCid:2528911
58. D. J. Chung, M. Rossi, E. Romano, J. Ghith, J. Yuan, D. H. Munn and J. W. Young: Indoleamine 2,3-dioxygenase-expressing mature human monocyte-derived dendritic cells expand potent autologous regulatory T cells. Blood, 114, 555-63 (2009)
doi:10.1182/blood-2008-11-191197
PMid:19465693 PMCid:2713474
59. B. Baban, P. R. Chandler, M. D. Sharma, J. Pihkala, P. A. Koni, D. H. Munn and A. L. Mellor: IDO activates regulatory T cells and blocks their conversion into Th17-like T cells. J Immunol, 183, 2475-83 (2009)
doi:10.4049/jimmunol.0900986
PMid:19635913
60. M. D. Sharma, D. Y. Hou, B. Baban, P. A. Koni, Y. He, P. R. Chandler, B. R. Blazar, A. L. Mellor and D. H. Munn: Reprogrammed Foxp3+ Tregs provide essential help to support cross-presentation and CD8+ T cell priming in naive mice. Immunity, (in press) (2010)
doi:10.1016/j.immuni.2010.11.022
PMid:21145762
61. P. Hwu, M. X. Du, R. Lapointe, M. Do, M. W. Taylor and H. A. Young: Indoleamine 2,3-dioxygenase production by human dendritic cells results in the inhibition of T cell proliferation. J Immunol, 164, 3596-3599 (2000)
PMid:10725715
62. D. H. Munn, M. D. Sharma, J. R. Lee, K. G. Jhaver, T. S. Johnson, D. B. Keskin, B. Marshall, P. Chandler, S. J. Antonia, R. Burgess, C. L. Slingluff and A. L. Mellor: Potential regulatory function of human dendritic cells expressing indoleamine 2,3-dioxygenase. Science, 297, 1867-1870 (2002)
doi:10.1126/science.1073514
PMid:12228717
63. D. H. Munn, M. D. Sharma and A. L. Mellor: Ligation of B7-1/B7-2 by human CD4+ T cells triggers indoleamine 2,3-dioxygenase activity in dendritic cells. J Immunol, 172, 4100-4110 (2004)
PMid:15034022
64. C. Vacca, F. Fallarino, K. Perruccio, C. Orabona, R. Bianchi, S. Gizzi, A. Velardi, M. C. Fioretti, P. Puccetti and U. Grohmann: CD40 ligation prevents onset of tolerogenic properties in human dendritic cells treated with CTLA-4-Ig. Microbes Infect, 7, 1040-1048 (2005)
doi:10.1016/j.micinf.2005.03.030
PMid:15925532
65. S. C. Beutelspacher, P. H. Tan, M. O. McClure, D. F. Larkin, R. I. Lechler and A. J. George: Expression of indoleamine 2,3-dioxygenase (IDO) by endothelial cells: implications for the control of alloresponses. Am J Transplant 6, 1320-1330 (2006)
doi:10.1111/j.1600-6143.2006.01324.x
PMid:16686756
66. M. Wobser, H. Voigt, R. Houben, A. O. Eggert, M. Freiwald, U. Kaemmerer, E. Kaempgen, D. Schrama and J. C. Becker: Dendritic cell based antitumor vaccination: impact of functional indoleamine 2,3-dioxygenase expression. Cancer Immunol Immunother, 56, 1017-1024 (2007)
doi:10.1007/s00262-006-0256-1
PMid:17195079
67. M. Brenk, M. Scheler, S. Koch, J. Neumann, O. Takikawa, G. Hacker, T. Bieber and D. von Bubnoff: Tryptophan deprivation induces inhibitory receptors ILT3 and ILT4 on dendritic cells favoring the induction of human CD4+CD25+ Foxp3+ T regulatory cells. J Immunol, 183, 145-54 (2009)
doi:10.4049/jimmunol.0803277
PMid:19535644
68. S. Rutella, G. Bonanno, A. Procoli, A. Mariotti, D. G. de Ritis, A. Curti, S. Danese, G. Pessina, S. Pandolfi, F. Natoni, A. Di Febo, G. Scambia, R. Manfredini, S. Salati, S. Ferrari, L. Pierelli, G. Leone and R. M. Lemoli: Hepatocyte growth factor favors monocyte differentiation into regulatory interleukin (IL)-10++IL-12low/neg accessory cells with dendritic-cell features. Blood, 108, 218-227 (2006)
doi:10.1182/blood-2005-08-3141
PMid:16527888
69. D. Braun, R. S. Longman and M. L. Albert: A two step induction of indoleamine 2,3 dioxygenase (IDO) activity during dendritic cell maturation. Blood, 106, 2375-2381 (2005)
doi:10.1182/blood-2005-03-0979
PMid:15947091 PMCid:1895261
70. P. Terness, J. J. Chuang, T. Bauer, L. Jiga and G. Opelz: Regulation of human auto- and alloreactive T cells by indoleamine 2,3-dioxygenase (IDO)-producing dendritic cells: too much ado about IDO? Blood, 105, 2480-2486 (2005)
doi:10.1182/blood-2004-06-2103
PMid:15572592
71. D. H. Munn, E. Shafizadeh, J. T. Attwood, I. Bondarev, A. Pashine and A. L. Mellor: Inhibition of T cell proliferation by macrophage tryptophan catabolism. J Exp Med, 189, 1363-1372 (1999)
doi:10.1084/jem.189.9.1363
PMid:10224276 PMCid:2193062
72. D. Duluc, Y. Delneste, F. Tan, M. P. Moles, L. Grimaud, J. Lenoir, L. Preisser, I. Anegon, L. Catala, N. Ifrah, P. Descamps, E. Gamelin, H. Gascan, M. Hebbar and P. Jeannin: Tumor-associated leukemia inhibitory factor and IL-6 skew monocyte differentiation into tumor-associated-macrophage-like cells. Blood, 110, 4319-4330 (2007)
doi:10.1182/blood-2007-02-072587
PMid:17848619
73. A. Boasso, J. P. Herbeuval, A. W. Hardy, S. A. Anderson, M. J. Dolan, D. Fuchs and G. M. Shearer: HIV inhibits CD4+ T-cell proliferation by inducing indoleamine 2,3-dioxygenase in plasmacytoid dendritic cells. Blood, 109, 3351-9 (2007)
doi:10.1182/blood-2006-07-034785
PMid:17158233 PMCid:1852248
74. A. Curti, S. Pandolfi, B. Valzasina, M. Aluigi, A. Isidori, E. Ferri, V. Salvestrini, G. Bonanno, S. Rutella, I. Durelli, A. L. Horenstein, F. Fiore, M. Massaia, M. P. Colombo, M. Baccarani and R. M. Lemoli: Modulation of tryptophan catabolism by human leukemic cells results in the conversion of CD25- into CD25+ T regulatory cells. Blood, 109, 2871-2877 (2007)
PMid:17164341
75. L. K. Jasperson, C. Bucher, A. Panoskaltsis-Mortari, A. L. Mellor, D. H. Munn and B. R. Blazar: Inducing the tryptophan catabolic pathway, indoleamine 2,3-dioxygenase (IDO), for suppression of graft-versus-host disease (GVHD) lethality. Blood, 114, 5062-70 (2009)
doi:10.1182/blood-2009-06-227587
PMid:19828695 PMCid:2788979
76. P. Reddy, Y. Sun, T. Toubai, R. Duran-Struuck, S. G. Clouthier, E. Weisiger, Y. Maeda, I. Tawara, O. Krijanovski, E. Gatza, C. Liu, C. Malter, P. Mascagni, C. A. Dinarello and J. L. Ferrara: Histone deacetylase inhibition modulates indoleamine 2,3-dioxygenase-dependent DC functions and regulates experimental graft-versus-host disease in mice. J Clin Invest, 118, 2562-2573 (2008)
PMid:18568076 PMCid:2430497
77. U. Hainz, P. Obexer, C. Winkler, P. Sedlmayr, O. Takikawa, H. Greinix, A. Lawitschka, U. Potschger, D. Fuchs, S. Ladisch and A. Heitger: Monocyte-mediated T-cell suppression and augmented monocyte tryptophan catabolism after human hematopoietic stem-cell transplantation. Blood, 105, 4127-4134 (2005)
doi:10.1182/blood-2004-05-1726
PMid:15677560 PMCid:1895091
78. U. Hainz, B. Jurgens, T. Wekerle, M. G. Seidel and A. Heitger: Indoleamine 2,3-dioxygenase in hematopoietic stem cell transplantation. Curr Drug Metab, 8, 267-72 (2007)
doi:10.2174/138920007780362554
PMid:17430114
79. A. Y. Huang, P. Golumbek, M. Ahmadzadeh, E. Jaffee, D. Pardoll and H. Levitsky: Role of bone marrow-derived cells in presenting MHC class I-restricted tumor antigens. Science, 264, 961-965 (1994)
doi:10.1126/science.7513904
PMid:7513904
80. K. Hildner, B. T. Edelson, W. E. Purtha, M. Diamond, H. Matsushita, M. Kohyama, B. Calderon, B. U. Schraml, E. R. Unanue, M. S. Diamond, R. D. Schreiber, T. L. Murphy and K. M. Murphy: Batf3 deficiency reveals a critical role for CD8alpha+ dendritic cells in cytotoxic T cell immunity. Science, 322, 1097-100 (2008)
doi:10.1126/science.1164206
PMid:19008445 PMCid:2756611
81. A. J. Cochran, R. R. Huang, J. Lee, E. Itakura, S. P. Leong and R. Essner: Tumour-induced immune modulation of sentinel lymph nodes. Nat Rev Immunol, 6, 659-670 (2006)
doi:10.1038/nri1919
PMid:16932751
82. J. R. Lee, R. R. Dalton, J. L. Messina, M. D. Sharma, D. M. Smith, R. E. Burgess, F. Mazzella, S. J. Antonia, A. L. Mellor and D. H. Munn: Pattern of recruitment of immunoregulatory antigen presenting cells in malignant melanoma. Lab Invest, 83, 1457-1466 (2003)
doi:10.1097/01.LAB.0000090158.68852.D1
PMid:14563947
83. J. H. Lee, H. Torisu-Itakara, A. J. Cochran, A. Kadison, Y. Huynh, D. L. Morton and R. Essner: Quantitative analysis of melanoma-induced cytokine-mediated immunosuppression in melanoma sentinel nodes. Clin Cancer Res, 11, 107-112 (2005)
PMid:15671534
84. M. S. von Bergwelt-Baildon, A. Popov, T. Saric, J. Chemnitz, S. Classen, M. S. Stoffel, F. Fiore, U. Roth, M. Beyer, S. Debey, C. Wickenhauser, F. G. Hanisch and J. L. Schultze: CD25 and indoleamine 2,3-dioxygenase are up-regulated by prostaglandin E2 and expressed by tumor-associated dendritic cells in vivo: additional mechanisms of T-cell inhibition. Blood, 108, 228-237 (2006)
doi:10.1182/blood-2005-08-3507
PMid:16522817
85. D. H. Munn, M. D. Sharma, D. Hou, B. Baban, J. R. Lee, S. J. Antonia, J. L. Messina, P. Chandler, P. A. Koni and A. Mellor: Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes. J Clin Invest, 114, 280-290 (2004)
doi:10.1172/JCI200421583
PMid:15254595 PMCid:449750
86. T. Gu, R. B. Rowswell-Turner, M. O. Kilinc and N. K. Egilmez: Central role of IFNgamma-indoleamine 2,3-dioxygenase axis in regulation of interleukin-12-mediated antitumor immunity. Cancer Res, 70, 129-38 (2010)
doi:10.1158/0008-5472.CAN-09-3170
PMid:20028855 PMCid:2805056
87. E. Kallberg, P. Wikstrom, A. Bergh, F. Ivars and T. Leanderson: Indoleamine 2,3-dioxygenase (IDO) activity influence tumor growth in the TRAMP prostate cancer model. Prostate, 70, 1461-70 (2010)
doi:10.1002/pros.21181
PMid:20687219
88. B. A. Johnson, 3rd, D. J. Kahler, B. Baban, P. R. Chandler, B. Kang, M. Shimoda, P. A. Koni, J. Pihkala, B. Vilagos, M. Busslinger, D. H. Munn and A. L. Mellor: B-lymphoid cells with attributes of dendritic cells regulate T cells via indoleamine 2,3-dioxygenase. Proc Natl Acad Sci USA (2010)
PMid: 20498068
89. B. Baban, A. Hansen, P. Chandler, A. Manlapat, A. Bingaman, D. Kahler, D. Munn and A. Mellor: A minor population of splenic dendritic cells expressing CD19 mediates IDO-dependent T cell suppression via type 1 interferon-signaling following B7 ligation. Int Immunol, 17, 909-919 (2005)
doi:10.1093/intimm/dxh271
PMid:15967784
90. A. L. Mellor, B. Baban, P. R. Chandler, A. Manlapat, D. J. Kahler and D. H. Munn: Cutting Edge: CpG oligonucleotides induce splenic CD19+ dendritic cells to acquire potent indoleamine 2,3-dioxygenase-dependent T cell regulatory functions via IFN type 1 signaling. J Immunol, 175, 5601-5605 (2005)
PMid:16237046
91. G. Gerlini, P. Di Gennaro, G. Mariotti, C. Urso, A. Chiarugi, N. Pimpinelli and L. Borgognoni: Indoleamine 2,3-dioxygenase+ cells correspond to the BDCA2+ plasmacytoid dendritic cells in human melanoma sentinel nodes. J Invest Dermatol, 130, 898-901 (2010)
doi:10.1038/jid.2009.307
PMid:19829303
92. F. Qian, J. Villella, P. K. Wallace, P. Mhawech-Fauceglia, J. D. Tario, Jr., C. Andrews, J. Matsuzaki, D. Valmori, M. Ayyoub, P. J. Frederick, A. Beck, J. Liao, R. Cheney, K. Moysich, S. Lele, P. Shrikant, L. J. Old and K. Odunsi: Efficacy of Levo-1-Methyl Tryptophan and Dextro-1-Methyl Tryptophan in Reversing Indoleamine-2,3-Dioxygenase-Mediated Arrest of T-Cell Proliferation in Human Epithelial Ovarian Cancer. Cancer Res, 69, 5498-5504 (2009)
doi:10.1158/0008-5472.CAN-08-2106
PMid:19491279
93. C. Feder-Mengus, S. Wyler, T. Hudolin, R. Ruszat, L. Bubendorf, A. Chiarugi, M. Pittelli, W. P. Weber, A. Bachmann, T. C. Gasser, T. Sulser, M. Heberer, G. C. Spagnoli and M. Provenzano: High expression of indoleamine 2,3-dioxygenase gene in prostate cancer. Eur J Cancer, 44, 2266-75 (2008)
doi:10.1016/j.ejca.2008.05.023
PMid:18619832
94. C. Uyttenhove, L. Pilotte, I. Theate, V. Stroobant, D. Colau, N. Parmentier, T. Boon and B. J. Van Den Eynde: Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med, 9, 1269-1274 (2003)
doi:10.1038/nm934
PMid:14502282
95. J. R. Brody, C. L. Costantino, A. C. Berger, T. Sato, M. P. Lisanti, C. J. Yeo, R. V. Emmons and A. K. Witkiewicz: Expression of indoleamine 2,3-dioxygenase in metastatic malignant melanoma recruits regulatory T cells to avoid immune detection and affects survival. Cell Cycle, 8, 1930-4 (2009)
doi:10.4161/cc.8.12.8745
PMid:19448397
96. M. E. Polak, N. J. Borthwick, F. G. Gabriel, P. Johnson, B. Higgins, J. Hurren, D. McCormick, M. J. Jager and I. A. Cree: Mechanisms of local immunosuppression in cutaneous melanoma. Br J Cancer, 96, 1879-87 (2007)
doi:10.1038/sj.bjc.6603763
PMid:17565341 PMCid:2359967
97. A. Witkiewicz, T. K. Williams, J. Cozzitorto, B. Durkan, S. L. Showalter, C. J. Yeo and J. R. Brody: Expression of indoleamine 2,3-dioxygenase in metastatic pancreatic ductal adenocarcinoma recruits regulatory T cells to avoid immune detection. J Am Coll Surg, 206, 849-54; discussion 854-6 (2008)
doi:10.1016/j.jamcollsurg.2007.12.014
PMid:18471709
98. A. K. Witkiewicz, C. L. Costantino, R. Metz, A. J. Muller, G. C. Prendergast, C. J. Yeo and J. R. Brody: Genotyping and expression analysis of IDO2 in human pancreatic cancer: a novel, active target. J Am Coll Surg, 208, 781-7; discussion 787-9 (2009)
doi:10.1016/j.jamcollsurg.2008.12.018
PMid:19476837
99. G. Brandacher, A. Perathoner, R. Ladurner, S. Schneeberger, P. Obrist, C. Winkler, E. R. Werner, G. Werner-Felmayer, H. G. Weiss, G. Gobel, R. Margreiter, A. Konigsrainer, D. Fuchs and A. Amberger: Prognostic value of indoleamine 2,3-dioxygenase expression in colorectal cancer: effect on tumor-infiltrating T cells. Clin Cancer Res, 12, 1144-1151 (2006)
doi:10.1158/1078-0432.CCR-05-1966
PMid:16489067
100. A. Huang, D. Fuchs, B. Widner, C. Glover, D. C. Henderson and T. G. Allen-Mersh: Serum tryptophan decrease correlates with immune activation and impaired quality of life in colorectal cancer. Br J Cancer, 86, 1691-1696 (2002)
doi:10.1038/sj.bjc.6600336
PMid:12087451 PMCid:2375406
101. M. E. Chamuleau, A. A. van de Loosdrecht, C. J. Hess, J. J. Janssen, A. Zevenbergen, R. Delwel, P. J. Valk, B. Lowenberg and G. J. Ossenkoppele: High INDO (indoleamine 2,3-dioxygenase) mRNA level in blasts of acute myeloid leukemic patients predicts poor clinical outcome. Haematologica, 93, 1894-8 (2008)
doi:10.3324/haematol.13112
102. S. Corm, C. Berthon, M. Imbenotte, V. Biggio, M. Lhermitte, C. Dupont, I. Briche and B. Quesnel: Indoleamine 2,3-dioxygenase activity of acute myeloid leukemia cells can be measured from patients' sera by HPLC and is inducible by IFN-gamma. Leuk Res, 33, 490-4 (2009)
doi:10.1016/j.leukres.2008.06.014
PMid:18639339
103. K. Ino, N. Yoshida, H. Kajiyama, K. Shibata, E. Yamamoto, K. Kidokoro, N. Takahashi, M. Terauchi, A. Nawa, S. Nomura, T. Nagasaka, O. Takikawa and F. Kikkawa: Indoleamine 2,3-dioxygenase is a novel prognostic indicator for endometrial cancer. Br J Cancer, 95, 1555-1561 (2006)
doi:10.1038/sj.bjc.6603477
PMid:17117179 PMCid:2360726
104. K. Ino, E. Yamamoto, K. Shibata, H. Kajiyama, N. Yoshida, M. Terauchi, A. Nawa, T. Nagasaka, O. Takikawa and F. Kikkawa: Inverse correlation between tumoral indoleamine 2,3-dioxygenase expression and tumor-infiltrating lymphocytes in endometrial cancer: its association with disease progression and survival. Clin Cancer Res, 14, 2310-7 (2008)
doi:10.1158/1078-0432.CCR-07-4144
PMid:18413819
105. A. Okamoto, T. Nikaido, K. Ochiai, S. Takakura, M. Saito, Y. Aoki, N. Ishii, N. Yanaihara, K. Yamada, O. Takikawa, R. Kawaguchi, S. Isonishi, T. Tanaka and M. Urashima: Indoleamine 2,3-dioxygenase serves as a marker of poor prognosis in gene expression profiles of serous ovarian cancer cells. Clin Cancer Res, 11, 6030-6039 (2005)
doi:10.1158/1078-0432.CCR-04-2671
PMid:16115948
106. N. M. Haynes, R. G. van der Most, R. A. Lake and M. J. Smyth: Immunogenic anti-cancer chemotherapy as an emerging concept. Curr Opin Immunol, 20, 545-57 (2008)
doi:10.1016/j.coi.2008.05.008
PMid:18573339
107. Y. Ma, O. Kepp, F. Ghiringhelli, L. Apetoh, L. Aymeric, C. Locher, A. Tesniere, I. Martins, A. Ly, N. M. Haynes, M. J. Smyth, G. Kroemer and L. Zitvogel: Chemotherapy and radiotherapy: cryptic anticancer vaccines. Sem Immunol, 22, 113-24 (2010)
doi:10.1016/j.smim.2010.03.001
PMid:20403709
108. L. Zitvogel, L. Apetoh, F. Ghiringhelli, F. Andre, A. Tesniere and G. Kroemer: The anticancer immune response: indispensable for therapeutic success? J Clin Invest, 118, 1991-2001 (2008)
doi:10.1172/JCI35180
PMid:18523649 PMCid:2396905
109. R. Ramakrishnan, S. Antonia and D. I. Gabrilovich: Combined modality immunotherapy and chemotherapy: a new perspective. Cancer Immunol Immunother, 57, 1523-9 (2008)
doi:10.1007/s00262-008-0531-4
PMid:18488219
110. D. Y. Hou, A. J. Muller, M. D. Sharma, J. B. Duhadaway, T. Banerjee, M. Johnson, A. L. Mellor, G. C. Prendergast and D. H. Munn: Inhibition of IDO in dendritic cells by stereoisomers of 1-methyl-tryptophan correlates with anti-tumor responses. Cancer Res, 67, 792-801 (2007)
doi:10.1158/0008-5472.CAN-06-2925
PMid:17234791
111. K. Podsypanina, Y. Li and H. E. Varmus: Evolution of somatic mutations in mammary tumors in transgenic mice is influenced by the inherited genotype. BMC Med, 2, 24-34 (2004)
doi:10.1186/1741-7015-2-24
PMid:15198801 PMCid:446228
112. S. A. Quezada, K. S. Peggs, T. R. Simpson, Y. Shen, D. R. Littman and J. P. Allison: Limited tumor infiltration by activated T effector cells restricts the therapeutic activity of regulatory T cell depletion against established melanoma. J Exp Med, 205, 2125-38 (2008)
doi:10.1084/jem.20080099
PMid:18725522 PMCid:2526206
113. A. S. Almeida, P. M. Lago, N. Boechat, R. C. Huard, L. C. Lazzarini, A. R. Santos, M. Nociari, H. Zhu, B. M. Perez-Sweeney, H. Bang, Q. Ni, J. Huang, A. L. Gibson, V. C. Flores, L. R. Pecanha, A. L. Kritski, J. R. Lapa e Silva and J. L. Ho: Tuberculosis is associated with a down-modulatory lung immune response that impairs Th1-type immunity. J Immunol, 183, 718-31 (2009)
doi:10.4049/jimmunol.0801212
PMid:19535630
114. A. J. Muller, J. B. Duhadaway, D. Jaller, P. Curtis, R. Metz and G. C. Prendergast: Immunotherapeutic suppression of indoleamine 2,3-dioxygenase and tumor growth with ethyl pyruvate. Cancer Res, 70, 1845-53 (2010)
doi:10.1158/0008-5472.CAN-09-3613
PMid:20160032
115. X. Liu, N. Shin, H. K. Koblish, G. Yang, Q. Wang, K. Wang, L. Leffet, M. J. Hansbury, B. Thomas, M. Rupar, P. Waeltz, K. J. Bowman, P. Polam, R. B. Sparks, E. W. Yue, Y. Li, R. Wynn, J. S. Fridman, T. C. Burn, A. P. Combs, R. C. Newton and P. A. Scherle: Selective inhibition of indoleamine 2,3-dioxygenase (IDO1) effectively regulates mediators of anti-tumor immunity. Blood (2010)
PMID: 20197554
116. A. J. Muller and P. A. Scherle: Targeting the mechanisms of tumoral immune tolerance with small-molecule inhibitors. Nat Rev Cancer, 6, 613-25 (2006)
doi:10.1038/nrc1929
PMid:16862192
117. C. Lu, Y. Lin and S. R. Yeh: Inhibitory substrate binding site of human indoleamine 2,3-dioxygenase. J Am Chem Soc, 131, 12866-7 (2009)
doi:10.1021/ja9029768
PMid:19737010
118. N. Chauhan, S. J. Thackray, S. A. Rafice, G. Eaton, M. Lee, I. Efimov, J. Basran, P. R. Jenkins, C. G. Mowat, S. K. Chapman and E. L. Raven: Reassessment of the reaction mechanism in the heme dioxygenases. J Am Chem Soc, 131, 4186-7 (2009)
doi:10.1021/ja808326g
PMid:19275153
119. A. Curti, M. Aluigi, S. Pandolfi, E. Ferri, A. Isidori, V. Salvestrini, I. Durelli, A. L. Horenstein, F. Fiore, M. Massaia, M. Piccioli, S. A. Pileri, E. Zavatto, A. D'Addio, M. Baccarani and R. M. Lemoli: Acute myeloid leukemia cells constitutively express the immunoregulatory enzyme indoleamine 2,3-dioxygenase. Leukemia, 21, 353-5 (2007)
doi:10.1038/sj.leu.2404485
PMid:17170728
120. S. Lob, A. Konigsrainer, H. G. Rammensee, G. Opelz and P. Terness: Inhibitors of indoleamine-2,3-dioxygenase for cancer therapy: can we see the wood for the trees? Nat Rev Cancer, 9, 445-52 (2009)
doi:10.1038/nrc2639
PMid:19461669
121. L. Jia, K. Schweikart, J. Tomaszewski, J. G. Page, P. E. Noker, S. A. Buhrow, J. M. Reid, M. M. Ames and D. H. Munn: Toxicology and pharmacokinetics of 1-methyl-d-tryptophan: Absence of toxicity due to saturating absorption. Food Chem Toxicol, 46, 203-11 (2008)
doi:10.1016/j.fct.2007.07.017
PMid:17868966 PMCid:2744343
122. H. H. Soliman, S. J. Antonia, D. Sullivan, N. Vanahanian and C. Link: Overcoming tumor antigen anergy in human malignancies using the novel indoleamine 2,3-dioxygenase (IDO) enzyme inhibitor, 1-methyl-D-tryptophan (1MT). J Clin Oncol 27, 15s, 2009 (suppl; abstr 3004) (No linked doi available)
Abbreviations: 1MT: 1-methyl-tryptophan; IDO: indoleamine 2,3-dioxygenase
Key Words: IDO, Indoleamine 2 3-Dioxygenase, Tumors, Tolerance, Immunotherapy, Checkpoint Blockade, Vaccine, Adjuvant, Inhibitor, Review
Send correspondence to: David H. Munn, Cancer Immunotherapy Program, Room CN-4141, Augusta, GA 30912, Tel: 706-721-7141, Fax 706-721-8732, E-mail:dmunn@georgiahealth.edu