IDO1 Metabolites Activate β-catenin Signaling to Promote Cancer Cell Proliferation and Colon Tumorigenesis in Mice

Thaker, Ameet I.; Rao, Mahil; Bishnupuri, Kumar S.; Kerr, Thomas A.; Foster, Lynne; Marinshaw, Jeffrey M.; Newberry, Rodney D.; Stenson, William F.; Ciorba, Matthew A.

doi:10.1053/j.gastro.2013.05.002

Cited by 160 publications

(185 citation statements)

References 40 publications

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“…IDO is produced not only by some tumors but also by inhibitory immune cells such as suppressive dendritic cells and monocyte-derived macrophages (27,28). In fact, IDO expression within the tumor microenvironment and tumor draining lymph nodes correlates with poor cancer prognosis (29)(30)(31)(32). IDO enzymatic activity potentiates tryptophan degradation, causing cell-cycle arrest and induction of anergy in effector T cells.…”

Section: Introductionmentioning

confidence: 99%

Antigen-Specific Antitumor Responses Induced by OX40 Agonist Are Enhanced by the IDO Inhibitor Indoximod

Berrong

Mkrtichyan

Ahmad

et al. 2018

Cancer Immunology Research

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Although an immune response to tumors may be generated using vaccines, so far, this approach has only shown minimal clinical success. This is attributed to the tendency of cancer to escape immune surveillance via multiple immune suppressive mechanisms. Successful cancer immunotherapy requires targeting these inhibitory mechanisms along with enhancement of antigen-specific immune responses to promote sustained tumor-specific immunity. Here, we evaluated the effect of indoximod, an inhibitor of the immunosuppressive indoleamine-(2,3)-dioxygenase (IDO) pathway, on antitumor efficacy of anti-OX40 agonist in the context of vaccine in the IDO À TC-1 tumor model. We demonstrate that although the addition of anti-OX40 to the vaccine moderately enhances therapeutic efficacy, incorporation of indoximod into this treatment leads to enhanced tumor regression and cure of established tumors in 60% of treated mice. We show that the mechanisms by which the IDO inhibitor leads to this therapeutic potency include (i) an increment of vaccine-induced tumor-infiltrating effector T cells that is facilitated by anti-OX40 and (ii) a decrease of IDO enzyme activity produced by nontumor cells within the tumor microenvironment that results in enhancement of the specificity and the functionality of vaccine-induced effector T cells. Our findings suggest a translatable strategy to enhance the overall efficacy of cancer immunotherapy.

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Section: Introductionmentioning

confidence: 99%

Antigen-Specific Antitumor Responses Induced by OX40 Agonist Are Enhanced by the IDO Inhibitor Indoximod

Berrong

Mkrtichyan

Ahmad

et al. 2018

Cancer Immunology Research

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“…KN, the first breakdown product of tryptophan mediated by indoleamine-2,3-dioxygenases 1 and 2 (IDO1/2) or tryptophan-2,3-dioxygenase (TDO), activates the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, in various tumors (16). KN shows contrasting effects on cell growth depending on cell type; it inhibits growth of lymphoid cell lines (40) while promoting proliferation of non-lymphoid tumor cell lines (22). In the present study, we observed that KN reduced β-catenin expression, which was increased by IDO-1 inhibitor 1-MT.…”

Section: Discussionmentioning

confidence: 99%

“…Among the 4 tryptophan degradation pathways, the KN pathway accounts for ~95% of overall tryptophan degradation (21). IDO-1, which is the first enzyme to metabolize tryptophan along the KN pathway, is expressed in HT-29 cells (22). Thus, we examined whether KN stimulates goblet cell differentiation.…”

Section: Tryptophan and Its Metabolite Kn Promote The Differentiationmentioning

confidence: 99%

Kynurenine promotes the goblet cell differentiation of HT-29 colon carcinoma cells by modulating Wnt, Notch and AhR signals

Park

Lee

et al. 2018

Oncol Rep

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Abstract.Various amino acids regulate cell growth and differentiation. In the present study, we examined the ability of HT-29 cells to differentiate into goblet cells in RPMI and DMEM which are largely different in the amounts of numerous amino acids. Most of the HT-29 cells differentiated into goblet cells downregulating the stem cell marker Lgr5 when cultured in DMEM, but remained undifferentiated in RPMI. The goblet cell differentiation in DMEM was inhibited by 1-methyl-tryptophan (1-MT), an inhibitor of indoleamine 2,3 dioxygenase-1 which is the initial enzyme in tryptophan metabolism along the kynurenine (KN) pathway, whereas tryptophan and KN induced goblet cell differentiation in RPMI. The levels of Notch1 and its activation product Notch intracytoplasmic domain in HT-29 cells were lower in DMEM than those in RPMI and were increased by 1-MT in both media. HT-29 cells grown in both media expressed β-catenin at the same level on day 2 when goblet cell differentiation was not observed. β-catenin expression, which was increased by 1-MT in both media, was decreased by KN. DMEM reduced Hes1 expression while enhancing Hath1 expression. Finally, aryl hydrocarbon receptor (AhR) activation moderately induced goblet cell differentiation. Our results suggest that KN promotes goblet cell differentiation by regulating Wnt, Notch, and AhR signals and expression of Hes1 and Hath1. IntroductionCell lines are usually maintained in defined media that commonly contain amino acids, vitamins, glucose and inorganic salts for normal cell metabolism. However, the composition of medium formulations vary widely in concentrations of glucose and other metabolic precursors, including amino acids. Thus, many types of cells showed different responses to culture media in regards to proliferation and differentiation. Th17 differentiation was induced more efficiently in Iscove's modified Dulbecco's medium (IMDM) than in RPMI (1). Bone marrow-derived dendritic cells in IMDM expressed higher levels of co-stimulatory and MHC II molecules, compared to the cells generated in RPMI (2). In addition, hepatocyte differentiation and propagation and phenotype of corneal stroma-derived stem cells were modulated by culture media (3,4). Subsequently, the underlying mechanisms of the medium-induced changes in cell proliferation and differentiation have been partially elucidated. Differentiation of Th17 cells was increased by endogenous aryl hydrocarbon receptor (AhR) agonists derived from aromatic amino acids such as tryptophan, which is underrepresented in RPMI compared with IMDM (1). Mesenchymal stem cells co-cultured with AML12 liver cells were able to differentiate into hepatocytelike cells expressing hepatocyte-specific markers including albumin, α-fetoprotein and cytokeratin 18 mRNAs, which were expressed at the initial 7-day culture in DMEM while being expressed during the 7-to 14-day culture in DMEM/ F12 (3). In a study using MDA-MB-231 breast cancer cells, ~25.6% of genes were expressed at significantly different levels in cells grown in MEM, DM...

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“…It has been discovered that kynurenine can enhance polarization of CD4 T cells to a Treg phenotype versus Th17 cells [21,22] . Stimulation of the kynurenine pathway was also shown to create an immune-suppressive milieu in tumor cells through secretion of immunosuppressive tryptophan metabolites that lead to the induction of T cell apoptosis and increased proliferation of immunosuppressive regulatory T cells [23] . Based on these findings, IDO1 is becoming established as a target for drug discovery in cancer [24] .…”

Section: Discussionmentioning

confidence: 99%

Activation of Tryptophan and Phenylalanine Catabolism in the Remission Phase of Allergic Contact Dermatitis: A Pilot Study

Zinkevičienė

Kainov

Girkontaitė

et al. 2016

Int Arch Allergy Immunol

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Background: Allergic contact dermatitis (ACD) is an inflammatory skin disease caused by repeated skin exposure to contact allergens. The severity and duration of this disease are associated with many different factors. Some of these factors may represent markers for monitoring disease activity and the individual response to an intervention. Methods: We used a targeted metabolomics approach to find such factors in the serum of individuals with ACD. Metabolomics profiles were examined and compared in the acute phase of the disease and also in the absence of disease activity. Results: Our study identified a significant remission phase of ACD-associated systemic biochemical shifts in 2 metabolic pathways: tryptophan-kynurenine and phenylalanine-tyrosine. Conclusions: Although the responsible mechanisms are unclear, these results suggest that the remission phase of ACD is linked to tryptophan metabolism via kynurenine and phenylalanine-tyrosine pathways. However, further replication studies with a larger number of subjects and their subgroups are necessary to validate our results. These studies may provide a new perspective with which to understand the mechanism of and find potential biomarkers of ACD, as well as a new reference for personalized treatment.

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IDO1 Metabolites Activate β-catenin Signaling to Promote Cancer Cell Proliferation and Colon Tumorigenesis in Mice

Cited by 160 publications

References 40 publications

Antigen-Specific Antitumor Responses Induced by OX40 Agonist Are Enhanced by the IDO Inhibitor Indoximod

Antigen-Specific Antitumor Responses Induced by OX40 Agonist Are Enhanced by the IDO Inhibitor Indoximod

Kynurenine promotes the goblet cell differentiation of HT-29 colon carcinoma cells by modulating Wnt, Notch and AhR signals

Activation of Tryptophan and Phenylalanine Catabolism in the Remission Phase of Allergic Contact Dermatitis: A Pilot Study

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