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Background Indoleamine 2,3-dioxygenase catalyzes the conversion of tryptophan to kynurenine, an immunosuppressive metabolite involved in T regulatory cell differentiation. Indoleamine 2,3-dioxygenase is expressed in many cancer types, including breast cancer. Here, we analyze kynurenine and tryptophan and their ratio in breast cancer patients and healthy controls. Methods Breast cancer patients and healthy controls were prospectively enrolled in our study. All subjects underwent blood sample withdrawal at diagnosis or on the day of screening mammography for the healthy controls. Plasmatic kynurenine and tryptophan were determined on a TQ5500 tandem mass spectrometer after chromatographic separation. Results We enrolled 146 healthy controls and 202 women with stages I–III breast cancer of all subtypes. All patients underwent surgery, 126 underwent neoadjuvant chemotherapy with 43 showing a pathological complete response, and 43 underwent adjuvant chemotherapy. We observed significantly higher plasmatic kynurenine, tryptophan and their ratio for the healthy controls compared to patients with breast cancer. We observed a lower plasmatic tryptophan and a higher kynurenine/tryptophan ratio in hormone receptor-negative patients compared to hormone receptor-positive cancers. Lobular cancers showed a lower ratio than any other histologies. Advanced cancers were associated with a lower tryptophan level and higher grades with an increased kynurenine/tryptophan ratio. Pathological complete response was associated with higher kynurenine values. The plasmatic kynurenine, tryptophan and kynurenine/tryptophan ratios were not predictive of survival. Conclusions The plasmatic kynurenine, tryptophan and kynurenine/tryptophan ratio could differentiate breast cancer patients from healthy controls. The Kyn/Trp ratio and Trp also showed different values according to hormone receptor status, TNM stage, T grade and histology. These results suggest a rapid metabolism in breast cancer, but no associations with outcome or sensitivity to chemotherapy were observed.

To evade immune destruction, tumors exploit a wide range of immune escape mechanisms, including the induction of an immunosuppressive tumor microenvironment. This is mediated, in part, by amino acid degrading enzymes indoleamine 2,3-dioxygenase, tryptophan 2,3-dioxygenase, arginase 1 and arginase 2, which have emerged as key players in the regulation of tumor-induced immune tolerance. Here we describe how the expression of tryptophan- and arginine-degrading enzymes by tumor and tumor-infiltrating cells can hamper cancer-specific immune responses, and discuss how this knowledge is being exploited to develop new strategies for cancer immunotherapy.

This study evaluated the role of quercetin against cyclophosphamide‐induced distortion of rat testicular function. Adult rats were administered cyclophosphamide (100 mg/kg), quercetin (50 mg/kg) and in combination for seven days. Cyclophosphamide caused a significant increase in the activities of indoleamine 2, 3‐dioxygenases (IDO), tryptophan 2, 3‐dioxygenase (TDO), myeloperoxidase (MPO), and elevated the concentrations of interleukin 6 (IL‐6) and interferon‐γ (IFN‐γ). Cyclophosphamide increased testis malondialdehyde (MDA) concentrations but depleted superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH‐Px) and glutathione (GSH). However, quercetin co‐administration significantly (p < 0.05) prevented the increased values of IDO, TDO, MPO, IL‐6, IFN‐γ, MDA, SOD, CAT, GSH‐Px and GSH compared with control rats. Also, quercetin co‐treatment significantly increased serum testosterone, follicle‐stimulating hormone (FSH), prolactin, luteinizing hormone (LH), activities of testicular 3β‐hydroxysteroid dehydrogenase (3 β‐HSD), 17β‐hydroxysteroid dehydrogenase (17 β‐HSD) as well as sperm count, motility and viability but reduced abnormal sperm morphology. Quercetin exposure alone did not alter any of the parameters evaluated relative to control. Thus, quercetin protected the testes against cyclophosphamide‐induced alterations in immunosuppressive IDO/TDO activities elicited by oxidative‐inflammatory mediators.

BackgroundStrategies for deploying indoleamine 2,3-dioxygenase 1 (IDO1)-targeted therapies for use against cancer have focused on IDO1’s role in promoting peripheral immune tolerance that shields tumors from effector T cells. However, preclinical investigation of both primary and metastatic tumor development in the lungs has uncovered a previously unappreciated role for IDO1 in directing a counterregulatory response to interferon (IFN)-γ that realigns the local inflammatory environment to promote tumor neovascularization. Understanding how to therapeutically leverage the ability of IDO1 inhibitors to subvert inflammatory neovascularization within the tumor microenvironment has potential ramifications for future clinical development of these compounds.MethodsPulmonary metastases seeded by orthotopically implanted 4T1 breast carcinoma cells were evaluated by confocal microscopy for the impact of both genetic and pharmacological IDO1 inhibition, alone or in combination with ischemia-directed cytotoxic agents, on markers of blood vessel density, hypoxia and cell death. Tumor immunogenicity and programmed death-ligand 1 (PD-L1) elevation were also evaluated. Quantitative analysis of these results was used to guide combinatorial treatment regimen development.ResultsInhibiting IDO1 activity resulted in reduced neovascular density and elevated hypoxia in pulmonary metastases for which host IFN-γ was essential while adaptive immunity was dispensable. The tumors were consequently sensitized to the cytotoxic activity of ischemia-targeted agents including the protein kinase R-like endoplasmic reticulum kinase (PERK) inhibitor GSK2656157, the dithiol oxidative antimetabolite TTL-315, and the hypoxia-activated prodrug evofosfamide. Evofosfamide provoked the greatest degree of immunogenic cell death, while hypoxia, among other stressors, induced PD-L1. Based on this information, synergistic improvement in median survival was demonstrated in mice with established lung metastases through combined administration of anti-programmed cell death protein-1 (PD-1) antibody with evofosfamide and the IDO1 inhibitor epacadostat.ConclusionsImproving therapeutic outcomes for patients with lung tumors, arising either as primary lesions or metastatic colonies, is of vital clinical importance. Building on preclinical evidence for IDO1’s role in promoting inflammatory neovascularization of lung tumors, this study demonstrates how the intratumoral ischemic stress elicited by IDO1 inhibition can potentiate the immunogenic cytotoxicity of ischemia-targeted agents to effectively leverage immune checkpoint blockade responsiveness to confer a synergistic survival benefit. These findings provide a novel perspective on how IDO1 inhibitors can impact tumor biology and open up new possibilities for therapeutic applications.

Background Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the first and rate-limiting step in converting tryptophan to kynurenine. Chimeric antigen receptor (CAR) T cells are T cells with recombinant receptors targeting tumor-associated antigens. The Food and Drug Administration has approved CAR T cells that target CD19 for treatment of advanced B cell leukemia and lymphoma. However, CAR T cell therapy in solid tumors has been hampered by multiple obstacles. Preclinical and clinical studies suggest that combinatorial immune checkpoint blockade and IDO1 inhibition provide durable therapeutic efficacy against cancer. Yet, the combination of IDO1 inhibition and CAR T has not been attempted. Methods We analyze IDO1 downregulation by miR-153 in colon cancer cells and the association of IDO1 and miR-153 expression with colorectal patient survival. We generate CAR T cells targeting the epidermal growth factor receptor variant III and measure their tumor killing effects against colon cancer cells with or without miR-153 overexpression by killing assays and in xenografts. Results IDO1 is highly expressed in colorectal tumors and is inversely associated with patient survival. miR-153 directly inhibits IDO1 expression by targeting its 3′ untranslated region in colon cancer cells; yet, miR-153 overexpression does not affect cancer cell survival, apoptosis, and colony formation. When colon cancer cells are targeted by CAR T cells, miR-153 overexpression within tumor cells significantly enhances T cell killing in vitro and suppresses xenograft tumor growth in mice. Conclusions These findings indicate that miR-153 inhibits IDO1 expression in colon cancer cells and is a tumor-suppressive miRNA that enhances CAR T cell immunotherapy. This study supports the combinatorial use of IDO1 inhibitors and CAR T cells in treating solid tumors.

This study aimed to determine the effects of mitotherapy on learning and memory and hippocampal kynurenine (Kyn) pathway, mitochondria function, and dendritic arborization and spines density in aged rats subjected to chronic mild stress. Twenty-eight male Wistar rats (22 months old( were randomly divided into Aged, Aged + Mit, Aged + Stress, and Aged + Stress + Mit groups. Aged rats in the stress groups were subjected to different stressors for 28 days. The Aged + Mit and Aged + stress + Mit groups were treated with intracerebroventricular injection (10 µl) of fresh mitochondria harvested from the young rats' brains, and other groups received 10 µl mitochondria storage buffer. Spatial and episodic-like memories were assessed via the Barnes maze and novel object recognition tests. Indoleamine 2,3-dioxygenase (IDO) expression and activity, Kyn, Tryptophan (TRY), ATP levels, and mitochondrial membrane potential (MMP) were measured in the hippocampus region. Golgi-Cox staining was also performed to assess the dendritic branching pattern and dendritic spines in the hippocampal CA1 subfield. The results showed that mitotherapy markedly improved both spatial and episodic memories in the Aged + Stress + Mit group compared to the Aged + Stress. Moreover, mitotherapy decreased IDO protein expression and activity and Kyn levels, while it increased ATP levels and improved MMP in the hippocampus of the Aged + Stress + Mit group. Besides, mitotherapy restored dendritic atrophy and loss of spine density in the hippocampal neurons of the stress-exposed aged rats. These findings provide evidence for the therapeutic effect of mitotherapy against stress-induced cognitive deterioration in aged rats by improving hippocampal mitochondrial function and modulation of the Kyn pathway.

Indoleamine 2, 3-dioxygenase (IDO) is a potent immunoenzyme found in dendritic cells (DCs). Research has demonstrated that Trichinella spiralis induces IDO expression in the host immune response through its excretory-secretory (ES) antigens. However, the role of IDO in the immune response to T. spiralis remains unclear. To examine the effects of T. spiralis ES antigens on IDO expression in DCs in vitro , assessments were conducted using qRT-PCR, Western blotting (WB), flow cytometry, and siRNA transfer. The findings indicated that ES antigen stimulation upregulated IDO expression in DCs in vitro . Furthermore, ES antigen significantly enhanced the expression of the proinflammatory cytokines TNF-α and IFN-γ, along with the anti-inflammatory cytokine IL-10, downstream of IDO in DCs. Flow cytometry analysis confirmed that surface molecules CD40, MHC-II, CD80, and CD86 on DCs were upregulated following stimulation with ES antigen and lipopolysaccharide (LPS). Compared to the ES antigen alone, siRNA620 effectively inhibited IDO levels, demonstrating a statistically significant reduction. Continuous stimulation of DCs by ES antigens may lead to immune tolerance through the activation of IDO-mediated inflammation-associated factors. These results suggest that IDO expression in DCs plays a crucial role in T. spiralis infection. L’indoleamine 2,3-dioxygénase (IDO) est une immunoenzyme puissante présente dans les cellules dendritiques (CD). Des recherches ont démontré que Trichinella spiralis induit l’expression d’IDO dans la réponse immunitaire de l’hôte via ses antigènes excrétés-sécrétés (ES). Cependant, le rôle de l’IDO dans la réponse immunitaire à T. spiralis reste incertain. Afin d’examiner les effets des antigènes ES de T. spiralis sur l’expression d’IDO dans les CD in vitro , des évaluations ont été réalisées par qRT-PCR, Western blot (WB), cytométrie de flux et transfert d’ARNsi. Les résultats ont indiqué que la stimulation par les antigènes ES régulait positivement l’expression d’IDO dans les CD in vitro . De plus, les antigènes ES ont significativement augmenté l’expression des cytokines pro-inflammatoires TNF-α et IFN-γ, ainsi que de la cytokine anti-inflammatoire IL-10, en aval de l’IDO dans les DC. L’analyse par cytométrie de flux a confirmé que les molécules de surface CD40, MHC-II, CD80 et CD86 sur les DC étaient régulées positivement après stimulation par les antigènes ES et le lipopolysaccharide (LPS). Comparé aux antigènes ES seul, le siRNA620 a inhibé efficacement les taux d’IDO, démontrant une réduction statistiquement significative. La stimulation continue des DC par les antigènes ES pourrait induire une tolérance immunitaire via l’activation de facteurs associés à l’inflammation médiés par l’IDO. Ces résultats suggèrent que l’expression d’IDO dans les DC joue un rôle crucial dans l’infection à T. spiralis .

The gut microbiota plays a pivotal role in modulating obesity pathogenesis, yet the molecular mechanisms underlying its protective effects remain elusive. In this study, we demonstrate that L-ornithine (L-orn), a metabolite produced by Lactobacillus , confers resistance against high-fat diet (HFD)-induced obesity in mice by modulating macrophage function through its downstream metabolites spermine (SPM) and spermidine (SPD). Mechanistically, SPM suppressed pro-inflammatory cytokine production in macrophages by inhibiting the NF-κB and Akt signaling pathways, while SPD activated Src kinase and upregulated indoleamine 2,3-dioxygenase 1 (IDO-1), thereby promoting the polarization of immunosuppressive IDO-1 + macrophages. Clinically, circulating L-orn levels were inversely correlated with body mass index (BMI) in obese individuals, underscoring its potential relevance in human obesity. Single-cell RNA sequencing (scRNA-seq) analysis further revealed dysregulated macrophage signaling in obese adipose tissue, characterized by hyperactivation of NF-κB and Akt pathways and downregulation of Src signaling in inflammatory macrophages. Collectively, our findings highlight a novel mechanism by which gut microbiota-derived L-orn mitigates obesity through metabolite-driven reprogramming of macrophages toward an anti-inflammatory phenotype, offering new therapeutic avenues for metabolic disorders.

Regulation of amino acid availability and metabolism in immune cells is essential for immune system homeostasis and responses to exogenous and endogenous challenges including microbial infection, tumorigenesis and autoimmunity. In myeloid cells the consumption of amino acids such as arginine and tryptophan and availability of their metabolites are key drivers of cellular identity impacting development, functional polarization to an inflammatory or regulatory phenotype, and interaction with other immune cells. In this review, we discuss recent developments and emerging concepts in our understanding of the impact amino acid availability and consumption has on cellular phenotype focusing on two key myeloid cell populations, macrophages and myeloid derived suppressor cells (MDSCs). We also highlight the potential of myeloid-specific of amino acid transporters and catabolic enzymes as immunotherapy targets in a variety of conditions such as cancer and autoimmune disease discussing the opportunities and limitations in targeting these pathways for clinical therapy.

The kynurenine pathway is the primary route for tryptophan catabolism and has received increasing attention as its association with inflammation and the immune system has become more apparent. This review provides a broad overview of the kynurenine pathway in respiratory diseases, from the initial observations to the characterization of the different cell types involved in the synthesis of kynurenine metabolites and the underlying immunoregulatory mechanisms. With a focus on respiratory infections, the various attempts to characterize the kynurenine/tryptophan (K/T) ratio as an inflammatory marker are reviewed. Its implication in chronic lung inflammation and its exacerbation by respiratory pathogens is also discussed. The emergence of preclinical interventional studies targeting the kynurenine pathway opens the way for the future development of new therapies.