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https://www.readbyqxmd.com/read/28344890/suppression-of-indoleamine-2-3-dioxygenase-1-expression-by-promoter-hypermethylation-in-er-positive-breast-cancer
#1
Dyah L Dewi, Soumya R Mohapatra, Saioa Blanco Cabañes, Isabell Adam, Luis F Somarribas Patterson, Bianca Berdel, Masroor Kahloon, Loreen Thürmann, Stefanie Loth, Katharina Heilmann, Dieter Weichenhan, Oliver Mücke, Ines Heiland, Pauline Wimberger, Jan Dominik Kuhlmann, Karl-Heinz Kellner, Sarah Schott, Christoph Plass, Michael Platten, Clarissa Gerhäuser, Saskia Trump, Christiane A Opitz
Kynurenine formation by tryptophan-catabolic indoleamine-2,3-dioxygenase 1 (IDO1) plays a key role in tumor immune evasion and inhibition of IDO1 is efficacious in preclinical models of breast cancer. As the response of breast cancer to immune checkpoint inhibitors may be limited, a better understanding of the expression of additional targetable immunomodulatory pathways is of importance. We therefore investigated the regulation of IDO1 expression in different breast cancer subtypes. We identified estrogen receptor α (ER) as a negative regulator of IDO1 expression...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28344865/identification-of-genetic-determinants-of-breast-cancer-immune-phenotypes-by-integrative-genome-scale-analysis
#2
Wouter Hendrickx, Ines Simeone, Samreen Anjum, Younes Mokrab, François Bertucci, Pascal Finetti, Giuseppe Curigliano, Barbara Seliger, Luigi Cerulo, Sara Tomei, Lucia Gemma Delogu, Cristina Maccalli, Ena Wang, Lance D Miller, Francesco M Marincola, Michele Ceccarelli, Davide Bedognetti
Cancer immunotherapy is revolutionizing the clinical management of several tumors, but has demonstrated limited activity in breast cancer. The development of more effective treatments is hindered by incomplete knowledge of the genetic determinant of immune responsiveness. To fill this gap, we mined copy number alteration, somatic mutation, and expression data from The Cancer Genome Atlas (TCGA). By using RNA-sequencing data from 1,004 breast cancers, we defined distinct immune phenotypes characterized by progressive expression of transcripts previously associated with immune-mediated rejection...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28336906/identification-and-evaluation-of-new-immunoregulatory-genes-in-mesenchymal-stromal-cells-of-different-origins-comparison-of-normal-and-inflammatory-conditions
#3
Mohammad Fayyad-Kazan, Mehdi Najar, Hussein Fayyad-Kazan, Gordana Raicevic, Laurence Lagneaux
BACKGROUND Mesenchymal stromal cells (MSCs) possess potent immunomodulatory properties that increase their value as a cell-based therapeutic tool for managing various immune-based disorders. Over the past years, accumulated results from trials using MSCs-based therapy have shown substantial contradictions. Although the reasons underlying these discrepancies are still not completely understood, it is well known that the immunomodulatory activities mediated by distinct MSCs differ in a manner dependent on their tissue origin and adequate response to inflammation priming...
March 24, 2017: Medical Science Monitor Basic Research
https://www.readbyqxmd.com/read/28336214/indoleamine-2-3-dioxygenase-1-ido1-inhibitors-activate-the-aryl-hydrocarbon-receptor
#4
Benjamin J Moyer, Itzel Y Rojas, Iain A Murray, Seokwon Lee, Haley F Hazlett, Gary H Perdew, Craig R Tomlinson
Indoleamine 2,3-dioxygenase 1 (IDO1) plays a key role in the immune system by regulating tryptophan levels and T cell differentiation. Several tumor types overexpress IDO1 to avoid immune surveillance making IDO1 of interest as a target for therapeutic intervention. As a result, several IDO1 inhibitors are currently being tested in clinical trials for cancer treatment as well as several other diseases. Many of the IDO1 inhibitors in clinical trials naturally bear structural similarities to the IDO1 substrate tryptophan, as such, they fulfill many of the structural and functional criteria as potential AHR ligands...
March 20, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28324751/the-rationale-of-indoleamine-2-3-dioxygenase-inhibition-for-cancer-therapy
#5
REVIEW
Lieve Brochez, Ines Chevolet, Vibeke Kruse
Indoleamine 2,3-dioxygenase (IDO, also referred to as IDO1) has been demonstrated to be a normal endogenous mechanism of acquired peripheral immune tolerance in vivo. In the field of oncology, IDO expression and/or activity has been observed in several cancer types and has usually been associated with negative prognostic factors and worse outcome measures. This manuscript reviews current available data on the role of IDO in cancer and the current results obtained with IDO inhibition, both in animal models and in phase 1 and 2 clinical trials in humans...
March 18, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28319781/systematic-study-of-imidazoles-inhibiting-ido1-via-the-integration-of-molecular-mechanics-and-quantum-mechanics-calculations
#6
Yi Zou, Fang Wang, Yan Wang, Wenjie Guo, Yihua Zhang, Qiang Xu, Yisheng Lai
Indoleamine 2,3-dioxygenase 1 (IDO1) is regarded as an attractive target for cancer immunotherapy. To rationalize the detailed interactions between IDO1 and its inhibitors at the atomic level, an integrated computational approach by combining molecular mechanics and quantum mechanics methods was employed in this report. Specifically, the binding modes of 20 inhibitors was initially investigated using the induced fit docking (IFD) protocol, which outperformed other two docking protocols in terms of correctly predicting ligand conformations...
March 14, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28285566/involvement-of-the-cytokine-ido1-ahr-loop-in-zinc-oxide-nanoparticle-induced-acute-pulmonary-inflammation
#7
Chia-Chi Ho, Hui-Ling Lee, Chao-Yu Chen, Yueh-Hsia Luo, Ming-Hsien Tsai, Hui-Ti Tsai, Pinpin Lin
Zinc oxide nanoparticles (ZnONPs) are widely used in our daily life, such as in sunscreens and electronic nanodevices. However, pulmonary exposure to ZnONPs causes acute pulmonary inflammation, which is considered as an initial event for various respiratory diseases. Thus, elucidation of the underlying cellular mechanisms of ZnONPs can help us in predicting their potential effects in respiratory diseases. In this study, we observed that ZnONPs increased proinflammatory cytokines, accompanied with an increased expression of aryl hydrocarbon receptor (AhR) and its downstream target cytochrome P450 1A1 (CYP1A1) in macrophages in vitro and in mouse lung epithelia in vivo...
March 13, 2017: Nanotoxicology
https://www.readbyqxmd.com/read/28283500/in-vitro-interactions-of-epacadostat-and-its-major-metabolites-with-human-efflux-and-uptake-transporters-implications-for-pharmacokinetics-and-drug-interactions
#8
Qiang Zhang, Yan Zhang, Jason Boer, Jack G Shi, Peidi Hu, Sharon Diamond, Swamy Yeleswaram
Epacadostat (EPAC) is a first-in-class, orally active inhibitor of the enzyme indoleamine 2,3-dioxygenase 1 (IDO1) and has demonstrated promising clinical activity. In humans, three major plasma metabolites were identified: M9 (a glucuronide-conjugate), M11 (a gut microbiota metabolite), and M12 (a secondary metabolite formed from M11). It is proposed that the biliary excretion of M9, the most abundant metabolite, leads to the enterohepatic circulation of EPAC suggested by the human pharmacokinetics of EPAC...
March 10, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28266612/microbiota-alteration-is-associated-with-the-development-of-stress-induced-despair-behavior
#9
Ioana A Marin, Jennifer E Goertz, Tiantian Ren, Stephen S Rich, Suna Onengut-Gumuscu, Emily Farber, Martin Wu, Christopher C Overall, Jonathan Kipnis, Alban Gaultier
Depressive disorders often run in families, which, in addition to the genetic component, may point to the microbiome as a causative agent. Here, we employed a combination of behavioral, molecular and computational techniques to test the role of the microbiota in mediating despair behavior. In chronically stressed mice displaying despair behavior, we found that the microbiota composition and the metabolic signature dramatically change. Specifically, we observed reduced Lactobacillus and increased circulating kynurenine levels as the most prominent changes in stressed mice...
March 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28264972/synovial-fibroblasts-selectively-suppress-th1-cell-responses-through-ido1-mediated-tryptophan-catabolism
#10
Lars-Oliver Tykocinski, Anna M Lauffer, Antonia Bohnen, Nathalie-Christin Kaul, Stefan Krienke, Theresa Tretter, Isabell Adam, Soumya R Mohapatra, Philippe Saikali, Max Löhning, Michel Neidhart, Steffen Gay, Iris Oezen, Michael Platten, Christiane A Opitz, Hanns-Martin Lorenz
The development of rheumatoid arthritis (RA) is linked to functional changes in synovial fibroblasts (SF) and local infiltration of T lymphocytes. Fibroblasts possess the capacity to suppress T cell responses, although the molecular mechanisms of this suppression remain incompletely understood. In this study, we aimed to define the mechanisms by which noninflammatory SF modulate Th cell responses and to determine the immunosuppressive efficacy of RASF. Hence, the influence of SF from osteoarthritis or RA patients on total Th cells or different Th cell subsets of healthy donors was analyzed in vitro...
March 6, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28264810/promoter-methylation-modulates-indoleamine-2-3-dioxygenase-1-induction-by-activated-t-cells-in-human-breast-cancers
#11
Satish K Noonepalle, Franklin Gu, Eun-Joon Lee, Jeong-Hyeon Choi, Qimei Han, Jaejik Kim, Maria Ouzounova, Austin Y Shull, Lirong Pei, Pei-Yin Hsu, Ravindra Kohle, Fang Shi, Jiseok Choi, Katie Chiou, Tim H M Huang, Hasan Korkaya, Libin Deng, Hong-Bo Xin, Shuang Huang, Muthusamy Thangaraju, Arun Sreekumar, Stefan Ambs, Shou-Ching Tang, David H Munn, Huidong Shi
Triple-negative breast cancer (TNBC) cells are modulated in reaction to tumor-infiltrating lymphocytes. However, their specific responses to this immune pressure are unknown. In order to address this question, we first used mRNA sequencing to compare the immunophenotype of the TNBC cell line MDA-MB-231 and the luminal breast cancer cell line MCF7 after both were cocultured with activated human T cells. Despite similarities in the cytokine-induced immune signatures of the two cell lines, MDA-MD-231 cells were able to transcribe more IDO1 than MCF7 cells...
March 6, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28260094/immunosuppressive-macrophages-induced-by-ido1-promote-the-growth-of-endometrial-stromal-cells-in-endometriosis
#12
Jie Mei, Kai-Kai Chang, Hai-Xiang Sun
It was previously demonstrated that anomalous expression of indoleamine 2,3-dioxygenase-1 (IDO1) in endometrial stromal cells (ESCs) stimulated an inflammatory response that subsequently initiated the activation of immunosuppressive macrophages in endometriosis. The aim of the present study was to clarify the effect of IDO1‑induced macrophages on the growth of ESCs in endometriosis. Normal ESCs, ectopic ESCs and normal ESCs treated with plasmid pEGFP‑N1‑IDO1 or SD11‑IDO1 short hairpin RNA were co‑cultured with peripheral blood‑derived monocyte (PBMC)‑driven macrophages directly for 48 h...
February 22, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28245795/in-search-of-druggable-targets-for-gbm-amino-acid-metabolism
#13
Eduard H Panosyan, Henry J Lin, Jan Koster, Joseph L Lasky
BACKGROUND: Amino acid (AA) pathways may contain druggable targets for glioblastoma (GBM). Literature reviews and GBM database ( http://r2.amc.nl ) analyses were carried out to screen for such targets among 95 AA related enzymes. METHODS: First, we identified the genes that were differentially expressed in GBMs (3 datasets) compared to non-GBM brain tissues (5 datasets), or were associated with survival differences. Further, protein expression for these enzymes was also analyzed in high grade gliomas (HGGs) (proteinatlas...
February 28, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28223071/therapeutic-antibody-targeting-of-indoleamine-2-3-dioxygenase-ido2-inhibits-autoimmune-arthritis
#14
Lauren M F Merlo, Samantha Grabler, James B DuHadaway, Elizabeth Pigott, Kaylend Manley, George C Prendergast, Lisa D Laury-Kleintop, Laura Mandik-Nayak
Rheumatoid arthritis (RA) is a debilitating inflammatory autoimmune disease with no known cure. Recently, we identified the immunomodulatory enzyme indoleamine-2,3-dioxygenase 2 (IDO2) as an essential mediator of autoreactive B and T cell responses driving RA. However, therapeutically targeting IDO2 has been challenging given the lack of small molecules that specifically inhibit IDO2 without also affecting the closely related IDO1. In this study, we develop a novel monoclonal antibody (mAb)-based approach to therapeutically target IDO2...
February 20, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/28214225/a-relay-pathway-between-arginine-and-tryptophan-metabolism-confers-immunosuppressive-properties-on-dendritic-cells
#15
Giada Mondanelli, Roberta Bianchi, Maria Teresa Pallotta, Ciriana Orabona, Elisa Albini, Alberta Iacono, Maria Laura Belladonna, Carmine Vacca, Francesca Fallarino, Antonio Macchiarulo, Stefano Ugel, Vincenzo Bronte, Federica Gevi, Lello Zolla, Auke Verhaar, Maikel Peppelenbosch, Emilia Maria Cristina Mazza, Silvio Bicciato, Yasmina Laouar, Laura Santambrogio, Paolo Puccetti, Claudia Volpi, Ursula Grohmann
Arginase 1 (Arg1) and indoleamine 2,3-dioxygenase 1 (IDO1) are immunoregulatory enzymes catalyzing the degradation of l-arginine and l-tryptophan, respectively, resulting in local amino acid deprivation. In addition, unlike Arg1, IDO1 is also endowed with non-enzymatic signaling activity in dendritic cells (DCs). Despite considerable knowledge of their individual biology, no integrated functions of Arg1 and IDO1 have been reported yet. We found that IDO1 phosphorylation and consequent activation of IDO1 signaling in DCs was strictly dependent on prior expression of Arg1 and Arg1-dependent production of polyamines...
February 21, 2017: Immunity
https://www.readbyqxmd.com/read/28212884/desipramine-decreases-expression-of-human-and-murine-indoleamine-2-3-dioxygenases
#16
Alexandra K Brooks, Tiffany M Janda, Marcus A Lawson, Jennifer L Rytych, Robin A Smith, Cecilia Ocampo-Solis, Robert H McCusker
Abundant evidence connects depression symptomology with immune system activation, stress and subsequently elevated levels of kynurenine. Anti-depressants, such as the tricyclic norepinephrine/serotonin reuptake inhibitor desipramine (Desip), were developed under the premise that increasing extracellular neurotransmitter level was the sole mechanism by which they alleviate depressive symptomologies. However, evidence suggests that anti-depressants have additional actions that contribute to their therapeutic potential...
February 16, 2017: Brain, Behavior, and Immunity
https://www.readbyqxmd.com/read/28201999/effect-of-myeloid-differentiation-primary-response-gene-88-on-expression-profiles-of-genes-during-the-development-and-progression-of-helicobacter-induced-gastric-cancer
#17
Ivonne Lozano-Pope, Arnika Sharma, Michael Matthias, Kelly S Doran, Marygorret Obonyo
BACKGROUND: Gastric cancer is one of the most common and lethal type of cancer worldwide. Infection with Helicobacter pylori (H. pylori) is recognized as the major cause of gastric cancer. However, it remains unclear the mechanism by which Helicobacter infection leads to gastric cancer. Furthermore, the underlying molecular events involved during the progression of Helicobacter infection to gastric malignancy are not well understood. In previous studies, we demonstrated that that H. felis-infected Myd88 (-/-) mice exhibited dramatic pathology and an accelerated progression to gastric dysplasia; however, the MyD88 downstream gene targets responsible for this pathology have not been described...
February 15, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28191010/role-of-dietary-metabolites-in-regulating-the-host-immune-response-in-gastrointestinal-disease
#18
REVIEW
Mohamad El-Zaatari, John Y Kao
The host immune response to gastrointestinal (GI) infections, hypersensitivity reactions, or GI cancers comprises numerous pathways that elicit responses on different host cells. Some of these include (1) the stimulation of mast cells via their IgE receptor, (2) the production of antibodies leading to antibody-mediated cytotoxic T/natural killer cell killing, (3) the activation of the complement pathway, and (4) the activation of the adaptive immune response via antigen-presenting cell, T cell, and B cell interactions...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28181858/evaluation-of-immunomodulatory-properties-of-feline-mesenchymal-stem-cells
#19
Maciej Parys, John M Kruger, Vilma Yuzbasiyan-Gurkan
Mesenchymal stem cells (MSC) offer a novel approach to treatment of inflammatory disorders in humans and companion animals. Cats spontaneously develop a wide variety of inflammatory disorders and may potentially benefit from MSC-based therapies. Multiple genes are involved in immunomodulation by MSC and interspecies differences between expressions of these genes exist. The goals of the study were to characterize the expression of genes known to be involved in MSC-based immunomodulation and determine the effect of MSC on proliferation of T-cells in co-culture experiments with PBMC...
February 9, 2017: Stem Cells and Development
https://www.readbyqxmd.com/read/28179106/non-tumor-cell-ido1-predominantly-contributes-to-enzyme-activity-and-response-to-ctla-4-pd-l1-inhibition-in-mouse-glioblastoma
#20
Lijie Zhai, Erik Ladomersky, Carlos R Dostal, Kristen L Lauing, Kathleen Swoap, Leah K Billingham, Galina Gritsina, Meijing Wu, Robert H McCusker, David C Binder, Derek A Wainwright
Glioblastoma (GBM) is the most common malignant brain tumor in adults with a median survival of 14.6months. A contributing factor to GBM aggressiveness is the intratumoral expression of the potently immunosuppressive enzyme, indoleamine 2,3 dioxygenase 1 (IDO1). The enzymatic activity of IDO1 is associated with the conversion of tryptophan into downstream kynurenine (Kyn), which has previously been hypothesized to contribute toward the suppression of tumor immunity. Utilizing the syngeneic, immunocompetent, intracranial GL261 cell GBM model, we previously demonstrated that tumor cell, but not non-tumor cell IDO1, suppresses T cell-mediated brain tumor regression in mice...
February 4, 2017: Brain, Behavior, and Immunity
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