RESUMEN
Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) are key enzymes for tryptophan degradation, regulating immune tolerance during pregnancy. The intrauterine renin-angiotensin system is also involved in the progression of a healthy pregnancy. Angiotensin(1-7) maintains the integrity of fetal membranes via counteracting the pro-inflammatory actions of Angiotensin II. No data are available on placental Angiotensin(1-7) co-expression with TDO. We aimed to characterize TDO mRNA expression and its localization in different areas of the placenta of physiological pregnancies delivered at term; its co-expression with Angiotensin(1-7) and its correlation with the plasma kynurenine/tryptophan (Kyn/Trp) ratio was investigated. This prospective observational study included a nonconsecutive series of 20 singleton uncomplicated pregnancies delivered vaginally. TDO mRNA was expressed in both maternal and fetal sides of the placentas and TDO protein also in the villi and it was co-expressed with IDO1 in almost half of the placental cells at these sites. The percentage of TDO+ and IDO1+ cells appeared to be influenced by maternal pre-gestational smoking and newborn weight. A strong correlation was found between the percentage of TDO+ and IDO1+ cells in the villi. TDO+ cells also expressed Angiotensin(1-7), with a higher percentage on the fetal side and in the villi compared to the maternal one. Kyn/Trp plasma ratio was not correlated with IDO and TDO expression nor with the patient's characteristics. Collectively, our data indicate that TDO is detectable in placental tissue and is co-expressed with IDO and with Angiotensin(1-7)+ on the fetal side and in the villi.
Asunto(s)
Angiotensina I , Tolerancia Inmunológica , Indolamina-Pirrol 2,3,-Dioxigenasa , Fragmentos de Péptidos , Placenta , Triptófano Hidroxilasa , Angiotensina I/genética , Angiotensina I/inmunología , Angiotensina II/inmunología , Femenino , Humanos , Tolerancia Inmunológica/genética , Tolerancia Inmunológica/inmunología , Indolamina-Pirrol 2,3,-Dioxigenasa/biosíntesis , Indolamina-Pirrol 2,3,-Dioxigenasa/genética , Indolamina-Pirrol 2,3,-Dioxigenasa/inmunología , Recién Nacido , Quinurenina/análisis , Quinurenina/genética , Quinurenina/inmunología , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/inmunología , Placenta/enzimología , Placenta/inmunología , Embarazo , ARN Mensajero , Triptófano/análisis , Triptófano/genética , Triptófano/inmunología , Triptófano Hidroxilasa/genética , Triptófano Hidroxilasa/inmunología , Triptófano Oxigenasa/genética , Triptófano Oxigenasa/inmunologíaRESUMEN
Despite extensive basic and clinical research on immune checkpoint regulatory pathways, little is known about the effects of the ionic tumor microenvironment on immune checkpoint expression and function. Here we describe a mechanistic link between Na+/K+-ATPase (NKA) inhibition and activity of the immune checkpoint protein indoleamine-pyrrole 2',3'-dioxygenase 1 (IDO1). We found that IDO1 was necessary and sufficient for production of kynurenine, a downstream tryptophan metabolite, in cancer cells. We developed a spectrophotometric assay to screen a library of 31 model ion transport-targeting compounds for potential effects on IDO1 function in A549 lung and MDA-MB-231 breast cancer cells. This revealed that the cardiac glycosides ouabain and digoxin inhibited kynurenine production at concentrations that did not affect cell survival. NKA inhibition by ouabain and digoxin resulted in increased intracellular Na+ levels and downregulation of IDO1 mRNA and protein levels, which was consistent with the reduction in kynurenine levels. Knockdown of ATP1A1, the É1 subunit of the NKA and target of cardiac glycosides, increased Na+ levels to a lesser extent than cardiac glycoside treatment and did not affect IDO1 expression. However, ATP1A1 knockdown significantly enhanced the effect of cardiac glycosides on IDO1 expression and kynurenine production. Mechanistically, we show that cardiac glycoside treatment resulted in curtailing the length of phosphorylation-mediated stabilization of STAT1, a transcriptional regulator of IDO1 expression, an effect enhanced by ATP1A1 knockdown. Our findings reveal cross talk between ionic modulation via cardiac glycosides and immune checkpoint protein expression in cancer cells with broad mechanistic and clinical implications.
Asunto(s)
Glicósidos Cardíacos , Indolamina-Pirrol 2,3,-Dioxigenasa , Neoplasias , Factor de Transcripción STAT1 , ATPasa Intercambiadora de Sodio-Potasio , Células A549 , Glicósidos Cardíacos/farmacología , Línea Celular Tumoral , Digoxina/farmacología , Humanos , Proteínas de Punto de Control Inmunitario , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Indolamina-Pirrol 2,3,-Dioxigenasa/biosíntesis , Quinurenina/metabolismo , Neoplasias/patología , Ouabaína/metabolismo , Ouabaína/farmacología , Factor de Transcripción STAT1/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/antagonistas & inhibidores , ATPasa Intercambiadora de Sodio-Potasio/metabolismoRESUMEN
Programmed death ligand-1 (PD-L1) and indoleamine 2, 3-dioxygenase 1 (IDO1) are immune checkpoints induced by interferon-γ (IFN-γ) in the tumor microenvironment, leading to immune escape of tumors. Myricetin (MY) is a flavonoid distributed in many edible and medicinal plants. In this study, MY was identified to inhibit IFN-γ-induced PD-L1 expression in human lung cancer cells. It also reduced the expression of IDO1 and the production of kynurenine which is the product catalyzed by IDO1, while didn't show obvious effect on the expression of major histocompatibility complex-I (MHC-I), a crucial molecule for antigen presentation. In addition, the function of T cells was evaluated using a co-culture system consist of lung cancer cells and the Jurkat-PD-1 T cell line overexpressing PD-1. MY restored the survival, proliferation, CD69 expression and interleukin-2 (IL-2) secretion of Jurkat-PD-1 T cells suppressed by IFN-γ-treated lung cancer cells. Mechanistically, IFN-γ up-regulated PD-L1 and IDO1 at the transcriptional level through the JAK-STAT-IRF1 axis, which was targeted and inhibited by MY. Together, our research revealed a new mechanism of MY mediated anti-tumor activity and highlighted the potential implications of MY in tumor immunotherapy.
Asunto(s)
Antígeno B7-H1/antagonistas & inhibidores , Flavonoides/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Interferón gamma/farmacología , Neoplasias Pulmonares/metabolismo , Células A549 , Antígeno B7-H1/biosíntesis , Antígeno B7-H1/genética , Técnicas de Cocultivo , Relación Dosis-Respuesta a Droga , Regulación Neoplásica de la Expresión Génica/fisiología , Células HCT116 , Células HEK293 , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/biosíntesis , Indolamina-Pirrol 2,3,-Dioxigenasa/genética , Células Jurkat , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/fisiologíaRESUMEN
While their function, as immune checkpoint molecules, is well known, B7-family proteins also function as regulatory molecules in bone remodeling. B7-H3 is a receptor ligand of the B7 family that functions primarily as a negative immune checkpoint. While the regulatory function of B7-H3 in osteoblast differentiation has been established, its role in osteoclast differentiation remains unclear. Here we show that B7-H3 is highly expressed in mature osteoclasts and that B7-H3 deficiency leads to the inhibition of osteoclastogenesis in human osteoclast precursors (OCPs). High-throughput transcriptomic analyses reveal that B7-H3 inhibition upregulates IFN signaling as well as IFN-inducible genes, including IDO. Pharmacological inhibition of type-I IFN and IDO knockdown leads to reversal of B7-H3-deficiency-mediated osteoclastogenesis suppression. Although synovial-fluid macrophages from rheumatoid-arthritis patients express B7-H3, inhibition of B7-H3 does not affect their osteoclastogenesis. Thus, our findings highlight B7-H3 as a physiologic positive regulator of osteoclast differentiation and implicate type-I IFN-IDO signaling as its downstream mechanism.
Asunto(s)
Antígenos B7/metabolismo , Diferenciación Celular , Indolamina-Pirrol 2,3,-Dioxigenasa/biosíntesis , Interferón Tipo I/metabolismo , Osteoclastos/metabolismo , Osteoclastos/patología , Animales , Anticuerpos Neutralizantes/farmacología , Artritis Reumatoide/patología , Antígenos B7/deficiencia , Antígenos B7/genética , Inducción Enzimática/efectos de los fármacos , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Interferón beta/metabolismo , Factor Estimulante de Colonias de Macrófagos/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/patología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Osteogénesis/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Transducción de Señal/efectos de los fármacos , Células Madre/efectos de los fármacos , Células Madre/metabolismo , Proteína 1 Supresora de la Señalización de Citocinas/metabolismo , Líquido Sinovial/metabolismo , Triptófano/metabolismoRESUMEN
Immune escape is an early phenomenon in cancer development/progression. Indoleamine 2,3-dioxygenase 1 (IDO1) is a normal endogenous mechanism of acquired peripheral immune tolerance and may therefore be tumor-promoting. This study investigated the clinical relevance of IDO1 expression by immune cells in the lymph nodes and blood and of the serum kynurenine/tryptophan (Kyn/Trp) ratio in 65 systemic treatment naïve stage I-III melanoma patients. Blood samples were collected within the first year of diagnosis. Patients had a median follow-up of 61 months. High basal IDO1 expression in peripheral monocytes and low IFNγ-induced IDO1 upregulation correlated with worse outcome independent from disease stage. Interestingly studied factors were not interrelated. During follow-up, the risk of relapse was 9% (2/22) in the subgroup with high IFNγ-induced IDO1 upregulation in monocytes. In contrast, if IDO1 upregulation was low, relapse occurred in 30% (3/10) of patients with low basal IDO1 expression in monocytes and in 61.5% (8/13) in the subgroup with high basal IDO1 expression in monocytes (Log-Rank test, p=0.008). This study reveals some immune features in the blood of early stage melanoma that may be of relevance for disease outcome. These may offer a target for sub-stratification and early intervention.
Asunto(s)
Indolamina-Pirrol 2,3,-Dioxigenasa/biosíntesis , Interferón gamma/farmacología , Quinurenina/sangre , Melanoma/sangre , Monocitos/efectos de los fármacos , Neoplasias Cutáneas/sangre , Triptófano/sangre , Adulto , Células Cultivadas , Inducción Enzimática , Femenino , Humanos , Masculino , Melanoma/enzimología , Melanoma/inmunología , Melanoma/terapia , Persona de Mediana Edad , Monocitos/enzimología , Monocitos/inmunología , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Estudios Retrospectivos , Neoplasias Cutáneas/enzimología , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/terapia , Factores de Tiempo , Resultado del Tratamiento , Escape del TumorRESUMEN
The association of immune markers and clinicopathologic features and patient outcome has not been extensively studied in Merkel cell carcinoma (MCC). We correlated tumoral PD-L1 and IDO1 expression, and intratumoral CD8+ and FoxP3+ lymphocytes count with clinicopathologic variables, Merkel cell polyomavirus (MCPyV) status, and patient outcomes in a series of 132 MCC. By univariate analyses, tumoral PD-L1 expression >1% and combined tumoral PD-L1 >1% and high intratumoral FoxP3+ lymphocyte count correlated with improved overall survival (OS) (p = 0.016, 0.0072), MCC-specific survival (MSS) (p = 0.019, 0.017), and progression-free survival (PFS) (p = 0.043, 0.004, respectively). High intratumoral CD8+ and FoxP3+ lymphocyte count correlated with longer MSS (p = 0.036) and improved PFS (p = 0.047), respectively. Ulceration correlated with worse OS and worse MSS. Age, male gender, and higher stage (3 and 4) significantly correlated with worse survival. MCPyV positivity correlated with immune response. By multivariate analyses, only ulceration and age remained as independent predictors of worse OS; gender and stage remained for shorter PFS. Tumoral PD-L1 expression and increased density of intratumoral CD8+ lymphocytes and FoxP+ lymphocytes may represent favorable prognosticators in a subset of MCCs. Tumoral PD-L1 expression correlated with intratumoral CD8+ and FoxP3+ lymphocytes, which is supportive of an adaptive immune response.
Asunto(s)
Antígeno B7-H1/biosíntesis , Linfocitos T CD8-positivos/inmunología , Carcinoma de Células de Merkel/mortalidad , Indolamina-Pirrol 2,3,-Dioxigenasa/biosíntesis , Linfocitos Infiltrantes de Tumor/inmunología , Proteínas de Neoplasias/biosíntesis , Neoplasias Cutáneas/mortalidad , Subgrupos de Linfocitos T/inmunología , Inmunidad Adaptativa , Factores de Edad , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor , Linfocitos T CD8-positivos/química , Carcinoma de Células de Merkel/química , Carcinoma de Células de Merkel/inmunología , Carcinoma de Células de Merkel/virología , Femenino , Factores de Transcripción Forkhead/análisis , Neoplasias de Cabeza y Cuello/química , Neoplasias de Cabeza y Cuello/inmunología , Neoplasias de Cabeza y Cuello/mortalidad , Neoplasias de Cabeza y Cuello/virología , Humanos , Estimación de Kaplan-Meier , Recuento de Linfocitos , Masculino , Poliomavirus de Células de Merkel/aislamiento & purificación , Persona de Mediana Edad , Análisis Multivariante , Estadificación de Neoplasias , Neoplasias Primarias Secundarias/química , Neoplasias Primarias Secundarias/inmunología , Neoplasias Primarias Secundarias/mortalidad , Neoplasias Primarias Secundarias/virología , Pronóstico , Supervivencia sin Progresión , Modelos de Riesgos Proporcionales , Factores Sexuales , Neoplasias Cutáneas/química , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/virología , Úlcera Cutánea/etiología , Infecciones Tumorales por VirusRESUMEN
OBJECTIVES: Although exosomes carrying Epstein-Barr virus-encoded small RNA-1 (EBER-1) are involved in the immunosuppressive tumor microenvironments of EBV-associated head and neck carcinomas, the effects of EBER-1-associated exosomes on tumor-infiltrating macrophages are poorly understood. MATERIALS AND METHODS: The association between EBV infection and expression of indoleamine 2,3-dioxygenase (IDO) was assessed in 165 paraffin-embedded oral squamous cell carcinoma (OSCC) tissue samples. Using in vitro techniques, we investigated whether stimulation of the RIG-I/IL-6/TNF-α pathway by exosomes carrying EBER-1 is critical for IDO induction in macrophages. We performed a thymidine incorporation and a cell cytolytic assay to test for up-regulated IDO in macrophages that can block the proliferation and function of effector T cells. RESULTS: Some infiltrated macrophages expressed levels of IDO higher than OSCC cells which was significantly associated with presence of EBV. The production of IDO, tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in human monocyte-derived macrophages (MDMs) was induced by EBV-associated exosomes in vitro. Mechanistically, the retinoic acid-inducible gene I (RIG-I) pathway in MDMs was stimulated by EBV-encoded small RNA-1 (EBER-1) whereas the inhibition of these pathways by BX-795 almost abolished the production of these two cytokines and IDO induction. Also, the EBER-1-activated IDO in MDMs suppressed the proliferation of T lymphocytes and diminished the cytolytic activity of CD8+ T cells. CONCLUSION: Exosomes carrying EBER-1 could induce IDO expression in MDMs, considerably aided by an IL-6 and TNF-α-dependent mechanism via the RIG-I signaling pathway, which might create an immunosuppressive microenvironment affecting T-cell immune responses.
Asunto(s)
Exosomas , Indolamina-Pirrol 2,3,-Dioxigenasa , Macrófagos , Neoplasias de la Boca , ARN Viral , Carcinoma de Células Escamosas de Cabeza y Cuello , Linfocitos T CD8-positivos , Proteína 58 DEAD Box/metabolismo , Herpesvirus Humano 4 , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/biosíntesis , Interleucina-6/metabolismo , Macrófagos/enzimología , Neoplasias de la Boca/genética , Neoplasias de la Boca/inmunología , Neoplasias de la Boca/terapia , ARN Viral/inmunología , Receptores Inmunológicos/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/terapia , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Indoleamine 2,3-dioxygenase 1 (IDO1) is the first rate-limiting enzyme that metabolizes tryptophan to the kynurenine pathway. Its activity is highly inducible by pro-inflammatory cytokines and correlates with the severity of major depressive disorder (MDD). MicroRNAs (miRNAs) are involved in gene regulation and the development of neuropsychiatric disorders including MDD. However, the role of miRNAs in targeting IDO1 in the pathophysiology of MDD is still unknown. In this study, we investigated the role of novel miRNAs in the regulation of IDO1 activity and its effect on lipopolysaccharide (LPS)-induced depression-like behavior in mice. LPS up-regulated miR-874-3p concomitantly with increase in IDO1 expression in the prefrontal cortex (PFC), increase in immobility in the forced swimming test as depression-like behavior and decrease in locomotor activity as sickness behavior without motor dysfunction. The miR-874-3p increased in both neuron and microglia after LPS. Its mimic significantly suppressed LPS-induced IDO1 expression in the PFC. Infusion of IDO1 inhibitor (1-methyl-l-tryptophan) and miR-874-3p into PFC prevented an increase in immobility in the forced swimming test, but did not decrease in locomotor activity induced by LPS. These results suggest that miR-874-3p may play an important role in preventing the LPS-induced depression-like behavior through inhibition of IDO1 expression. This may also serve as a novel potential target molecule for the treatment of MDD.
Asunto(s)
Depresión/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Indolamina-Pirrol 2,3,-Dioxigenasa/biosíntesis , Lipopolisacáridos/toxicidad , MicroARNs/biosíntesis , Corteza Prefrontal/metabolismo , Animales , Depresión/inducido químicamente , Depresión/genética , Regulación Enzimológica de la Expresión Génica , Indolamina-Pirrol 2,3,-Dioxigenasa/genética , Masculino , Ratones , Ratones Endogámicos C57BL , MicroARNs/genética , Corteza Prefrontal/efectos de los fármacosRESUMEN
BACKGROUND: The disappointing activity of single agent immune-checkpoint inhibitors in epitherlial ovarian cancer (EOC) has been attributed in part to its unique tumor microenvironment (TME). IDO, PDL1, LAG3 and TIM3 have been implicated in the immunotolerance of EOC. We investigated the expression of these co-regulators, their change with neoadjuvant chemotherapy (NACT), and their association with outcome. METHOD: We identified 98 patients with EOC treated with NACT and performed IDO, PDL1, LAG3 and TIM3 immunohistochemistry on samples obtained before and after NACT. The cut-off threshold to consider a positive sample was set at 5%. RESULTS: In our cohort, TIM3 was the most prevalent co-regulator, with more than 75% of the samples being TIM3 positive. In comparison, only 22%, 28% and 17% of the samples were considered IDO, PDL1 and LAG3 positive. More than half of ovarian tumors expressed 2, 3 or even all 4 co-inhibitory molecules. However, biomarkers were not correlated with each other. NACT had a marked impact on immune co-regulator expression with over 70% of patients showing a change in biomarker status from negative to positive or vice versa. There was no significant difference in the pattern of co-regulator expression between platinum-sensitive and resistant patients. Co-expression of multiple inhibitory molecules did not appear to affect overall and progression-free survival. CONCLUSION: TIM3 is the most abundant co-inhibitory molecule in OC and may represent an attractive target. In addition, OC frequently co-expressed 2 or more markers supporting ICI combinatorial approaches. Finally, NACT significantly altered the expression of immunosuppressive molecules suggesting that the choice of ICI combinations should be adapted to the composition of the post-NACT immune TME.
Asunto(s)
Proteínas de Punto de Control Inmunitario/biosíntesis , Neoplasias Ováricas/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD/biosíntesis , Antígenos CD/inmunología , Antígeno B7-H1/biosíntesis , Antígeno B7-H1/inmunología , Carcinoma Epitelial de Ovario/inmunología , Femenino , Receptor 2 Celular del Virus de la Hepatitis A/biosíntesis , Receptor 2 Celular del Virus de la Hepatitis A/inmunología , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Proteínas de Punto de Control Inmunitario/inmunología , Inmunohistoquímica , Indolamina-Pirrol 2,3,-Dioxigenasa/biosíntesis , Indolamina-Pirrol 2,3,-Dioxigenasa/inmunología , Persona de Mediana Edad , Terapia Neoadyuvante , Estudios Retrospectivos , Microambiente Tumoral/inmunología , Adulto Joven , Proteína del Gen 3 de Activación de LinfocitosRESUMEN
Multiple sclerosis (MS) is a complex inflammatory disease in which demyelination occurs in the central nervous system affecting approximately 2.5 million people worldwide. Recent reports have shown that the gut microbiome plays a crucial role in the functioning of the immune system in inflammatory diseases such as MS. In this study, the cuprizone-induced demyelination mouse model was used to investigate the effect of Lactobacillus casei strain T2 (IBRC-M10783) on the alleviation of these mice. Female C57BL/6 mice (8-10 weeks old) were divided into 6 groups: group 1, normal control; group 2, cuprizone control (oral administration of cuprizone 0.2% w/w for 4 weeks); group 3, probiotic control (oral administration of 1 × 109 CFU/ml probiotic for 4 weeks); group 4, treatment 1 (probiotic for 4 weeks then cuprizone for 4 weeks); group 5, treatment 2 (cuprizone for 4 weeks then probiotic for 4 weeks); and group 6, treatment 3 (cuprizone for 4 weeks then probiotic for 4 weeks with vitamin D3 at a dose of 20 IU/day). Then, TGF-ß and IL-17 were measured by ELISA, and the expression of miR-155, miR-25, and IDO-1 was evaluated by real-time PCR. Among the measured microRNAs, the results showed that there was a significant decrease in miR-155 expression between the treatment 1 group and the cuprizone group. In the case of IL-17, the results also showed a significant reduction between the three treatment groups and the cuprizone group. These observations suggest that L. casei can reduce proinflammatory cytokines and reduce demyelinating symptoms in the mouse model.
Asunto(s)
Enfermedades Desmielinizantes/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenasa/biosíntesis , Lacticaseibacillus casei , MicroARNs/biosíntesis , Linfocitos T Reguladores/metabolismo , Células Th17/metabolismo , Animales , Cuprizona/toxicidad , Enfermedades Desmielinizantes/inducido químicamente , Enfermedades Desmielinizantes/terapia , Modelos Animales de Enfermedad , Femenino , Expresión Génica , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Ratones , Ratones Endogámicos C57BL , MicroARNs/antagonistas & inhibidores , Probióticos/administración & dosificación , Linfocitos T Reguladores/efectos de los fármacos , Células Th17/efectos de los fármacosRESUMEN
Indoleamine 2,3-dioxygenase 1 (IDO1) is a cytosolic haem-containing enzyme involved in the degradation of tryptophan to kynurenine. Although initially thought to be solely implicated in the modulation of innate immune responses during infection, subsequent discoveries demonstrated IDO1 as a mechanism of acquired immune tolerance. In cancer, IDO1 expression/activity has been observed in tumor cells as well as in the tumor-surrounding stroma, which is composed of endothelial cells, immune cells, fibroblasts, and mesenchymal cells. IDO1 expression/activity has also been reported in the peripheral blood. This manuscript reviews available data on IDO1 expression, mechanisms of its induction, and its function in cancer for each of these compartments. In-depth study of the biological function of IDO1 according to the expressing (tumor) cell can help to understand if and when IDO1 inhibition can play a role in cancer therapy.
Asunto(s)
Regulación Enzimológica de la Expresión Génica/inmunología , Regulación Neoplásica de la Expresión Génica/inmunología , Indolamina-Pirrol 2,3,-Dioxigenasa/inmunología , Proteínas de Neoplasias/inmunología , Neoplasias/inmunología , Microambiente Tumoral/inmunología , Animales , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/biosíntesis , Proteínas de Neoplasias/biosíntesis , Neoplasias/enzimología , Neoplasias/patología , Neoplasias/terapiaRESUMEN
Covid-19 is the acute illness caused by SARS-CoV-2 with initial clinical symptoms such as cough, fever, malaise, headache, and anosmia. After entry into cells, corona viruses (CoV) activate aryl hydrocarbon receptors (AhRs) by an indoleamine 2,3-dioxygenase (IDO1)-independent mechanism, bypassing the IDO1-kynurenine-AhR pathway. The IDO1-kynurenine-AhR signaling pathway is used by multiple viral, microbial and parasitic pathogens to activate AhRs and to establish infections. AhRs enhance their own activity through an IDO1-AhR-IDO1 positive feedback loop prolonging activation induced by pathogens. Direct activation of AhRs by CoV induces immediate and simultaneous up-regulation of diverse AhR-dependent downstream effectors, and this, in turn, results in a "Systemic AhR Activation Syndrome" (SAAS) consisting of inflammation, thromboembolism, and fibrosis, culminating in multiple organ injuries, and death. Activation of AhRs by CoV may lead to diverse sets of phenotypic disease pictures depending on time after infection, overall state of health, hormonal balance, age, gender, comorbidities, but also diet and environmental factors modulating AhRs. We hypothesize that elimination of factors known to up-regulate AhRs, or implementation of measures known to down-regulate AhRs, should decrease severity of infection. Although therapies selectively down-regulating both AhR and IDO1 are currently lacking, medications in clinical use such as dexamethasone may down-regulate both AhR and IDO1 genes, as calcitriol/vitamin D3 may down-regulate the AhR gene, and tocopherol/vitamin E may down-regulate the IDO1 gene. Supplementation of calcitriol should therefore be subjected to epidemiological studies and tested in prospective trials for prevention of CoV infections, as should tocopherol, whereas dexamethasone could be tried in interventional trials. Because lack of physical exercise activates AhRs via the IDO1-kynurenine-AhR signaling pathway increasing risk of infection, physical exercise should be encouraged during quarantines and stay-at-home orders during pandemic outbreaks. Understanding which factors affect gene expression of both AhR and IDO1 may help in designing therapies to prevent and treat humans suffering from Covid-19.
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Betacoronavirus/fisiología , Infecciones por Coronavirus/fisiopatología , Indolamina-Pirrol 2,3,-Dioxigenasa/fisiología , Pandemias , Neumonía Viral/fisiopatología , Receptores de Hidrocarburo de Aril/fisiología , Contaminantes Atmosféricos/efectos adversos , COVID-19 , Calcitriol/uso terapéutico , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/tratamiento farmacológico , Dexametasona/uso terapéutico , Ejercicio Físico , Retroalimentación Fisiológica , Femenino , Fibrosis/etiología , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/biosíntesis , Indolamina-Pirrol 2,3,-Dioxigenasa/genética , Inflamación/etiología , Quinurenina/fisiología , Masculino , Terapia Molecular Dirigida , Insuficiencia Multiorgánica/etiología , Trabajo de Parto Prematuro/etiología , Neumonía Viral/complicaciones , Neumonía Viral/tratamiento farmacológico , Embarazo , Complicaciones Infecciosas del Embarazo/fisiopatología , Receptores de Hidrocarburo de Aril/biosíntesis , Receptores de Hidrocarburo de Aril/genética , SARS-CoV-2 , Trastornos de la Sensación/etiología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Tromboembolia/etiología , Tocoferoles/uso terapéutico , Tratamiento Farmacológico de COVID-19RESUMEN
AIM: Indoleamine 2,3-dioxygenase 1 (IDO) is responsible for the progression of the kynurenine pathway, which has been implicated in the pathophysiology of inflammation-induced depression. It has been reported that asperosaponin VI (ASA VI) could play a neuroprotective role through anti-inflammatory and antioxidant. In this study, we examined the antidepressant effect of ASA VI in lipopolysaccharide (LPS)-treated mice and further explored its molecular mechanism by looking into the microglial kynurenine pathway. METHODS: To generate the model, LPS (0.83 mg/kg) was administered intraperitoneally to mice. The mice received ASA VI (10 mg/kg, 20 mg/kg, 40 mg/kg, and 80 mg/kg, i.p.) 30 min before LPS injection. Depressive-like behaviors were evaluated based on the duration of immobility in the forced swim test. Microglial activation and inflammatory cytokines were detected by immunohistochemistry, real-time PCR, and ELISA. The TLR4/NF-κB signaling pathway and the expression of IDO, GluA2, and CamKIIß were also measured by western blotting. RESULTS: ASA VI exhibited significant antidepressant activity in the presence of LPS on immobility and latency times in the forced swim test. The LPS-induced activation of microglia and inflammatory response were inhibited by ASA VI, which showed a dose-dependent pattern. TLR4/NF-κB signaling pathway also was suppressed by ASA VI in the hippocampus and prefrontal cortex of LPS-treated mice. Furthermore, ASA VI inhibited the increase in IDO protein expression and normalized the aberrant glutamate transmission in the hippocampus and prefrontal cortex caused by LPS administration. CONCLUSION: Our results propose a promising antidepressant effect for ASA VI possibly through the downregulation of IDO expression and normalization of the aberrant glutamate transmission. This remedying effect of ASA VI could be attributed to suppress microglia-mediated neuroinflammatory response via inhibiting the TLR4/NF-κB signaling pathway.
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Antidepresivos/farmacología , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Microglía/efectos de los fármacos , FN-kappa B/antagonistas & inhibidores , Saponinas/farmacología , Receptor Toll-Like 4/antagonistas & inhibidores , Animales , Antiinflamatorios/farmacología , Antidepresivos/uso terapéutico , Células Cultivadas , Depresión/inducido químicamente , Depresión/metabolismo , Depresión/psicología , Expresión Génica , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenasa/biosíntesis , Indolamina-Pirrol 2,3,-Dioxigenasa/genética , Lipopolisacáridos/toxicidad , Masculino , Ratones , Ratones Endogámicos C57BL , Microglía/metabolismo , FN-kappa B/metabolismo , Saponinas/uso terapéutico , Receptor Toll-Like 4/metabolismoRESUMEN
Although Indoleamine 2,3-dioxygenase (IDO), tryptophan-2,3-dioxygenase (TDO), and aryl hydrocarbon receptor (AHR) are involved in cancer immune escape, their prognostic impact on diffuse large B-cell lymphoma (DLBCL) is unknown.To examine the prognostic impact of IDO, TDO, and AHR on patients with DLBCL.This was a retrospective study on treatment-naïve patients with newly diagnosed DLBCL at the Henan Province People's Hospital between 01/2012 and 06/2015. Patients with inflammatory reactive lymph nodes were included as controls. All cases were reviewed by 2 pathologists. IDO, TDO, and AHR positivity was determined through immunochemistry. Survival was examined using the Kaplan-Meier method and multivariable Cox analyses.The positive expression of TDO (50.0% vs 16.7%, Pâ=â.005) and AHR (60.0% vs 8.3%, Pâ<â.001) were higher in DLBCL than in inflammatory control. The overall survival of IDO, TDO, and AHR positive expression in DLBCL patients was 34.6, 26.7, and 32.2 months, respectively, which is significantly shorter than that of the corresponding negative patients (49.0 months, Pâ=â.04; 58.2 months, Pâ<â.001; 58.0 months, Pâ<â.001; respectively). The multivariable analysis showed that TDO expression and Ann-Arbor stage were independently associated with PFS (TDO: HRâ=â8.347, 95%CI: 2.992-23.289, Pâ<â.001; stage: HRâ=â2.729, 95%CI: 1.571-4.739, Pâ<â.001) and OS (TDO: HRâ=â9.953, 95%CI: 3.228-30.686, Pâ<â.001; stage: HRâ=â2.681, 95%CI: 1.524-4.719, Pâ=â.001) in DLBCL patients.Overexpression of IDO, TDO, and AHR is associated with poor survival of patients with DLBCL and could be involved in the immune escape of cancer cells. Further studies are necessary to determine whether these proteins can be targeted by treatment regimens.
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Antineoplásicos Inmunológicos/uso terapéutico , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/fisiología , Indolamina-Pirrol 2,3,-Dioxigenasa/fisiología , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/mortalidad , Receptores de Hidrocarburo de Aril/fisiología , Rituximab/uso terapéutico , Triptófano Oxigenasa/fisiología , Adulto , Anciano , Anciano de 80 o más Años , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/biosíntesis , Femenino , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/biosíntesis , Masculino , Persona de Mediana Edad , Pronóstico , Receptores de Hidrocarburo de Aril/biosíntesis , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del Tratamiento , Triptófano Oxigenasa/biosíntesis , Adulto JovenRESUMEN
There is limited understanding of the role of host metabolism in the pathophysiology of human tuberculosis (TB). Using high-resolution metabolomics with an unbiased approach to metabolic pathway analysis, we discovered that the tryptophan pathway is highly regulated throughout the spectrum of TB infection and disease. This regulation is characterized by increased catabolism of tryptophan to kynurenine, which was evident not only in active TB disease but also in latent TB infection (LTBI). Further, we found that tryptophan catabolism is reversed with effective treatment of both active TB disease and LTBI in a manner commensurate with bacterial clearance. Persons with active TB and LTBI also exhibited increased expression of indoleamine 2,3-dioxygenase-1 (IDO-1), suggesting IDO-1 mediates observed increases in tryptophan catabolism. Together, these data indicate IDO-1-mediated tryptophan catabolism is highly preserved in the human response to Mycobacterium tuberculosis and could be a target for biomarker development as well as host-directed therapies.
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Regulación Enzimológica de la Expresión Génica , Indolamina-Pirrol 2,3,-Dioxigenasa/biosíntesis , Tuberculosis Latente/metabolismo , Mycobacterium tuberculosis/metabolismo , Triptófano/metabolismo , Tuberculosis Pulmonar/metabolismo , Adulto , Biomarcadores/metabolismo , Femenino , Humanos , Tuberculosis Latente/patología , Masculino , Tuberculosis Pulmonar/patologíaRESUMEN
Previous studies have pointed out that indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme initiating tryptophan metabolism, plays a role in the regulation of the immune system. This project was designed to investigate the potential role of IDO in monocyte-derived dendritic cells (moDCs) obtained from active Vogt-Koyanagi-Harada (VKH) disease patients. In this study, we found that the IDO mRNA expression and enzyme activity were increased in active VKH patients as compared with healthy controls and patients in remission. To investigate the role of IDO in immune regulation, an effective inhibitor 1-methyl-L-tryptophan (1-MT) was used to suppress its activity in DCs. The results showed that inhibition of IDO with 1-MT significantly decreased the expression of DC marker CD86. IDO inhibition did not affect the cytokine production of IL-6, IL-1ß, TNF-α, IL-10, and TGF-ß in DCs. Downregulation of IDO in DCs also led to the reduction of regulatory T (Treg) cells and an increased CD4+ T cell proliferation. Treatment with 1-MT did not affect the phosphorylation of the MAPK pathway in DCs. In general, our study suggests that IDO may play an important role in the pathogenesis of VKH disease by regulating DC and CD4+ T cell function. Tryptophan deficiency and kynurenine accumulation may account for the complicated effects of IDO. Further research is needed to study the precise tryptophan metabolites that may limit immune responses in VKH disease.
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Regulación Enzimológica de la Expresión Génica , Indolamina-Pirrol 2,3,-Dioxigenasa/biosíntesis , Linfocitos T Reguladores/enzimología , Síndrome Uveomeningoencefálico/enzimología , Adulto , Células Cultivadas , Técnicas de Cocultivo , Citocinas/metabolismo , Femenino , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/genética , Leucocitos Mononucleares/enzimología , Leucocitos Mononucleares/patología , Masculino , Linfocitos T/enzimología , Linfocitos T/patología , Linfocitos T Reguladores/patología , Síndrome Uveomeningoencefálico/genética , Síndrome Uveomeningoencefálico/patologíaRESUMEN
Indoleamine 2, 3-dioxygenase (IDO), an immunosuppressive enzyme that mediates the conversion of tryptophan to kynurenine, was shown to play a key role in placental development during normal pregnancy. However, little is known about the pattern of IDO expression in the endometrium and its attendant functional significance in pregnancies complicated with recurrent miscarriage (RM). Immunohistochemical studies of IDO, Foxp3, CD56, and CD163 expression were performed in endometrial samples from women with RM and healthy fertile controls. Our study found that IDO was localized in glandular epithelial cells, surface epithelial cells, and a small number of cells within the stromal compartment (including stromal cells and leukocytes) in endometrium. Indoleamine 2, 3-dioxygenase expression in the RM group was significantly lower than control group. The Foxp3 and CD56 expression were significantly increased with the elevated IDO expression in controls but not in RM. The percentage of Foxp3 + Tregs was significantly correlated with the level of IDO expression in the control group. Comparatively, no correlation was found between the percentage of CD56 + cells, CD163 + cells, and the level of IDO expression, no matter in controls and RM patients. This study demonstrated that the downregulation of IDO expression and noncoordinated association between IDO and other endometrial immune cells were associated with RM. Our findings provide insights into the contribution of IDO in immune regulation to maintain normal pregnancy, which could be used to develop potential therapeutic methods for RM.
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Aborto Habitual/enzimología , Endometrio/metabolismo , Regulación del Desarrollo de la Expresión Génica , Indolamina-Pirrol 2,3,-Dioxigenasa/biosíntesis , Aborto Habitual/genética , Adulto , Femenino , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/genética , EmbarazoRESUMEN
PURPOSE: This study examined the expression of programmed cell death-ligand 1 (PD-L1), programmed cell death-ligand 2 (PD-L2), and indoleamine 2,3-dioxygenase-1 (IDO1) in tumor cells and cluster of differentiation 8 (CD8)-positive tumor-infiltrating lymphocytes (TILs) in early-stage lung adenocarcinoma according to histological subtypes. METHODS: We evaluated PD-L1, PD-L2, and IDO1 expression in tumor cells and CD8-positive TILs in surgically resected specimens from 196 stage 0 or I lung adenocarcinoma patients by immunohistochemical staining. We also examined the relationships between the expression of PD-L1, PD-L2, and IDO1 in tumor cells and the density of CD8-positive TILs and clinical factors. Patients were divided into three groups: A, adenocarcinoma in situ and minimally invasive adenocarcinoma (N = 32); B, lepidic predominant invasive adenocarcinoma (IAD; LPA; N = 66); and C, IAD except for LPA (N = 98). RESULTS: PD-L1 was expressed only in Group C, but not in Groups A or B. The positive ratio of PD-L2 was significantly higher in Group C (63.3%), and that of IDO1 was also significantly higher in Group C (65.3%). The density of CD8-positive TILs was significantly higher in Group C (45 ± 2.4). There was no significant difference between the positive ratios of PD-L2 and IDO1 and the density of CD8-positive TILs in Group A (50.0%, 21.9%, and 36 ± 4.1, respectively) or Group B (60.6%, 25.8%, and 44 ± 3.0, respectively). CONCLUSIONS: No cases in Groups A and B expressed PD-L1. The expression of immune-related factors, especially PD-L1 and IDO1, was significantly associated with Group C. This is the first report of the detailed examination of PD-L1, PD-L2, IDO1, and CD8 expression in lung adenocarcinoma subtypes with lepidic predominant components. Our results could help identify patients who would benefit from perioperative immunotherapy.
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Adenocarcinoma del Pulmón/inmunología , Antígeno B7-H1/biosíntesis , Linfocitos T CD8-positivos/inmunología , Indolamina-Pirrol 2,3,-Dioxigenasa/biosíntesis , Neoplasias Pulmonares/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Proteína 2 Ligando de Muerte Celular Programada 1/biosíntesis , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/metabolismo , Adenocarcinoma del Pulmón/patología , Adulto , Anciano , Anciano de 80 o más Años , Antígeno B7-H1/inmunología , Linfocitos T CD8-positivos/patología , Receptores ErbB/genética , Femenino , Humanos , Inmunohistoquímica , Indolamina-Pirrol 2,3,-Dioxigenasa/inmunología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Linfocitos Infiltrantes de Tumor/patología , Masculino , Persona de Mediana Edad , Proteína 2 Ligando de Muerte Celular Programada 1/inmunología , Estudios RetrospectivosRESUMEN
Hypomethylating agents (HMAs) are widely used in patients with higher-risk myelodysplastic syndromes (MDS) not eligible for stem cell transplantation; however, the response rate is <50%. Reliable predictors of response are still missing, and it is a major challenge to develop new treatment strategies. One current approach is the combination of azacytidine (AZA) with checkpoint inhibitors; however, the potential benefit of targeting the immunomodulator indoleamine-2,3-dioxygenase (IDO-1) has not yet been evaluated. We observed moderate to strong IDO-1 expression in 37% of patients with high-risk MDS. IDO-1 positivity was predictive of treatment failure and shorter overall survival. Moreover, IDO-1 positivity correlated inversely with the number of infiltrating CD8+ T cells, and IDO-1+ patients failed to show an increase in CD8+ T cells under AZA treatment. In vitro experiments confirmed tryptophan catabolism and depletion of CD8+ T cells in IDO-1+ MDS, suggesting that IDO-1 expression induces an immunosuppressive microenvironment in MDS, thereby leading to treatment failure under AZA treatment. In conclusion, IDO-1 is expressed in more than one-third of patients with higher-risk MDS, and is predictive of treatment failure and shorter overall survival. Therefore, IDO-1 is emerging as a promising predictor and therapeutic target, especially for combination therapies with HMAs or checkpoint inhibitors.
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Azacitidina/uso terapéutico , Indolamina-Pirrol 2,3,-Dioxigenasa/sangre , Síndromes Mielodisplásicos/sangre , Anciano , Anciano de 80 o más Años , Azacitidina/farmacología , Biomarcadores , Médula Ósea/patología , Linfocitos T CD8-positivos/inmunología , Células Cultivadas , Terapia Combinada , Metilación de ADN/efectos de los fármacos , Quimioterapia Combinada , Inducción Enzimática/efectos de los fármacos , Femenino , Trasplante de Células Madre Hematopoyéticas , Humanos , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Indolamina-Pirrol 2,3,-Dioxigenasa/biosíntesis , Indolamina-Pirrol 2,3,-Dioxigenasa/genética , Macrófagos/enzimología , Macrófagos/ultraestructura , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/mortalidad , Síndromes Mielodisplásicos/terapia , Pronóstico , Riesgo , Triptófano/metabolismoRESUMEN
Renal cell carcinoma (RCC) with sarcomatoid changes and rhabdoid features has shown poor outcomes. Several immune checkpoint inhibitors including programmed cell death protein 1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitors have been approved for the treatment of RCC. Combination therapy using PD-1/PD-L1 and indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors has also been used to treat various malignancies. However, little is known about IDO1 expression and therapeutic effects of the IDO1 inhibitor in RCC. Herein, we retrospectively analyzed the expression of PD-L1/IDO1 and examined its relationship with tumor-infiltrating lymphocyte (TIL) status and prognostic effect. We investigated the PD-L1, IDO1, CD3+, CD4+, and CD8+ immunoexpression status in 60 cases of sarcomatoid/rhabdoid RCC. The PD-L1 and IDO1 results were defined by the tumor proportion score. For the evaluation of TIL status, we counted the number of lymphocytes located in the tumor and averaged the numbers over five high-power fields for each case. The results revealed PD-L1 and IDO1 expression was observed more frequently in the sarcomatoid/rhabdoid component than in the nonsarcomatoid/nonrhabdoid component. The correlation between PD-L1 and IDO1 expression was significant (P = 0.0076). PD-L1 expression and coexpression of PD-L1 and IDO1 were correlated with a high density of CD3+, CD4+, and CD8+ T cells. There was no significant difference in overall survival among the patients with PD-L1 and/or IDO1 expression, but PD-L1 expression and coexpression were related to poor progression-free survival. Our results suggest that combination therapy using the PD-1/PD-L1 inhibitor and IDO1 inhibitor may be effective for treating sarcomatoid/rhabdoid RCC.