RESUMEN
The aryl hydrocarbon receptor (AhR) is a sensor of products of tryptophan metabolism and a potent modulator of immunity. Here, we examined the impact of AhR in tumor-associated macrophage (TAM) function in pancreatic ductal adenocarcinoma (PDAC). TAMs exhibited high AhR activity and Ahr-deficient macrophages developed an inflammatory phenotype. Deletion of Ahr in myeloid cells or pharmacologic inhibition of AhR reduced PDAC growth, improved efficacy of immune checkpoint blockade, and increased intra-tumoral frequencies of IFNγ+CD8+ T cells. Macrophage tryptophan metabolism was not required for this effect. Rather, macrophage AhR activity was dependent on Lactobacillus metabolization of dietary tryptophan to indoles. Removal of dietary tryptophan reduced TAM AhR activity and promoted intra-tumoral accumulation of TNFα+IFNγ+CD8+ T cells; provision of dietary indoles blocked this effect. In patients with PDAC, high AHR expression associated with rapid disease progression and mortality, as well as with an immune-suppressive TAM phenotype, suggesting conservation of this regulatory axis in human disease.
Asunto(s)
Tolerancia Inmunológica/inmunología , Receptores de Hidrocarburo de Aril/inmunología , Triptófano/inmunología , Macrófagos Asociados a Tumores/inmunología , Animales , Linfocitos T CD8-positivos/inmunología , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/patología , Humanos , Indoles/inmunología , Indoles/metabolismo , Linfocitos Infiltrantes de Tumor/inmunología , Ratones , Microbiota/inmunología , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Pronóstico , Receptores de Hidrocarburo de Aril/antagonistas & inhibidores , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/metabolismo , Triptófano/metabolismo , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Macrófagos Asociados a Tumores/metabolismoRESUMEN
The transcription factor AhR modulates immunity at multiple levels. Here we report that phagocytes exposed to apoptotic cells exhibited rapid activation of AhR, which drove production of the cytokine IL-10. Activation of AhR was dependent on interactions between apoptotic-cell DNA and the pattern-recognition receptor TLR9 that was required for the prevention of immune responses to DNA and histones in vivo. Moreover, disease progression in mouse systemic lupus erythematosus (SLE) correlated with strength of the AhR signal, and the disease course could be altered by modulation of AhR activity. Deletion of AhR in the myeloid lineage caused systemic autoimmunity in mice, and an enhanced AhR transcriptional signature correlated with disease in patients with SLE. Thus, AhR activity induced by apoptotic cell phagocytes maintains peripheral tolerance.
Asunto(s)
Apoptosis/inmunología , Tolerancia Inmunológica/inmunología , Lupus Eritematoso Sistémico/inmunología , Macrófagos/inmunología , Receptores de Hidrocarburo de Aril/inmunología , Animales , Humanos , Ratones , Transducción de Señal/inmunología , Receptor Toll-Like 9/inmunologíaRESUMEN
Muscle wasting can be caused by nutrition deficiency and inefficient metabolism of amino acids, including Branched Chain Amino Acids (BCAAs). Branched Chain Amino Acids are a major contributor to the metabolic needs of healthy muscle and account for over a tenth of lean muscle mass. Branched chain alpha-ketoacid dehydrogenase (BCKD) is the rate limiting enzyme of BCAA metabolism. Inhibition of BCKD is achieved through a reversible phosphorylation event by Branched Chain a-ketoacid dehydrogenase kinase (BCKDK). Our study set out to determine the importance of BCKDK in the maintenance of skeletal muscle. We used the Gene Expression Omnibus Database to understand the role of BCKDK in skeletal muscle pathogenesis, including aging, muscular disease, and interrupted muscle metabolism. We found BCKDK expression levels were consistently decreased in pathologic conditions. These results were most consistent when exploring muscular disease followed by aging. Based on our findings, we hypothesize that decreased BCKDK expression alters BCAA catabolism and impacts loss of normal muscle integrity and function. Further research could offer valuable insights into potential therapeutic strategies for addressing muscle-related disorders.
Asunto(s)
Aminoácidos de Cadena Ramificada , Músculo Esquelético , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Humanos , Aminoácidos de Cadena Ramificada/metabolismo , Animales , Envejecimiento/metabolismo , Envejecimiento/genética , Enfermedades Musculares/metabolismo , Enfermedades Musculares/patología , Enfermedades Musculares/genética , 3-Metil-2-Oxobutanoato Deshidrogenasa (Lipoamida)/metabolismo , 3-Metil-2-Oxobutanoato Deshidrogenasa (Lipoamida)/genética , Proteínas QuinasasRESUMEN
Understanding the pathophysiology behind age-related diseases is an urgent need as the elderly population continues to grow. With age, there is a high risk of musculoskeletal deterioration and associated morbidity and mortality. Although the exact mechanism behind age-related degeneration is unknown, it is well established that alteration in cellular metabolism is one of the important contributing factors. Alteration in signaling pathways with age leads to the accumulation or depletion of several metabolites that play a vital role in musculoskeletal pathophysiology. This study aimed to identify age-related changes in bone tissue metabolites in C57BL/6 mice. We then correlated the differentially expressed metabolites with their functions in bone biology. In both aged males and females, hydroxyproline, glutamine, and alpha-linolenic acid levels were decreased. In aged females, Ornithine (p value = 0.001), L-Proline (p value = 0.008), Uridine (p value = 0.001), Aspartic Acid (p value = 0.004) levels were significantly decreased, and glutamate (p value = 0.002) was elevated. In aged males, N-acetyl-D-glucosamine (pvalue = 0.010), Adrenic acid (pvalue = 0.0099), Arachidonic acid (p value = 0.029) and Allantoin (p value = 0.004) levels were decreased. Metabolic pathway analysis revealed that purine and D-glutamine and D-glutamate metabolism were significantly altered in both sexes, while arginine biosynthesis in females and lipid metabolism in males were highly affected. These differences in metabolic signaling might be one of the reasons for the discrepancy in musculoskeletal disease manifestation between the two sexes. Understanding the role of these metabolites play in the aging bone will allow for new sex-specific targeted therapies against the progression of musculoskeletal diseases.
Asunto(s)
Envejecimiento , Metabolismo de los Lípidos , Anciano , Envejecimiento/metabolismo , Animales , Huesos , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ornitina/metabolismoRESUMEN
The combination of immune checkpoint blockade with chemotherapy is currently under investigation as a promising strategy for the treatment of triple negative breast cancer (TNBC). Tumor-associated macrophages (TAMs) are the most prominent component of the breast cancer microenvironment because they influence tumor progression and the response to therapies. Here we show that macrophages acquire an immunosuppressive phenotype and increase the expression of programmed death ligand-1 (PD-L1) when treated with reactive oxygen species (ROS) inducers such as the glutathione synthesis inhibitor, buthionine sulphoximine (BSO), and paclitaxel. Mechanistically, these agents cause accumulation of ROS that in turn activate NF-κB signaling to promote PD-L1 transcription and the release of immunosuppressive chemokines. Systemic in vivo administration of paclitaxel promotes PD-L1 accumulation on the surface of TAMS in a mouse model of TNBC, consistent with in vitro results. Combinatorial treatment with paclitaxel and an anti-mouse PD-L1 blocking antibody significantly improved the therapeutic efficacy of paclitaxel by reducing tumor burden and increasing the number of tumor-associated cytotoxic T cells. Our results provide a strong rationale for the use of anti-PD-L1 blockade in the treatment of TNBC patients. Furthermore, interrogation of chemotherapy-induced PD-L1 expression in TAMs is warranted to define appropriate patient selection in the use of PD-L1 blockade.
Asunto(s)
Antígeno B7-H1/metabolismo , Inmunosupresores/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Especies Reactivas de Oxígeno/farmacología , Animales , Antígeno B7-H1/genética , Neoplasias de la Mama/metabolismo , Butionina Sulfoximina/farmacología , Línea Celular Tumoral , Quimiocinas , Quimioterapia , Femenino , Glutatión/metabolismo , Humanos , Ratones , Paclitaxel/farmacología , Fenotipo , ARN Mensajero/metabolismo , Neoplasias de la Mama Triple Negativas , Microambiente Tumoral , Regulación hacia ArribaRESUMEN
The aryl hydrocarbon receptor (AhR) is a cytoplasmic receptor and transcription factor activated through cognate ligand binding. It is an important factor in immunity and tissue homeostasis, and structurally diverse compounds from the environment, diet, microbiome, and host metabolism can induce AhR activity. Emerging evidence suggests that AhR is a key sensor allowing immune cells to adapt to environmental conditions and changes in AhR activity have been associated with autoimmune disorders and cancer. Furthermore, AhR agonists or antagonists can impact immune disease outcomes identifying AhR as a potentially actionable target for immunotherapy. In this review, we describe known ligands stimulating AhR activity, downstream proinflammatory and suppressive mechanisms potentiated by AhR, and how this understanding is being applied to immunopathology to help control disease outcomes.
Asunto(s)
Microambiente Celular/inmunología , Inmunidad/inmunología , Receptores de Hidrocarburo de Aril/inmunología , Animales , Humanos , Receptores de Hidrocarburo de Aril/agonistas , Receptores de Hidrocarburo de Aril/antagonistas & inhibidoresRESUMEN
In this study, we report the expeditious synthesis of ten new antifungal and antioxidant agents containing heterocyclic linked 7-arylidene indanone moiety. The solvent-free microwave technique, ample substrate scope, superfast synthesis, and very simple operation are noteworthy features of this protocol. Antifungal activities of the newly synthesized compounds were evaluated against four fungal strains namely Rhizophus oryzae, Mucor mucido, Aspergillus niger, and Candida albicans. Most of the compounds were shown strong inhibition of the investigated fungal agents. In vitro, antioxidant potential against DPPH and OH radicals affirmed that the synthesized compounds are good to excellent radicals scavenging agents. The cytotoxicity data of the synthesized compounds towards HL-60 cells uncovered that the synthesized compounds display very low to negligible cytotoxicity. The structural and quantum chemical parameters of the synthesized compounds were explored by employing density functional theory (DFT) at B3LYP functional using 6-311G(d,p) basis set. The compound 3a is discussed in detail for the theoretical and experimental correlation. Time-dependent density functional theory (TD-DFT) at CAM-B3LYP functional with 6-311G(d,p) basis set was used for the electronic absorption study in the gas phase and indichloromethane and benzene solvents. The UV-Visible absorption peaks and fundamental vibrational wavenumbers were computed and a good agreement between observed and theoretical results has been achieved. From the DFT and antifungal activity correlation, it has been found that the 7-heteroarylidene indanones with more stabilized LUMO energy levels display good antifungal potential.
Asunto(s)
Antifúngicos/farmacología , Antineoplásicos/farmacología , Antioxidantes/farmacología , Compuestos Heterocíclicos/farmacología , Indanos/farmacología , Microondas , Antifúngicos/síntesis química , Antifúngicos/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Antioxidantes/síntesis química , Antioxidantes/química , Aspergillus niger/efectos de los fármacos , Candida albicans/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HL-60 , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/química , Humanos , Indanos/síntesis química , Indanos/química , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Mucor/efectos de los fármacos , Oryza/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Autoimmune diseases are characterized by pathogenic immune responses to self-antigens. In systemic lupus erythematosus (SLE), many self-antigens are found in apoptotic cells (ACs), and defects in removal of ACs from the body are linked to a risk for developing SLE. This includes pathological memory that gives rise to disease flares. In this study, we investigated how memory to AC-derived self-antigens develops and the contribution of self-memory to the development of lupus-related pathology. Multiple injections of ACs without adjuvant into wild-type mice induce a transient primary autoimmune response without apparent anti-nuclear Ab reactivity or kidney pathology. Interestingly, as the transient Ab response reached baseline, a single boost injection fully recalled the immune response to ACs, and this memory response was furthermore transferable into naive mice. Additionally, the memory response contains elements of pathogenicity, accompanied by selective memory to selective Ags. Thus, we provide evidence for a selective self-memory that underlies progression of the response to self-antigens with implications for SLE development therapy.
Asunto(s)
Apoptosis/inmunología , Autoanticuerpos/inmunología , Autoantígenos/inmunología , Memoria Inmunológica/inmunología , Lupus Eritematoso Sistémico/inmunología , Animales , Lupus Eritematoso Sistémico/terapia , Ratones , Ratones Endogámicos C57BLRESUMEN
Efficient apoptotic cell clearance and induction of immunologic tolerance is a critical mechanism preventing autoimmunity and associated pathology. Our laboratory has reported that apoptotic cells induce tolerance by a mechanism dependent on the tryptophan catabolizing enzyme indoleamine 2,3 dioxygenase 1 (IDO1) in splenic macrophages (MΦ). The metabolic-stress sensing protein kinase GCN2 is a primary downstream effector of IDO1; thus, we tested its role in apoptotic cell-driven immune suppression. In vitro, expression of IDO1 in MΦs significantly enhanced apoptotic cell-driven IL-10 and suppressed IL-12 production in a GCN2-dependent mechanism. Suppression of IL-12 protein production was due to attenuation of IL-12 mRNA association with polyribosomes inhibiting translation while IL-10 mRNA association with polyribosomes was not affected. In vivo, apoptotic cell challenge drove a rapid, GCN2-dependent stress response in splenic MΦs with increased IL-10 and TGF-ß production, whereas myeloid-specific deletion of GCN2 abrogated regulatory cytokine production with provocation of inflammatory T-cell responses to apoptotic cell antigens and failure of long-tolerance induction. Consistent with a role in prevention of apoptotic cell driven autoreactivity, myeloid deletion of GCN2 in lupus-prone mice resulted in increased immune cell activation, humoral autoimmunity, renal pathology, and mortality. In contrast, activation of GCN2 with an agonist significantly reduced anti-DNA autoantibodies and protected mice from disease. Thus, this study implicates a key role for GCN2 signals in regulating the tolerogenic response to apoptotic cells and limiting autoimmunity.
Asunto(s)
Apoptosis/fisiología , Autoinmunidad/fisiología , Tolerancia Inmunológica/fisiología , Proteínas Serina-Treonina Quinasas/fisiología , Aminoácidos/metabolismo , Animales , Apoptosis/efectos de los fármacos , Células Cultivadas , Citocinas/biosíntesis , Citocinas/genética , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Indolamina-Pirrol 2,3,-Dioxigenasa/fisiología , Inflamación , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/patología , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células Mieloides/inmunología , Piperidinas/farmacología , Proteínas Serina-Treonina Quinasas/deficiencia , Quinazolinonas/farmacología , Transducción de SeñalRESUMEN
Humoral responses to nonproteinaceous Ags (i.e., T cell independent [TI]) are a key component of the early response to bacterial and viral infection and a critical driver of systemic autoimmunity. However, mechanisms that regulate TI humoral immunity are poorly defined. In this study, we report that B cell-intrinsic induction of the tryptophan-catabolizing enzyme IDO1 is a key mechanism limiting TI Ab responses. When Ido1(-/-) mice were immunized with TI Ags, there was a significant increase in Ab titers and formation of extrafollicular Ab-secreting cells compared with controls. This effect was specific to TI Ags, as Ido1 disruption did not affect Ig production after immunization with protein Ags. The effect of IDO1 abrogation was confined to the B cell compartment, as adoptive transfer of Ido1(-/-) B cells to B cell-deficient mice was sufficient to replicate increased TI responses observed in Ido1(-/-) mice. Moreover, in vitro activation with TLR ligands or BCR crosslinking rapidly induced Ido1 expression and activity in purified B cells, and Ido1(-/-) B cells displayed enhanced proliferation and cell survival associated with increased Ig and cytokine production compared with wild-type B cells. Thus, our results demonstrate a novel, B cell-intrinsic, role for IDO1 as a regulator of humoral immunity that has implications for both vaccine design and prevention of autoimmunity.
Asunto(s)
Antígenos T-Independientes/inmunología , Linfocitos B/inmunología , Inmunidad Humoral/inmunología , Indolamina-Pirrol 2,3,-Dioxigenasa/inmunología , Traslado Adoptivo , Animales , Formación de Anticuerpos/inmunología , Apoptosis/genética , Apoptosis/inmunología , Linfocitos B/metabolismo , Western Blotting , Proliferación Celular/genética , Femenino , Citometría de Flujo , Inmunidad Humoral/genética , Inmunoglobulina G/inmunología , Inmunoglobulina G/metabolismo , Inmunoglobulina M/inmunología , Inmunoglobulina M/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenasa/genética , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Interleucina-10/inmunología , Interleucina-10/metabolismo , Interleucina-6/inmunología , Interleucina-6/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Microscopía Confocal , Receptores de Antígenos de Linfocitos B/inmunología , Receptores de Antígenos de Linfocitos B/metabolismoRESUMEN
Inflammatory kidney disease is a major clinical problem that can result in end-stage renal failure. In this article, we show that Ab-mediated inflammatory kidney injury and renal disease in a mouse nephrotoxic serum nephritis model was inhibited by amino acid metabolism and a protective autophagic response. The metabolic signal was driven by IFN-γ-mediated induction of indoleamine 2,3-dioxygenase 1 (IDO1) enzyme activity with subsequent activation of a stress response dependent on the eIF2α kinase general control nonderepressible 2 (GCN2). Activation of GCN2 suppressed proinflammatory cytokine production in glomeruli and reduced macrophage recruitment to the kidney during the incipient stage of Ab-induced glomerular inflammation. Further, inhibition of autophagy or genetic ablation of Ido1 or Gcn2 converted Ab-induced, self-limiting nephritis to fatal end-stage renal disease. Conversely, increasing kidney IDO1 activity or treating mice with a GCN2 agonist induced autophagy and protected mice from nephritic kidney damage. Finally, kidney tissue from patients with Ab-driven nephropathy showed increased IDO1 abundance and stress gene expression. Thus, these findings support the hypothesis that the IDO-GCN2 pathway in glomerular stromal cells is a critical negative feedback mechanism that limits inflammatory renal pathologic changes by inducing autophagy.
Asunto(s)
Aminoácidos/metabolismo , Enfermedad por Anticuerpos Antimembrana Basal Glomerular/inmunología , Enfermedad por Anticuerpos Antimembrana Basal Glomerular/metabolismo , Autoanticuerpos/inmunología , Autofagia/inmunología , Animales , Enfermedad por Anticuerpos Antimembrana Basal Glomerular/genética , Enfermedad por Anticuerpos Antimembrana Basal Glomerular/patología , Citocinas/biosíntesis , Modelos Animales de Enfermedad , Activación Enzimática , Femenino , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/genética , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Ratones , Ratones Noqueados , Podocitos/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal , Estrés FisiológicoRESUMEN
Tolerance to apoptotic cells is essential to prevent inflammatory pathology. Though innate responses are critical for immune suppression, our understanding of early innate immunity driven by apoptosis is lacking. Herein we report apoptotic cells induce expression of the chemokine CCL22 in splenic metallophillic macrophages, which is critical for tolerance. Systemic challenge with apoptotic cells induced rapid production of CCL22 in CD169(+) (metallophillic) macrophages, resulting in accumulation and activation of FoxP3(+) Tregs and CD11c(+) dendritic cells, an effect that could be inhibited by antagonizing CCL22-driven chemotaxis. This mechanism was essential for suppression after apoptotic cell challenge, because neutralizing CCL22 or its receptor, reducing Treg numbers, or blocking effector mechanisms abrogated splenic TGF-ß and IL-10 induction; this promoted a shift to proinflammatory cytokines associated with a failure to suppress T cells. Similarly, CCR4 inhibition blocked long-term, apoptotic cell-induced tolerance to allografts. Finally, CCR4 inhibition resulted in a systemic breakdown of tolerance to self after apoptotic cell injection with rapid increases in anti-dsDNA IgG and immune complex deposition. Thus, the data demonstrate CCL22-dependent chemotaxis is a key early innate response required for apoptotic cell-induced suppression, implicating a previously unknown mechanism of macrophage-dependent coordination of early events leading to stable tolerance.
Asunto(s)
Apoptosis/inmunología , Quimiocina CCL22/inmunología , Macrófagos/inmunología , Lectina 1 Similar a Ig de Unión al Ácido Siálico/inmunología , Tolerancia al Trasplante/inmunología , Animales , Movimiento Celular/fisiología , Quimiocina CCL22/metabolismo , Citocinas/inmunología , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Inmunohistoquímica , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores CCR4/genética , Lectina 1 Similar a Ig de Unión al Ácido Siálico/metabolismo , Tolerancia al Trasplante/genéticaRESUMEN
Tolerance to self-antigens present in apoptotic cells is critical to maintain immune-homeostasis and prevent systemic autoimmunity. However, mechanisms that sustain self-tolerance are poorly understood. Here we show that systemic administration of apoptotic cells to mice induced splenic expression of the tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase (IDO). IDO expression was confined to the splenic marginal zone and was abrogated by depletion of CD169(+) cells. Pharmacologic inhibition of IDO skewed the immune response to apoptotic cells, resulting in increased proinflammatory cytokine production and increased effector T-cell responses toward apoptotic cell-associated antigens. Presymptomatic lupus-prone MRL(lpr/lpr) mice exhibited abnormal elevated IDO expression in the marginal zone and red pulp and inhibition of IDO markedly accelerated disease progression. Moreover, chronic exposure of IDO-deficient mice to apoptotic cells induced a lupus-like disease with serum autoreactivity to double-stranded DNA associated with renal pathology and increased mortality. Thus, IDO limits innate and adaptive immunity to apoptotic self-antigens and IDO-mediated regulation inhibits inflammatory pathology caused by systemic autoimmune disease.
Asunto(s)
Apoptosis , Indolamina-Pirrol 2,3,-Dioxigenasa/farmacología , Animales , Autoinmunidad , Citocinas/metabolismo , ADN/metabolismo , Células Dendríticas/citología , Femenino , Sistema Inmunológico , Inflamación , Macrófagos/metabolismo , Glicoproteínas de Membrana/biosíntesis , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Receptores Inmunológicos/biosíntesis , Lectina 1 Similar a Ig de Unión al Ácido Siálico , Bazo/citologíaRESUMEN
Patients with metastatic ovarian cancer (OvCa) have a 5-year survival rate of less than 30% due to persisting dissemination of chemoresistant cells in the peritoneal fluid and the immunosuppressive microenvironment in the peritoneal cavity. Here, we report that intraperitoneal administration of ß-glucan and IFNγ (BI) induced robust tumor regression in clinically relevant models of metastatic OvCa. BI induced tumor regression by controlling fluid tumor burden and activating localized antitumor immunity. ß-glucan alone cleared ascites and eliminated fluid tumor cells by inducing intraperitoneal clotting in the fluid and Dectin-1-Syk-dependent NETosis in the omentum. In omentum tumors, BI expanded a novel subset of immunostimulatory IL27+ macrophages and neutralizing IL27 impaired BI efficacy in vivo. Moreover, BI directly induced IL27 secretion in macrophages where single agent treatment did not. Finally, BI extended mouse survival in a chemoresistant model and significantly improved chemotherapy response in a chemo-sensitive model. In summary, we propose a new therapeutic strategy for the treatment of metastatic OvCa.
RESUMEN
The tumor suppressor TP53 is the most frequently mutated gene in cancer and is mutationally inactivated in 50% of sporadic tumors. Inactivating mutations in TP53 also occur in Li Fraumeni syndrome (LFS). In addition to germline mutations in TP53 in LFS that completely inactivate this protein, there are many more germline mutant forms of TP53 in human populations that partially inactivate this protein: we call these partially inactivating mutations "hypomorphs." One of these hypomorphs is a SNP that exists in 6%-10% of Africans and 1%-2% of African Americans, which changes proline at amino acid 47 to serine (Pro47Ser; P47S). We previously showed that the P47S variant of p53 is intrinsically impaired for tumor suppressor function, and that this SNP is associated with increased cancer risk in mice and humans. Here we show that this SNP also influences the tumor microenvironment, and the immune microenvironment profile in P47S mice is more protumorigenic. At basal levels, P47S mice show impaired memory T-cell formation and function, along with increased anti-inflammatory (so-called "M2") macrophages. We show that in tumor-bearing P47S mice, there is an increase in immunosuppressive myeloid-derived suppressor cells and decreased numbers of activated dendritic cells, macrophages, and B cells, along with evidence for increased T-cell exhaustion in the tumor microenvironment. Finally, we show that P47S mice demonstrate an incomplete response to anti-PD-L1 therapy. Our combined data suggest that the African-centric P47S variant leads to both intrinsic and extrinsic defects in tumor suppression. Significance: Findings presented here show that the P47S variant of TP53 influences the immune microenvironment, and the immune response to cancer. This is the first time that a naturally occurring genetic variant of TP53 has been shown to negatively impact the immune microenvironment and the response to immunotherapy.
Asunto(s)
Síndrome de Li-Fraumeni , Proteína p53 Supresora de Tumor , Humanos , Ratones , Animales , Proteína p53 Supresora de Tumor/genética , Inhibidores de Puntos de Control Inmunológico , Síndrome de Li-Fraumeni/genética , Genes p53 , Mutación de Línea Germinal , Microambiente Tumoral/genéticaRESUMEN
Acetate metabolism is an important metabolic pathway in many cancers and is controlled by acetyl-CoA synthetase 2 (ACSS2), an enzyme that catalyzes the conversion of acetate to acetyl-CoA. While the metabolic role of ACSS2 in cancer is well described, the consequences of blocking tumor acetate metabolism on the tumor microenvironment and antitumor immunity are unknown. We demonstrate that blocking ACSS2, switches cancer cells from acetate consumers to producers of acetate thereby freeing acetate for tumor-infiltrating lymphocytes to use as a fuel source. We show that acetate supplementation metabolically bolsters T-cell effector functions and proliferation. Targeting ACSS2 with CRISPR-Cas9 guides or a small-molecule inhibitor promotes an antitumor immune response and enhances the efficacy of chemotherapy in preclinical breast cancer models. We propose a paradigm for targeting acetate metabolism in cancer in which inhibition of ACSS2 dually acts to impair tumor cell metabolism and potentiate antitumor immunity.
Asunto(s)
Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Acetilcoenzima A/metabolismo , Línea Celular Tumoral , Acetatos/farmacología , Acetatos/uso terapéutico , Acetatos/metabolismo , Linfocitos T/metabolismo , Factores Inmunológicos , Microambiente TumoralRESUMEN
The composition of the gut microbiome can control innate and adaptive immunity and has emerged as a key regulator of tumor growth, especially in the context of immune checkpoint blockade (ICB) therapy. However, the underlying mechanisms for how the microbiome affects tumor growth remain unclear. Pancreatic ductal adenocarcinoma (PDAC) tends to be refractory to therapy, including ICB. Using a nontargeted, liquid chromatography-tandem mass spectrometry-based metabolomic screen, we identified the gut microbe-derived metabolite trimethylamine N-oxide (TMAO), which enhanced antitumor immunity to PDAC. Delivery of TMAO intraperitoneally or via a dietary choline supplement to orthotopic PDAC-bearing mice reduced tumor growth, associated with an immunostimulatory tumor-associated macrophage (TAM) phenotype, and activated effector T cell response in the tumor microenvironment. Mechanistically, TMAO potentiated the type I interferon (IFN) pathway and conferred antitumor effects in a type I IFN-dependent manner. Delivering TMAO-primed macrophages intravenously produced similar antitumor effects. Combining TMAO with ICB (anti-PD1 and/or anti-Tim3) in a mouse model of PDAC significantly reduced tumor burden and improved survival beyond TMAO or ICB alone. Last, the levels of bacteria containing CutC (an enzyme that generates trimethylamine, the TMAO precursor) correlated with long-term survival in patients with PDAC and improved response to anti-PD1 in patients with melanoma. Together, our study identifies the gut microbial metabolite TMAO as a driver of antitumor immunity and lays the groundwork for potential therapeutic strategies targeting TMAO.
Asunto(s)
Microbioma Gastrointestinal , Neoplasias Pancreáticas , Animales , Inhibidores de Puntos de Control Inmunológico , Metilaminas , Ratones , Neoplasias Pancreáticas/tratamiento farmacológico , Microambiente Tumoral , Neoplasias PancreáticasRESUMEN
Nuclear receptors (NRs) are key regulators of innate immune responses and tissue homeostasis. Evidence indicates that NRs significantly impact steady-state immune regulation, uptake and processing of apoptotic cells, tolerance induction, and control of inflammatory immunity. In this review, we describe our current understanding of the NR activity for balancing inflammation and tolerance, the signaling cascade inducing the NR activation and functional responses, and different mechanisms of the NR-driven immune effects in the context of autoimmune diseases. We further describe the ligand-activated transcription factor the aryl hydrocarbon receptor (AhR) that exhibits analogous functionality. Moreover, we will discuss the putative role of NRs and AhR in immune regulation and disease pathogenesis providing a rationale for therapeutic targeting as a unique opportunities in the clinical management of autoimmune diseases.
Asunto(s)
Macrófagos , Receptores de Hidrocarburo de Aril , Regulación de la Expresión Génica , Humanos , Inmunidad Innata , Inflamación , Macrófagos/metabolismo , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/metabolismoRESUMEN
Multisystem inflammatory syndrome in children (MIS-C) is a post-infectious immune-mediated condition, seen 3-5 weeks after COVID-19. Maternal SARS-CoV-2 may potentially cause a similar hyperinflammatory syndrome in neonates due to transplacental transfer of antibodies. We reviewed the perinatal history, clinical features, and outcomes of 20 neonates with features consistent with MIS-C related to maternal SARS-CoV-2 in Kolhapur, India, from 1 September 2020 to 30 April 2021. Anti-SARS-CoV-2 IgG and IgM antibodies were tested in all neonates. Fifteen singletons and five twins born to eighteen mothers with a history of COVID-19 disease or exposure during pregnancy presented with features consistent with MIS-C during the first 5 days after birth. Nineteen were positive for anti-SARS-CoV-2 IgG and all were negative for IgM antibodies. All mothers were asymptomatic and therefore not tested by RTPCR-SARS-CoV-2 at delivery. Eighteen neonates (90%) had cardiac involvement with prolonged QTc, 2:1 AV block, cardiogenic shock, or coronary dilatation. Other findings included respiratory failure (40%), fever (10%), feeding intolerance (30%), melena (10%), and renal failure (5%). All infants had elevated inflammatory biomarkers and received steroids and IVIG. Two infants died. We speculate that maternal SARS-CoV-2 and transplacental antibodies cause multisystem inflammatory syndrome in neonates (MIS-N). Immunomodulation may be beneficial in some cases, but further studies are needed.
RESUMEN
A balanced diet is crucial for healthy development and prevention of musculoskeletal related diseases. Diets high in fat content are known to cause obesity, diabetes and a number of other disease states. Our group and others have previously reported that activity of the urea cycle enzyme arginase is involved in diabetes-induced dysregulation of vascular function due to decreases in nitric oxide formation. We hypothesized that diabetes may also elevate arginase activity in bone and bone marrow, which could lead to bone-related complications. To test this we determined the effects of diabetes on expression and activity of arginase, in bone and bone marrow stromal cells (BMSCs). We demonstrated that arginase 1 is abundantly present in the bone and BMSCs. We also demonstrated that arginase activity and expression in bone and bone marrow is up-regulated in models of diabetes induced by HFHS diet and streptozotocin (STZ). HFHS diet down-regulated expression of healthy bone metabolism markers (BMP2, COL-1, ALP, and RUNX2) and reduced bone mineral density, bone volume and trabecular thickness. However, treatment with an arginase inhibitor (ABH) prevented these bone-related complications of diabetes. In-vitro study of BMSCs showed that high glucose treatment increased arginase activity and decreased nitric oxide production. These effects were reversed by treatment with an arginase inhibitor (ABH). Our study provides evidence that deregulation of l-arginine metabolism plays a vital role in HFHS diet-induced diabetic complications and that these complications can be prevented by treatment with arginase inhibitors. The modulation of l-arginine metabolism in disease could offer a novel therapeutic approach for osteoporosis and other musculoskeletal related diseases.