RESUMEN
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of myeloid cells that play a major role in the regulation of immune responses in many pathological conditions. These cells have a common myeloid origin, relatively immature state, common genetic and biochemical profiles, and, most importantly, the ability to inhibit immune responses. Although initial studies of MDSCs were almost exclusively performed in tumor-bearing mice or cancer patients, in recent years, it became clear that MDSCs play a critical role in the regulation of different types of inflammation that are not directly associated with cancer. In this review we discuss the nature of the complex relationship between MDSCs and the different populations of CD4(+) T cells.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Células Mieloides/inmunología , Células Mieloides/metabolismo , Animales , Linfocitos T CD4-Positivos/patología , Comunicación Celular/inmunología , Humanos , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/patología , Ratones , Monocitos/inmunología , Monocitos/metabolismo , Monocitos/patología , Células Mieloides/patología , Neoplasias/inmunología , Neoplasias/metabolismo , Neoplasias/patologíaRESUMEN
Natriuretic peptide receptor A (NPRA), the signaling receptor for the cardiac hormone, atrial natriuretic peptide (ANP), is expressed abundantly in inflamed/injured tissues and tumors. NPRA deficiency substantially decreases tissue inflammation and inhibits tumor growth. However, the precise mechanism of NPRA function and whether it links inflammation and tumorigenesis remains unknown. Since both injury repair and tumor growth require stem cell recruitment and angiogenesis, we examined the role of NPRA signaling in tumor angiogenesis as a model of tissue injury repair in this study. In in vitro cultures, aortas from NPRA-KO mice show significantly lower angiogenic response compared to wild-type counterparts. The NPRA antagonist that decreases NPRA expression, inhibits lipopolysaccharide-induced angiogenesis. The reduction in angiogenesis correlates with decreased expression of vascular endothelial growth factor and chemokine (C-X-C motif) receptor 4 (CXCR4) implicating a cell recruitment defect. To test whether NPRA regulates migration of cells to tumors, mesenchymal stem cells (MSCs) were administered i.v., and the results showed that MSCs fail to migrate to the tumor microenvironment in NPRA-KO mice. However, coimplanting tumor cells with MSCs increases angiogenesis and tumorigenesis in NPRA-KO mice, in part by promoting expression of CXCR4 and its ligand, stromal cell-derived factor 1α. Taken together, these results demonstrate that NPRA signaling regulates stem cell recruitment and angiogenesis leading to tumor growth. Thus, NPRA signaling provides a key linkage between inflammation and tumorigenesis, and NPRA may be a target for drug development against cancers and tissue injury repair.
Asunto(s)
Carcinogénesis/metabolismo , Carcinoma Pulmonar de Lewis/irrigación sanguínea , Carcinoma Pulmonar de Lewis/metabolismo , Receptores del Factor Natriurético Atrial/metabolismo , Células Madre/citología , Células Madre/metabolismo , Animales , Carcinogénesis/genética , Carcinogénesis/patología , Carcinoma Pulmonar de Lewis/genética , Carcinoma Pulmonar de Lewis/patología , Femenino , Inmunohistoquímica , Inflamación/metabolismo , Inflamación/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Receptores del Factor Natriurético Atrial/genética , Transducción de Señal , Microambiente TumoralRESUMEN
Myeloid-derived suppressor cells (MDSCs) are a group of myeloid cells composed of hematopoietic progenitor cells, immature macrophages, dendritic cells, and granulocytes, which accumulate in inflammatory diseases and various cancers. Here, we investigated the dynamic changes and effects of MDSCs in graft-versus-host disease (GVHD) development and/or tumor relapse after syngeneic and allogeneic bone marrow transplantation (BMT). We found that adding functional MDSCs in donor graft alleviated GVHD, whereas removal of MDSCs in vivo exacerbated GVHD. After T cell-deplete BMT, MDSCs transiently accumulated in the blood and spleen of recipients without GVHD. In contrast, after T cell-replete BMT, the levels of blood MDSCs were constantly elevated in recipients with GVHD. MDSC accumulation positively correlated with the severity of GVHD. Additionally, MDSC accumulation was further increased upon tumor relapse. Although MDSCs isolated from both syngeneic and allogeneic BMT recipients inhibited T cell proliferation in response to alloantigen stimulation ex vivo, MDSCs from the recipients with GVHD showed much higher suppressive potency compared with those from recipients without GVHD. These results indicate that MDSCs can regulate the immune response in acute GVHD, and possibly tumor relapse, subsequent to allogeneic BMT.
Asunto(s)
Trasplante de Médula Ósea/métodos , Células Mieloides/inmunología , Animales , Procesos de Crecimiento Celular/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos DBA , Ratones Transgénicos , Células Mieloides/metabolismo , Inmunología del Trasplante , Trasplante Homólogo/métodosRESUMEN
Myeloid derived suppressor cells play a critical role in T cell suppression in cancer. Here, we discuss the mechanisms of how MDSC suppress CD4(+) or CD8(+) T cells in an antigen dependent or non-dependent manner.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Células Mieloides/inmunología , Neoplasias/inmunología , Animales , Antígenos de Neoplasias/inmunología , Linfocitos T CD8-positivos/inmunología , Humanos , Tolerancia Inmunológica , Escape del TumorRESUMEN
Myeloid-derived suppressor cells (MDSC) play a major role in cancer-related immune suppression, yet the nature of this suppression remains controversial. In this study, we evaluated the ability of MDSCs to elicit CD4(+) T-cell tolerance in different mouse tumor models. In contrast to CD8(+) T-cell tolerance, which could be induced by MDSCs in all the tumor models tested, CD4(+) T-cell tolerance could be elicited in only one of the models (MC38) in which a substantial level of MHC class II was expressed on MDSCs compared with control myeloid cells. Mechanistic investigations revealed that MDSCs deficient in MHC class II could induce tolerance to CD8(+) T cells but not to CD4(+) T cells. Unexpectedly, antigen-specific CD4(+) T cells (but not CD8(+) T cells) could dramatically enhance the immune suppressive activity of MDSCs by converting them into powerful nonspecific suppressor cells. This striking effect was mediated by direct cell-cell contact through cross-linking of MHC class II on MDSCs. We also implicated an Ets-1 transcription factor-regulated increase in expression of Cox-2 and prostaglandin E2 in MDSCs in mediating this effect. Together, our findings suggest that activated CD4(+) T cells that are antigen specific may enhance the immune suppressive activity of MDSCs, a mechanism that might serve normally as a negative feedback loop to control immune responses that becomes dysregulated in cancer.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Tolerancia Inmunológica , Neoplasias/inmunología , Linfocitos T Reguladores/inmunología , Animales , Linfocitos T CD8-positivos/inmunología , Epítopos , Femenino , Antígenos de Histocompatibilidad Clase II/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Células Mieloides/inmunologíaRESUMEN
PURPOSE OF REVIEW: In this review, we describe the 'state-of-the-art' in our knowledge of asthma and what gaps exist, which can be exploited in the future for effective translation of our knowledge from the bench or population studies to diagnosis and therapy. RECENT FINDINGS: The advent of microbiome research has expanded the potential role of microbes in asthma. There has been a significant increase in our understanding of the pathologic, genetic, cellular and molecular mechanisms of asthma. Nonetheless, the contribution of microbes to the genesis, exacerbation and treatment of asthma are poorly understood. SUMMARY: Asthma is a complex chronic disease of the lung whose incidence is growing at all ages despite the progress that has been made in the areas of diagnosis and treatment of asthma. The complexity is partly due to the environmental insults such as allergens and microbial infections that play differential roles in the pathogenesis of childhood vis-à-vis elderly asthma. Microbes may play important roles in the exacerbation of asthma and hence in the comorbidities due to asthma, and also in the causation of asthma.
Asunto(s)
Asma/microbiología , Infecciones por Corynebacterium/complicaciones , Infecciones del Sistema Respiratorio/microbiología , Infecciones Estafilocócicas/complicaciones , Factores de Edad , Anciano , Anciano de 80 o más Años , Asma/etiología , Asma/inmunología , Linfocitos T CD4-Positivos , Niño , Preescolar , Infecciones por Corynebacterium/inmunología , Femenino , Humanos , Lactante , Interleucina-1/inmunología , Interleucina-6/inmunología , Masculino , Metagenoma , Infecciones del Sistema Respiratorio/complicaciones , Infecciones del Sistema Respiratorio/inmunología , Infecciones Estafilocócicas/inmunología , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
Myeloid-derived suppressor cells are one of the major factors responsible for immune suppression in cancer. They also contribute to limited efficacy of current vaccination strategies. Here, we give an overview of the myeloid-derived suppressor cells field focusing primarily on the studies in cancer patients and current and future therapeutic options targeting these cells.
Asunto(s)
Células Presentadoras de Antígenos/microbiología , Células Mieloides/inmunología , Neoplasias/inmunología , Animales , Células Presentadoras de Antígenos/efectos de los fármacos , Células Presentadoras de Antígenos/patología , Sistemas de Liberación de Medicamentos/métodos , Humanos , Ratones , Células Mieloides/efectos de los fármacos , Células Mieloides/patología , Neoplasias/patología , Neoplasias/terapia , Linfocitos T Reguladores/inmunologíaRESUMEN
Dendritic cells (DCs), a type of professional antigen-presenting cells, are responsible for initiation and maintenance of immune responses. Here we report that a substantial proportion of DCs in tumor-bearing mice and people with cancer have high amounts of triglycerides as compared with DCs from tumor-free mice and healthy individuals. In our studies, lipid accumulation in DCs was caused by increased uptake of extracellular lipids due to upregulation of scavenger receptor A. DCs with high lipid content were not able to effectively stimulate allogeneic T cells or present tumor-associated antigens. DCs with high and normal lipid levels did not differ in expression of major histocompatibility complex and co-stimulatory molecules. However, lipid-laden DCs had a reduced capacity to process antigens. Pharmacological normalization of lipid abundance in DCs with an inhibitor of acetyl-CoA carboxylase restored the functional activity of DCs and substantially enhanced the effects of cancer vaccines. These findings suggest that immune responses in cancer can be improved by manipulating the lipid levels in DCs.
Asunto(s)
Células Dendríticas/fisiología , Metabolismo de los Lípidos/fisiología , Neoplasias/inmunología , Neoplasias/metabolismo , Animales , Compuestos de Boro/farmacocinética , Células Dendríticas/inmunología , Células Dendríticas/patología , Ácidos Grasos/análisis , Ácidos Grasos/farmacocinética , Colorantes Fluorescentes/farmacocinética , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Trasplante de Neoplasias , Neoplasias/patología , Neoplasias/fisiopatología , Receptores Depuradores de Clase A/genética , Receptores Depuradores de Clase A/metabolismo , Espectrometría de Masa por Ionización de Electrospray , Células Tumorales CultivadasRESUMEN
Cancer immunotherapy faces a serious challenge because of low clinical efficacy. Recently, a number of clinical studies have reported the serendipitous finding of high rates of objective clinical response when cancer vaccines are combined with chemotherapy in patients with different types of cancers. However, the mechanism of this phenomenon remains unclear. Here, we tested in mice several cancer vaccines and an adoptive T cell transfer approach to cancer immunotherapy in combination with several widely used chemotherapeutic drugs. We found that chemotherapy made tumor cells more susceptible to the cytotoxic effect of CTLs through a dramatic perforin-independent increase in permeability to GrzB released by the CTLs. This effect was mediated via upregulation of mannose-6-phosphate receptors on the surface of tumor cells and was observed in mouse and human cells. When combined with chemotherapy, CTLs raised against specific antigens were able to induce apoptosis in neighboring tumor cells that did not express those antigens. These data suggest that small numbers of CTLs could mediate a potent antitumor effect when combined with chemotherapy. In addition, these results provide a strong rationale for combining these modalities for the treatment of patients with advanced cancers.
Asunto(s)
Antineoplásicos/farmacología , Citotoxicidad Inmunológica/efectos de los fármacos , Inmunoterapia , Neoplasias Experimentales/terapia , Linfocitos T Citotóxicos/inmunología , Animales , Línea Celular Tumoral , Cisplatino/farmacología , Células Dendríticas/inmunología , Femenino , Granzimas/fisiología , Humanos , Ratones , Ratones Endogámicos C57BL , Neoplasias Experimentales/inmunología , Paclitaxel/farmacología , VacunaciónRESUMEN
PURPOSE: Myeloid-derived suppressor cells (MDSC) are one of the major factors responsible for immune suppression in cancer. Therefore, it would be important to identify effective therapeutic means to modulate these cells. EXPERIMENTAL DESIGN: We evaluated the effect of the synthetic triterpenoid C-28 methyl ester of 2-cyano-3,12-dioxooleana-1,9,-dien-28-oic acid (CDDO-Me; bardoxolone methyl) in MC38 colon carcinoma, Lewis lung carcinoma, and EL-4 thymoma mouse tumor models, as well as blood samples from patients with renal cell cancer and soft tissue sarcoma. Samples were also analyzed from patients with pancreatic cancer treated with CDDO-Me in combination with gemcitabine. RESULTS: CDDO-Me at concentrations of 25 to 100 nmol/L completely abrogated immune suppressive activity of MDSC in vitro. CDDO-Me reduced reactive oxygen species in MDSCs but did not affect their viability or the levels of nitric oxide and arginase. Treatment of tumor-bearing mice with CDDO-Me did not affect the proportion of MDSCs in the spleens but eliminated their suppressive activity. This effect was independent of antitumor activity. CDDO-Me treatment decreased tumor growth in mice. Experiments with severe combined immunodeficient-beige mice indicated that this effect was largely mediated by the immune system. CDDO-Me substantially enhanced the antitumor effect of a cancer vaccines. Treatment of pancreatic cancer patients with CDDO-Me did not affect the number of MDSCs in peripheral blood but significantly improved the immune response. CONCLUSIONS: CDDO-Me abrogated the immune suppressive effect of MDSCs and improved immune responses in tumor-bearing mice and cancer patients. It may represent an attractive therapeutic option by enhancing the effect of cancer immunotherapy.
Asunto(s)
Células Dendríticas/inmunología , Tolerancia Inmunológica/efectos de los fármacos , Inmunosupresores/farmacología , Células Mieloides/inmunología , Neoplasias Experimentales/inmunología , Ácido Oleanólico/análogos & derivados , Anciano , Anciano de 80 o más Años , Animales , Arginasa/metabolismo , Ensayos Clínicos Fase I como Asunto , Células Dendríticas/patología , Células Dendríticas/trasplante , Femenino , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones SCID , Persona de Mediana Edad , Células Mieloides/patología , Células Mieloides/trasplante , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Óxido Nítrico/metabolismo , Ácido Oleanólico/farmacología , Pronóstico , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Ag-specific T cell tolerance plays a critical role in tumor escape. Recent studies implicated myeloid-derived suppressor cells (MDSCs) in the induction of CD8(+) T cell tolerance in tumor-bearing hosts. However, the mechanism of this phenomenon remained unclear. We have found that incubation of Ag-specific CD8(+) T cells, with peptide-loaded MDSCs, did not induce signaling downstream of TCR. However, it prevented subsequent signaling from peptide-loaded dendritic cells. Using double TCR transgenic CD8(+) T cells, we have demonstrated that MDSC induced tolerance to only the peptide, which was presented by MDSCs. T cell response to the peptide specific to the other TCR was not affected. Incubation of MDSCs with Ag-specific CD8(+) T cells caused nitration of the molecules on the surface of CD8(+) T cells, localized to the site of physical interaction between MDSC and T cells, which involves preferentially only TCR specific for the peptide presented by MDSCs. Postincubation with MDSCs, only nitrotyrosine-positive CD8(+) T cells demonstrated profound nonresponsiveness to the specific peptide, whereas nitrotyrosine-negative CD8(+) T cells responded normally to that stimulation. MDSCs caused dissociation between TCR and CD3zeta molecules, disrupting TCR complexes on T cells. Thus, these data describe a novel mechanism of Ag-specific CD8(+) T cell tolerance in cancer.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Células Mieloides/inmunología , Neoplasias Experimentales/inmunología , Tolerancia al Trasplante/inmunología , Traslado Adoptivo , Animales , Presentación de Antígeno/genética , Presentación de Antígeno/inmunología , Linfocitos T CD8-positivos/patología , Linfocitos T CD8-positivos/trasplante , Línea Celular Tumoral , Epítopos de Linfocito T/inmunología , Epítopos de Linfocito T/metabolismo , Femenino , Genes Codificadores de la Cadena beta de los Receptores de Linfocito T/inmunología , Leucemia Experimental/genética , Leucemia Experimental/inmunología , Leucemia Experimental/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Células Mieloides/patología , Células Mieloides/trasplante , Neoplasias Experimentales/genética , Neoplasias Experimentales/patología , Transducción de Señal/genética , Transducción de Señal/inmunología , Tolerancia al Trasplante/genética , Células Tumorales CultivadasRESUMEN
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that expand during cancer, inflammation and infection, and that have a remarkable ability to suppress T-cell responses. These cells constitute a unique component of the immune system that regulates immune responses in healthy individuals and in the context of various diseases. In this Review, we discuss the origin, mechanisms of expansion and suppressive functions of MDSCs, as well as the potential to target these cells for therapeutic benefit.
Asunto(s)
Sistema Inmunológico/inmunología , Tolerancia Inmunológica , Células Mieloides/inmunología , Linfocitos T/inmunología , Animales , Movimiento Celular , Enfermedades Transmisibles/inmunología , Humanos , Inflamación/inmunología , Activación de Linfocitos , Mielopoyesis , Neoplasias/inmunología , Células Madre/inmunología , Linfocitos T/metabolismo , Linfocitos T Reguladores/inmunologíaRESUMEN
Myeloid-derived suppressor cells (MDSC) are a heterogeneous group of cells that play a critical role in tumor associated immune suppression. In an attempt to identify a specific subset of MDSC primarily responsible for immunosuppressive features of these cells, 10 different tumor models were investigated. All models showed variable but significant increase in the population of MDSC. Variability of MDSC expansion in vivo matched closely the effect of tumor cell condition medium in vitro. MDSC consists of two major subsets of Ly6G(+)Ly6C(low) granulocytic and Ly6G(-)Ly6C(high) monocytic cells. Granulocytic MDSC have increased level of reactive oxygen species and undetectable level of NO whereas monocytic MDSC had increased level of NO but undetectable levels of reactive oxygen species. However, their suppressive activity per cell basis was comparable. Almost all tumor models demonstrated a preferential expansion of granulocytic subset of MDSC. We performed a phenotypical and functional analysis of several surface molecules previously suggested to be involved in MDSC-mediated suppression of T cells: CD115, CD124, CD80, PD-L1, and PD-L2. Although substantial proportion of MDSC expressed those molecules no differences in the level of their expression or the proportion, positive cells were found between MDSC and cells from tumor-free mice that lack immune suppressive activity. The level of MDSC-mediated T cell suppression did not depend on the expression of these molecules. These data indicate that suppressive features of MDSC is caused not by expansion of a specific subset but more likely represent a functional state of these cells.
Asunto(s)
Granulocitos/inmunología , Monocitos/inmunología , Neoplasias Experimentales/inmunología , Animales , Antígenos de Diferenciación/biosíntesis , Antígenos de Diferenciación/inmunología , Femenino , Regulación de la Expresión Génica/inmunología , Granulocitos/metabolismo , Granulocitos/patología , Ratones , Ratones Endogámicos BALB C , Monocitos/metabolismo , Monocitos/patología , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Óxido Nítrico/inmunología , Óxido Nítrico/metabolismo , Especies Reactivas de Oxígeno/inmunología , Especies Reactivas de Oxígeno/metabolismoRESUMEN
OBJECTIVES: The major histocompatibility complex class II chaperone invariant chain (Ii) is widely used as a carrier for inserted antigenic sequences and their introduction into the class II processing pathway. The tumor-associated antigen core 2beta 1,6 N-acetylglucosaminyltransferase (C2GnT), a glycosyltransferase present in human pancreatic tumor cells, is not expressed by normal pancreatic tissues. METHODS: A set of expression vectors was engineered where the class II binding region of Ii was replaced by C2GnT-derived sequences. We investigated in vitro whether dendritic cells transfected with Ii-C2GnT constructs were capable to stimulate proliferation of CD4 T cells. We also tested whether vaccination with Ii-C2GnT would protect mice from tumor development. RESULTS: Invariant chain-C2GnT fusion proteins bind to human DR1, DR3, DR4 and to mouse I-A molecules. Our results demonstrate that the plasmid DNA encoding the C2GnT epitope embedded in Ii induces tumor-specific T-cell responses. Mice immunized with the Ii constructs showed reduced growth of Panc02 pancreatic tumor cells. CONCLUSIONS: Therefore, Ii clipped with the tumor-associated antigen C2GnT shows promise for the treatment of pancreatic cancer.
Asunto(s)
Antígenos de Diferenciación de Linfocitos B/inmunología , Linfocitos T CD4-Positivos/inmunología , Vacunas contra el Cáncer/inmunología , Proliferación Celular , Células Dendríticas/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , N-Acetilglucosaminiltransferasas/inmunología , Neoplasias Pancreáticas/terapia , Animales , Antígenos de Diferenciación de Linfocitos B/genética , Células COS , Vacunas contra el Cáncer/genética , Línea Celular Tumoral , Chlorocebus aethiops , Antígenos HLA-DR/inmunología , Antígenos de Histocompatibilidad Clase II/genética , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , N-Acetilglucosaminiltransferasas/genética , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Proteínas Recombinantes de Fusión/inmunología , Factores de Tiempo , TransfecciónRESUMEN
Accumulation of myeloid-derived suppressor cells (MDSCs) associated with inhibition of dendritic cell (DC) differentiation is one of the major immunological abnormalities in cancer and leads to suppression of antitumor immune responses. The molecular mechanism of this phenomenon remains unclear. We report here that STAT3-inducible up-regulation of the myeloid-related protein S100A9 enhances MDSC production in cancer. Mice lacking this protein mounted potent antitumor immune responses and rejected implanted tumors. This effect was reversed by administration of wild-type MDSCs from tumor-bearing mice to S100A9-null mice. Overexpression of S100A9 in cultured embryonic stem cells or transgenic mice inhibited the differentiation of DCs and macrophages and induced accumulation of MDSCs. This study demonstrates that tumor-induced up-regulation of S100A9 protein is critically important for accumulation of MDSCs and reveals a novel molecular mechanism of immunological abnormalities in cancer.
Asunto(s)
Calgranulina B/metabolismo , Diferenciación Celular/fisiología , Células Dendríticas/fisiología , Células Mieloides/fisiología , Neoplasias/inmunología , Animales , Células de la Médula Ósea/citología , Células de la Médula Ósea/fisiología , Calgranulina B/genética , Células Dendríticas/citología , Células Madre Embrionarias/citología , Células Madre Embrionarias/fisiología , Femenino , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/fisiología , Macrófagos/citología , Macrófagos/fisiología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Células Mieloides/citología , Células 3T3 NIH , Neoplasias/patología , Fenotipo , Especies Reactivas de Oxígeno/metabolismo , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismoRESUMEN
T-cell nonresponsiveness is a critical factor in immune escape and myeloid-derived suppressor cells play a major role in organizing this phenomenon. Recent findings indicate that myeloid-derived suppressor cells can induce antigen-specific CD8(+) T-cell tolerance through a posttranslation mechanism which involves modification (nitration) of CD8 and the T-cell receptor itself on the T-cell surface. Elucidation of this mechanism of T-cell tolerance offers new opportunities for therapeutic corrections of immune escape in cancer.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Tolerancia Inmunológica , Terapia de Inmunosupresión , Neoplasias/inmunología , Humanos , Complejo Mayor de Histocompatibilidad , Modelos Inmunológicos , Neoplasias/prevención & control , Especies Reactivas de Oxígeno/inmunologíaRESUMEN
OBJECTIVES: Orthotopic tumor models are regarded as being suitable for preclinical research on pancreatic cancer. The anatomic localization of the tumor in the retroperitoneum, however, provides little possibility for monitoring tumor growth. METHODS: To assess time-related changes in orthotopic tumor volume, we applied transabdominal high-resolution compound imaging to the murine pancreas. A 15-MHz ultrasound probe was used to determine the feasibility of real-time transabdominal high-resolution ultrasonography to initiate tumor growth by inoculation of pancreatic tumor cells into the pancreas and monitor tumor growth, as well as use as a tool for assessing response to chemotherapy. RESULTS: High-resolution ultrasound allows for precise tumor inoculation in the pancreas. Sonographic-evaluated tumor weight was found to be closely related to actual tumor weight (R = 0.97) measured during necropsy. CONCLUSIONS: High-resolution real-time compound imaging substitutes killing of mice during longitudinal studies and can be used for minimizing animal consumption because each mouse can be followed in an experimental group rather than having to resort to euthanasia for tissue harvesting.