RESUMEN
Exhaustion of cytotoxic effector natural killer (NK) and CD8+ T cells have important functions in the establishment of persistent viral infections, but how exhaustion is induced during chronic hepatitis C virus (HCV) infection remains poorly defined. Here we show, using the humanized C/OTg mice permissive for persistent HCV infection, that NK and CD8+ T cells become sequentially exhausted shortly after their transient hepatic infiltration and activation in acute HCV infection. HCV infection upregulates Qa-1 expression in hepatocytes, which ligates NKG2A to induce NK cell exhaustion. Antibodies targeting NKG2A or Qa-1 prevents NK exhaustion and promotes NK-dependent HCV clearance. Moreover, reactivated NK cells provide sufficient IFN-γ that helps rejuvenate polyclonal HCV CD8+ T cell response and clearance of HCV. Our data thus show that NKG2A serves as a critical checkpoint for HCV-induced NK exhaustion, and that NKG2A blockade sequentially boosts interdependent NK and CD8+ T cell functions to prevent persistent HCV infection.
Asunto(s)
Hepacivirus/inmunología , Hepatitis C Crónica/inmunología , Células Asesinas Naturales/inmunología , Subfamília C de Receptores Similares a Lectina de Células NK/inmunología , Animales , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Citocinas/inmunología , Modelos Animales de Enfermedad , Hepatitis C Crónica/virología , Hepatocitos/virología , Antígenos de Histocompatibilidad Clase I/inmunología , Interferón gamma/inmunología , Activación de Linfocitos/fisiología , Proteínas de la Membrana/inmunología , Ratones , Distribución AleatoriaRESUMEN
Inflammation is frequently associated with initiation, progression, and metastasis of colorectal cancer (CRC). Here, we unveil a CRC-specific metastatic programme that is triggered via the transcriptional repressor, GFI1. Using data from a large cohort of clinical samples including inflammatory bowel disease and CRC, and a cellular model of CRC progression mediated by cross-talk between the cancer cell and the inflammatory microenvironment, we identified GFI1 as a gating regulator responsible for a constitutively activated signalling circuit that renders CRC cells competent for metastatic spread. Further analysis of mouse models with metastatic CRC and human clinical specimens reinforced the influence of GFI1 downregulation in promoting CRC metastatic spread. The novel role of GFI1 is uncovered for the first time in a human solid tumour such as CRC. Our results imply that GFI1 is a potential therapeutic target for interfering with inflammation-induced CRC progression and spread.
Asunto(s)
Neoplasias Colorrectales/genética , Proteínas de Unión al ADN/genética , Regulación Neoplásica de la Expresión Génica , Enfermedades Inflamatorias del Intestino/genética , Neoplasias Hepáticas/genética , Factores de Transcripción/genética , Animales , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Proteínas de Unión al ADN/antagonistas & inhibidores , Proteínas de Unión al ADN/metabolismo , Progresión de la Enfermedad , Perfilación de la Expresión Génica , Células HT29 , Humanos , Inflamación , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/patología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundario , Metástasis Linfática , Ratones , Ratones Desnudos , Invasividad Neoplásica , Trasplante de Neoplasias , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Subtipo EP2 de Receptores de Prostaglandina E/genética , Subtipo EP2 de Receptores de Prostaglandina E/metabolismo , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/metabolismo , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta/farmacología , Microambiente Tumoral/genéticaRESUMEN
OBJECTIVE: The B7-H1/PD-1 co-signaling pathway has recently been found to play a pivotal role in the immune evasion of tumor cells from host immune system. The aim of this study was to examine the B7-H1 and PD-1 expression and TILs status in gastric cancer and to elucidate the clinical relevance of B7-H1 and PD-1 to the pathogenesis of gastric carcinoma. METHODS: Immunohistochemistry and ANAE histochemical staining were used to investigate the in situ expression of B7-H1 and PD-1 and TILs status in the gastric tissues. RT-PCR was used to explore B7-H1 and PD-1 expression at the transcriptional level. The B7-H1 expression at protein level was detected by Western blot. RESULTS: Expression of B7-H1 and PD-1 was found to be increased in gastric carcinoma, but absent in normal gastric tissue. B7-H1 expression in gastric carcinoma was inversely correlated with TILs infiltration. B7-H1 but not PD-1 expression in tumor tissue was significantly correlated with some clinicopathhological variables including depth of invasion, lymph node metastasis and distant metastasis. CONCLUSION: B7-H1 and PD-1 expressions are increased in gastric carcinoma. This signaling pathway may inhibit antitumor immune responses in gastric carcinoma. B7-H1 expression plays a critical role in the pathogenesis of human gastric carcinoma,and might be a promising prognostic marker and therapeutic target in the treatment of this disease.
Asunto(s)
Antígenos CD/metabolismo , Proteínas Reguladoras de la Apoptosis/metabolismo , Linfocitos Infiltrantes de Tumor/inmunología , Neoplasias Gástricas/inmunología , Adulto , Anciano , Antígenos CD/genética , Proteínas Reguladoras de la Apoptosis/genética , Antígeno B7-H1 , Linfocitos T CD4-Positivos/inmunología , Femenino , Humanos , Metástasis Linfática , Subgrupos Linfocitarios/inmunología , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Metástasis de la Neoplasia , Estadificación de Neoplasias , Receptor de Muerte Celular Programada 1 , ARN Mensajero/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologíaRESUMEN
PURPOSE: The B7 family molecules have been shown to regulate immune responses in both positive and negative fashions. Their roles in the progression of human cancers, however, are not well established. The aim of this study was to examine whether leukemic cells of acute myeloid leukemia express functional B7 family molecules and, if so, whether such expression has any clinical significance. EXPERIMENTAL DESIGN: The expression of four B7 family molecules, B7.1, B7.2, B7-H1, and B7-H2, on leukemic cells from acute myeloid leukemia patients was analyzed by flow cytometry. The function of the expressed molecules was examined by the allogeneic mixed lymphocyte-leukemic cell reaction, and their relationship to the clinical data and survival was analyzed. RESULTS: Although B7.1 and B7-H1 expressions were rare, the cells from a substantial number of acute myeloid leukemia cases expressed B7.2 and B7-H2 molecules [mean percentages of B7.2- and B7-H2-positive cells were 28.9% (n = 58) and 15.3% (n = 59), respectively]. Patients in whom >25% of leukemic cells expressed B7-H2 had significantly shorter survival, and this B7-H2 positivity had the strongest prognostic value when B7-H2 and other prognostic factors were analyzed together by multivariate analysis (P = 0.0108). Furthermore, B7.2 expression was associated with hyperleukocytosis (P = 0.026). Consistent with this finding, acute myeloid leukemia cells expressing B7.2 and B7-H2 induced allogeneic CD4+ T cells to proliferate and secrete interleukin-4 and interleukin-10 in vitro, effects that were partially blocked by antibodies against B7.2 and B7-H2. CONCLUSIONS: Our results indicate the expression of functional B7.2 and B7-H2 molecules, and these molecules may facilitate progression of acute myeloid leukemia.
Asunto(s)
Antígeno B7-2/genética , Leucemia Mieloide/patología , Proteínas/genética , Enfermedad Aguda , Adulto , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Antígenos CD , Antígeno B7-2/análisis , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/patología , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/metabolismo , Línea Celular Tumoral , Proliferación Celular , Técnicas de Cocultivo , Medios de Cultivo Condicionados/química , Medios de Cultivo Condicionados/metabolismo , Femenino , Citometría de Flujo , Regulación Neoplásica de la Expresión Génica , Células HL-60 , Humanos , Ligando Coestimulador de Linfocitos T Inducibles , Interferón gamma/metabolismo , Interleucina-10/metabolismo , Interleucina-2/metabolismo , Interleucina-4/metabolismo , Células Jurkat , Células K562 , Leucemia Mieloide/genética , Leucemia Mieloide/metabolismo , Masculino , Persona de Mediana Edad , Pronóstico , Proteínas/análisis , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de Supervivencia , Células U937RESUMEN
We identify a B7 family molecule, B7-H4, by protein sequence analysis and comparative molecular modeling. While B7-H4 mRNA is widely distributed in mouse and human peripheral tissues, cell surface expression of B7-H4 protein is limited and shows an inducible pattern on hematopoietic cells. Putative receptor of B7-H4 can be upregulated on activated T cells. By arresting cell cycle, B7-H4 ligation of T cells has a profound inhibitory effect on the growth, cytokine secretion, and development of cytotoxicity. Administration of B7-H4Ig into mice impairs antigen-specific T cell responses whereas blockade of endogenous B7-H4 by specific monoclonal antibody promotes T cell responses. B7-H4 thus may participate in negative regulation of cell-mediated immunity in peripheral tissues.