RESUMEN
Immune checkpoint inhibitors (ICI) have revolutionized treatment for various cancers; however, durable response is limited to only a subset of patients. Discovery of blood-based biomarkers that reflect dynamic change of the tumor microenvironment, and predict response to ICI, will markedly improve current treatment regimens. Here, we investigate CX3C chemokine receptor 1 (CX3CR1), a marker of T-cell differentiation, as a predictive correlate of response to ICI therapy. Successful treatment of tumor-bearing mice with ICI increases the frequency and T-cell receptor clonality of the peripheral CX3CR1+CD8+ T-cell subset that includes an enriched repertoire of tumor-specific and tumor-infiltrating CD8+ T cells. Furthermore, an increase in the frequency of the CX3CR1+ subset in circulating CD8+ T cells early after initiation of anti-PD-1 therapy correlates with response and survival in patients with non-small cell lung cancer. Collectively, these data support T-cell CX3CR1 expression as a blood-based dynamic early on-treatment predictor of response to ICI therapy.
Asunto(s)
Biomarcadores Farmacológicos/sangre , Receptor 1 de Quimiocinas CX3C/sangre , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Animales , Anticuerpos Monoclonales Humanizados/farmacología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/fisiología , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Línea Celular Tumoral , Femenino , Humanos , Antígeno Ki-67/sangre , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/mortalidad , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Masculino , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Persona de Mediana Edad , Neoplasias Experimentales/irrigación sanguínea , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/inmunología , Nivolumab/farmacología , Receptores de Antígenos de Linfocitos T/metabolismo , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
PURPOSE: Impaired angiogenesis is one of the most common findings in preeclamptic placentas. A new angiogenetic role of fractalkine (CX3CL1) is recently recognized apart from inflammatory activity. In this study, a link between CX3CL1 and the development of placental vasculature in preeclampsia was examined. METHODS: The study comprised 52 women allocated to Group 1 (normotensive, n = 23) and Group 2 (preeclampsia, n = 29). In each group Doppler parameters, serum levels of CX3CL1, soluble fms-like tyrosine kinase-1 (sFlt-1), and placental growth factor (PlGF) were assessed between 30 and 32 week of pregnancy. After the delivery, placental samples were taken and the vascularization and expression of CX3CR1 receptor were assessed after immunostaining. RESULTS: CX3CL1 and sFlt-1 serum levels were significantly higher levels in Group 2 vs Group 1, while PlGF serum levels was significantly lower in Group 2. Lower cerebroplacental ratio (CPR) was observed in Group 2. The vascular/extravascular tissue index (V/EVTI) was significantly lower in Group 2, while compared to Group 1, with the lowest value in the fetus growth restriction (FGR) subgroup (0.18 ± 0.02; 0.24 ± 0.03; 0.16 ± 0.02, respectively). The expression of examined CX3CR1 was higher in Group 2, while compared to Group 1, reaching the highest values in FGR subgroup. There was a moderate negative correlation between birth weight, V/EVTI and CX3CL1 serum level and CX3CR1 placental expression in the group of pregnancies complicated with preeclampsia. CONCLUSION: The significant underdevelopment of placental vascular network in preeclampsia is associated with the change in the CX3CL1/CX3CR1 system, especially in FGR complicated pregnancies.
Asunto(s)
Quimiocina CX3CL1/sangre , Placenta/irrigación sanguínea , Preeclampsia , Adulto , Biomarcadores/sangre , Receptor 1 de Quimiocinas CX3C/sangre , Estudios de Casos y Controles , Femenino , Humanos , Placenta/diagnóstico por imagen , Factor de Crecimiento Placentario/sangre , Embarazo , Estudios Prospectivos , Receptor 1 de Factores de Crecimiento Endotelial Vascular/sangreRESUMEN
PURPOSE: To investigate the clinical significance of CX3 chemokine ligand 1(CX3CL1) and CX3CR1 in patients with bone metastasis from lung cancer. The expression levels of CX3CL1 and CX3CR1 mRNA and protein in primary lung cancer and lung cancer bone metastasis were detected by qRT-PCR and Western blot. METHODS: One hundred patients with lung cancer were divided into a boneless metastasis group (50 patients with bone metastasis) and a bone metastasis group (50 patients without distant metastasis). The bone transfer component was graded by Soloway classification (0 to III). The expression levels of serum CX3CL1-CX3CR1 axis were detected by enzyme-linked immunosorbent assay (ELISA). RT-qPCR and Western Blot were used to verify the transfection efficiency. The scratching assay was used to detect the migration of CX3CL1 to 95-D cells after down-regulating the expression of CX3CR1. RESULTS: The expression levels of CX3CL1 and CX3CR1 mRNA and protein in the primary lung cancer and lung cancer bone metastasis were significantly higher than those in the adjacent tissues (P < 0.0001). The levels of serum CX3CL1 and CX3CR1 in bone metastasis group were significantly higher than those in boneless metastasis group and healthy control group (P < 0.05). In the bone metastasis group, the levels of serum CX3CL1 and CX3CR1 were significantly positively correlated with the degree of disease progression (P < 0.01). CONCLUSION: The expression level of serum CX3CL1-CX3CR1 axis is expected to be an auxiliary reference index for monitoring bone metastasis of lung cancer.
Asunto(s)
Neoplasias Óseas/metabolismo , Neoplasias Óseas/secundario , Receptor 1 de Quimiocinas CX3C/metabolismo , Quimiocina CX3CL1/metabolismo , Neoplasias Pulmonares/metabolismo , Adulto , Anciano , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/metabolismo , Western Blotting , Neoplasias Óseas/sangre , Neoplasias Óseas/diagnóstico , Receptor 1 de Quimiocinas CX3C/sangre , Carcinoma de Células Escamosas/sangre , Carcinoma de Células Escamosas/metabolismo , Quimiocina CX3CL1/sangre , Progresión de la Enfermedad , Regulación hacia Abajo , Detección Precoz del Cáncer , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , ARN Mensajero/metabolismo , Curva ROC , TransfecciónRESUMEN
Introducción y objetivos: La terapia de resincronización cardiaca (TRC) es beneficiosa para pacientes seleccionados con insuficiencia cardiaca (IC), aunque la ausencia de respuesta a la terapia es aún prevalente. Se investiga un conjunto de nuevos biomarcadores asociados a varias vías fisiopatológicas de la IC. El propósito fue valorar su capacidad para predecir los resultados clínicos con la TRC. Métodos: Se estudió a 136 pacientes con IC crónica y TRC. Se midieron los valores plasmáticos de fractalquina, pentraxina-3, factor de crecimiento hepatocitario (HGF), el antígeno carbohidrato 125 y la metaloproteinasa de matriz 9 tanto antes como 6 meses después del inicio de la TRC. El objetivo primario del estudio fue la mortalidad por todas las causas a 5 años, y se consideró la ausencia de remodelado inverso a los 6 meses (definido como al menos un 15% de descenso del volumen telesistólico) como un objetivo secundario. Resultados: Cincuenta y ocho pacientes fallecieron a lo largo de los 5 años de seguimiento y 66 pacientes se categorizaron como no respondedores. En modelos multivariables, solo un aumento del HGF resultó un predictor independiente, tanto de mortalidad (HR = 1,35; IC95%, 1,11-1,64; p = 0,003; por cada unidad de incremento de la desviación estándar) como de ausencia de remodelado inverso (OR = 1,83; IC95%, 1,10-3,04; p = 0,01; por cada unidad de incremento de la desviación estándar). Aplicando el HGF al modelo básico multivariable tanto de mortalidad (mejora neta de reclasificación = 0,69; IC95%, 0,39-0,99; p < 0,0001; mejora de discriminación integrada = 0,06; IC95%, 0,02-0,11) como de remodelado inverso (mejora neta de reclasificación = 0,39; IC95%, 0,07-0,71; p = 0,01; mejora de discriminación integrada = 0,03; IC95%, 0,00-0,06) se obtuvo una mejora estadísticamente significativa de reclasificación y discriminación. Conclusiones: De los biomarcadores investigados, solo el HGF predijo los resultados clínicos después de la TRC independientemente de otros parámetros. Los análisis de reclasificación mostraron que las mediciones de HGF podrían ser útiles para mejorar la selección de pacientes
Introduction and objectives: Cardiac resynchronization therapy (CRT) is beneficial for selected heart failure (HF) patients, although nonresponse to therapy is still prevalent. We investigated a set of novel biomarkers associated with various pathophysiological pathways of HF. Our purpose was to assess their ability to predict clinical outcomes after CRT. Methods: We studied 136 chronic HF patients undergoing CRT. We measured the plasma levels of fractalkine, pentraxin-3, hepatocyte growth factor (HGF), carbohydrate antigen-125, and matrix metalloproteinase-9 before and 6 months after CRT. The primary endpoint of the study was 5-year all-cause mortality, and we considered the absence of 6-month reverse remodelling (defined as at least a 15% decrease in end-systolic volume) as a secondary endpoint. Results: Fifty-eight patients died during the 5-year follow-up period and 66 patients were categorized as nonresponders. In multivariable models, only an increased HGF was an independent predictor of both mortality (HR, 1.35; 95%CI, 1.11-1.64; P = .003; per 1 standard deviation increase) and the absence of reverse remodelling (OR, 1.83; 95%CI, 1.10-3.04; P = .01; per 1 standard deviation increase). Applying HGF to the basic multivariable model of both mortality (net reclassification improvement = 0.69; 95%CI, 0.39-0.99; P < .0001; integrated discrimination improvement = 0.06; 95%CI, 0.02-0.11) and reverse remodelling (net reclassification improvement = 0.39; 95%CI, 0.07-0.71; P = .01; integrated discrimination improvement = 0.03; 95%CI, 0.00-0.06) resulted in a statistically significant reclassification and discrimination improvement. Conclusions: Of the investigated biomarkers, only HGF predicted clinical outcomes following CRT independently of other parameters. Reclassification analyses showed that HGF measurements could be useful in refining patient selection
Asunto(s)
Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Terapia de Resincronización Cardíaca/métodos , Factor de Crecimiento de Hepatocito/análisis , Insuficiencia Cardíaca/fisiopatología , Biomarcadores/análisis , Insuficiencia Cardíaca/terapia , Receptor 1 de Quimiocinas CX3C/sangre , Antígenos de Carbohidratos Asociados a Tumores/sangre , Metaloproteinasa 9 de la Matriz/sangre , MortalidadRESUMEN
Non-classical monocytes infiltrate the kidney parenchyma and participate in tissue damage in patients with lupus nephritis (LN). Circulating microparticles (MPs) seem to play critical roles in the activation of monocytes in systemic lupus erythematosus (SLE) patients. This study aims to characterize the phenotypes of MPs and monocyte subsets in LN patients and to determine their potential to discriminate between SLE patients with and without LN. Blood and urine samples from SLE patients were collected. In monocyte subsets from whole blood samples several phenotypic markers were evaluated. MPs were isolated from platelet-poor plasma and urine by centrifugation. This phenotypic marker characterization was performed using multiparametric flow cytometry. We observed that patients with active LN have lower counts of non-classical monocytes than do those without renal involvement. All monocyte subsets exhibited lower expression of CX3CR1 and ICAM-1 in LN than in patients without LN. High frequencies of MP-HMGB1+ and MP-HLA-DR+ were detected in circulation and urine of LN patients. Although MP-HMGB1+ , MP-HLA-DR+ , and MP-CX3CR1+ from urine were able to discriminate between patients with and without LN, only urinary MP-HMGB1+ were different between patients with active and inactive LN. Therefore, these vesicles may be useful as biomarkers of LN.
Asunto(s)
Micropartículas Derivadas de Células/metabolismo , Proteína HMGB1/metabolismo , Proteína HMGB1/orina , Nefritis Lúpica/orina , Monocitos/metabolismo , Adolescente , Adulto , Biomarcadores/sangre , Biomarcadores/orina , Receptor 1 de Quimiocinas CX3C/sangre , Femenino , Antígenos HLA-DR/sangre , Antígenos HLA-DR/orina , Proteína HMGB1/sangre , Humanos , Molécula 1 de Adhesión Intercelular/sangre , Molécula 1 de Adhesión Intercelular/orina , Nefritis Lúpica/sangre , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: We investigated the expression of chemokine receptors CCR2 (C-C chemokine receptor) 2 and CX3CR1 (C-X3-C receptor 1) on circulating monocyte subsets in patients with neovascular age-related macular degeneration (AMD) and patients with polypoidal choroidal vasculopathy (PCV). METHODS: We recruited patients with neovascular AMD, patients with PCV and age-matched healthy controls for this prospective case-control study. All participants underwent comprehensive clinical examination and imaging. Freshly sampled venous blood was prepared for flow cytometry, where we determined the proportion of CCR2+ - and CX3CR1+ -positive cells in monocyte subsets identified using monocyte identification and subgrouping surface markers CD14, CD16 and HLA-DR. RESULTS: Patients with neovascular AMD had significantly increased proportion of CCR2+ and CX3CR1+ non-classical monocytes. PCV type 1 was associated with significantly increased CCR2+ and CX3CR1+ in all monocyte subsets when compared to PCV type 2. CONCLUSIONS: Neovascular AMD is associated with increased expression of angiogenesis-associated chemokine receptors in the pro-inflammatory non-classical monocytes. PCV differs from neovascular AMD immunologically and show immunological heterogeneity across angiographic subtypes.
Asunto(s)
Receptor 1 de Quimiocinas CX3C/sangre , Enfermedades de la Coroides/sangre , Coroides/irrigación sanguínea , Pólipos/sangre , Receptores CCR2/sangre , Degeneración Macular Húmeda/sangre , Anciano , Biomarcadores/sangre , Estudios de Casos y Controles , Enfermedades de la Coroides/diagnóstico , Femenino , Citometría de Flujo , Angiografía con Fluoresceína , Estudios de Seguimiento , Fondo de Ojo , Humanos , Masculino , Monocitos/metabolismo , Monocitos/patología , Pólipos/diagnóstico , Estudios Prospectivos , Tomografía de Coherencia Óptica/métodos , Agudeza Visual , Degeneración Macular Húmeda/diagnósticoRESUMEN
This study was performed to gain further insight in the heterogeneity of monocytes in the different categories of acute coronary syndrome (ACS), especially between patients with unstable angina pectoris, ST-elevation myocardial infarction (STEMI), and non-ST-elevation myocardial infarction (NSTEMI). For this purpose, blood samples were collected in the acute phase from patients presenting with an ACS. These samples were examined with multiparameter flow cytometry to identify the different monocyte subsets and to analyze the expression of monocyte-associated molecules. Leukocytes, as well as an absolute number of monocytes, showed a clear and significant increase in patients with STEMI. This increase was seen in all subtypes of monocytes. The classical monocytes (CD14++CD16-) of patients with an NSTEMI had a significantly increased CD11b expression when compared to the control group, while these cells showed a decreased expression pattern in STEMI patients. This increased CD11b-expression was also seen in the intermediate monocytes of NSTEMI, while it was almost completely downregulated on the intermediate monocytes of STEMI. Finally, CX3CR1, which is almost exclusively expressed on intermediate and nonclassical monocytes, showed a significant decrease in expression in patients with STEMI. In conclusion, intermediate and nonclassical monocytes have a different immunophenotypic pattern in patients with STEMI versus NSTEMI. These differences reflect the pro-inflammatory state of the monocytes in NSTEMI and can be used as target molecules for novel therapeutic strategies to diminish the migration of proinflammatory monocytes into the myocardial tissue. © 2017 International Society for Advancement of Cytometry.
Asunto(s)
Síndrome Coronario Agudo/sangre , Angina Inestable/sangre , Monocitos/metabolismo , Infarto del Miocardio sin Elevación del ST/sangre , Infarto del Miocardio con Elevación del ST/sangre , Síndrome Coronario Agudo/patología , Anciano , Anciano de 80 o más Años , Angina Inestable/patología , Antígeno CD11b/sangre , Receptor 1 de Quimiocinas CX3C/sangre , Receptor 1 de Quimiocinas CX3C/genética , Diagnóstico Diferencial , Femenino , Citometría de Flujo/métodos , Humanos , Inmunofenotipificación/métodos , Masculino , Persona de Mediana Edad , Monocitos/patología , Infarto del Miocardio sin Elevación del ST/patología , Infarto del Miocardio con Elevación del ST/patologíaRESUMEN
BACKGROUND: Chemokine (C-X3-C motif) receptor 1 (CX3CR1) was identified as the most differentially expressed gene between survivors and non-survivors in two independent cohorts of septic shock patients and was proposed as a marker of sepsis-induced immunosuppression. Whether such a biomarker is associated with mortality in the heterogeneous group of critically ill patients is unknown. The primary objective of this study was to evaluate the association between CX3CR1 messenger RNA (mRNA) expression and mortality in intensive care unit (ICU) patients. The secondary objective was to evaluate similar endpoints in the subgroup of septic shock patients. METHODS: We performed a prospective, multicentre, non-interventional study in six ICUs of university hospitals in Lyon, France. Every consecutive adult patient with systemic inflammatory response syndrome and an expected length of stay in the ICU over 2 days was included. Whole-blood CX3CR1 mRNA expression was measured by quantitative real-time polymerase chain reaction at day 1 (D1) and D3 after inclusion. RESULTS: In ICU patients (n = 725), decreased CX3CR1 mRNA expression at D1 was associated with high D7 mortality (AUC 0.70, adjusted OR [aOR] 2.03, 95 % CI 1.19-3.46), while decreased expression at D3 was associated with increased D28 mortality (AUC 0.64, aOR 2.34, 95 % CI 1.45-3.77). In septic shock patients (n = 279), similar associations were observed between decreased D1 CX3CR1 mRNA expression and D7 mortality (AUC 0.69, aOR 2.76, 95 % CI 1.32-5.75) as well as decreased D3 expression and D28 mortality (AUC 0.72, aOR 3.98, 95 % CI 1.72-9.23). These associations were independent of lactacidaemia, Simplified Acute Physiology Score II, Sepsis-related Organ Failure Assessment score and Charlson comorbidity index. CONCLUSIONS: This study represents the largest evaluation of such an mRNA marker in a heterogeneous cohort of severely injured patients. Our results show that decreased CX3CR1 mRNA expression is associated with increased mortality in ICU patients. This suggests a link between injury-induced immunosuppression and mortality in critically ill patients. In this context, the monitoring of such a host response molecular biomarker could prove very helpful for the identification of patients at high risk of death in the ICU.