RESUMEN
Several studies have shown that expression of zinc-finger protein 143 (ZNF143) is closely related to tumour progression including colon cancer. However, it remains unclear how ZNF143 expression is related to tumour progression within the tumour microenvironment. Here, we investigated whether ZNF143 expression affects the tumour microenvironment and tumour progression by screening molecules secreted by colon cancer cells stably expressing short-hairpin RNAs against ZNF143 or control RNAs. We observed that secretion of interleukin (IL)-8 was increased when ZNF143 expression was reduced in two colon cancer cell lines. The mRNA and protein levels of IL-8 were increased in cells following ZNF143 knockdown, and this effect was reversed when ZNF143 expression was restored. The Janus tyrosine kinase/signal transducer and activator of transcription (JAK/STAT) and extracellular signal-regulated kinase pathways were also shown to contribute to IL-8 expression in ZNF143-knockdown cells. The expression levels of ZNF143 and IL-8 were inversely correlated with three-dimensionally grown spheroids and colon cancer tissues. THP-1 cells were differentiated when cells were incubated with condition media from colon cancer cell with less ZNF143, drastically. Loss of ZNF143 may contribute to the development of colon cancer by regulating intracellular and intercellular signalling for cell plasticity and the tumour microenvironment respectively.
Asunto(s)
Neoplasias del Colon/genética , Neoplasias del Colon/patología , Interleucina-8/genética , Transactivadores/genética , Diferenciación Celular/genética , Línea Celular Tumoral , Progresión de la Enfermedad , Quinasas MAP Reguladas por Señal Extracelular/genética , Células HCT116 , Células HT29 , Humanos , Transcripción Genética/genética , Microambiente Tumoral/genéticaRESUMEN
CD137 (4-1BB), a member of the tumor necrosis factor receptor superfamily, has been reported to be expressed in atherosclerotic plaques, and to promote lesion formation. However, the role of CD137 in mediating atherosclerotic plaque stability and the possible underlying molecular and cellular mechanisms are poorly understood. Here, apolipoprotein E-deficient (ApoE(-/-)) and CD137-deficient ApoE(-/-) (ApoE(-/-)CD137(-/-)) mice fed a chow diet for 66 wk were used. CD137 induces plaque instability, which is characterized by increased plaque necrosis, decreased collagen content, decreased vascular smooth muscle cell (VSMC) content, and increased macrophage infiltration. CD137 also increases the infiltration of effector T (Teff) cells into plaque lesion sites, resulting in increased interferon-γ (IFN-γ) expression. Interestingly, Teff-cell-derived IFN-γ inhibits collagen synthesis in atherosclerotic plaques. Furthermore, CD137 activation increases the apoptosis of VSMCs, possibly by decreasing the antiapoptotic regulator, Bcl-2, and subsequently up-regulating cleaved caspase-3. In macrophages, activation of CD137 signaling boosted the oxidized low density lipoprotein-induced expression of matrix metalloproteinase 9 via the p38 mitogen-activated protein kinase and extracellular signal-regulated kinase1/2 signaling pathways. In summary, activation of CD137 signaling decreases the stability of advanced atherosclerotic plaques via its combined effects on Teff cells, VSMCs, and macrophages.
Asunto(s)
Ligando 4-1BB/inmunología , Aterosclerosis/metabolismo , Hiperlipidemias/metabolismo , Macrófagos/metabolismo , Placa Aterosclerótica/metabolismo , Linfocitos T/metabolismo , Animales , Apoptosis/efectos de los fármacos , Aterosclerosis/inmunología , Interferón gamma/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Placa Aterosclerótica/inmunología , Transducción de Señal/inmunología , Linfocitos T/inmunologíaRESUMEN
Immunosuppressants are increasingly being used in the clinic to manage immune-related adverse effects. Consequently, the incidence of secondary infections associated with immunosuppression is increasing. However, little is known about primary infections during immune checkpoint inhibitor (ICI) treatment without immunosuppressants. We aimed to evaluate primary infectious diseases during antiprogrammed death ligand-1 immunotherapy without immunosuppressants. We retrospectively screened medical records of 233 patients who underwent ICI treatment for advanced non-small cell lung cancer between January 2014 and May 2018 at National Cancer Center, Republic of Korea. Subsequently, we evaluated the clinical characteristics and treatment outcomes of selected patients hospitalized for potential infectious disease without immunosuppressive treatment (n=80). Eight cases (3.4%) were identified as bacterial pneumonia (n=5) and cellulitis, inflamed epidermoid cyst, and wound infection (n=1 each). The bacterial pathogens Streptococcus pneumoniae and Haemophilus influenzae were identified in 4 patients with pneumonia. The period between the start of ICI treatment and infection varied between 3 and 189 days (median, 24.5 days). Five (62.5%) patients were infected within a month after ICI treatment initiation. All patients were treated with empirical antibiotics and discharged without complications. The median progression-free and overall survival for ICI treatment was 11.5 and 25.5 months, respectively. Six patients experienced ICI-associated adverse effects postinfection: Herpes zoster infection (n=4) and pneumonitis (n=2). Infectious disease independent of immunosuppression is a rare, but possible event in patients with lung cancer receiving ICI treatment. Clinical awareness would enable prompt diagnosis of primary infection during immunotherapy.
Asunto(s)
Antineoplásicos Inmunológicos , Carcinoma de Pulmón de Células no Pequeñas , Enfermedades Transmisibles , Neoplasias Pulmonares , Neumonía , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inmunosupresores/efectos adversos , Estudios Retrospectivos , Antineoplásicos Inmunológicos/uso terapéutico , Neumonía/epidemiología , Neumonía/etiología , Enfermedades Transmisibles/inducido químicamente , Enfermedades Transmisibles/tratamiento farmacológico , HospitalizaciónRESUMEN
BACKGROUND: The tumor necrosis factor receptor superfamily, which includes CD40, LIGHT, and OX40, plays important roles in atherosclerosis. CD137 (4-1BB), a member of the tumor necrosis factor receptor superfamily, has been reported to be expressed in human atherosclerotic lesions. However, limited information is available on the precise role of CD137 in atherosclerosis and the effects of blocking CD137/CD137 ligand signaling on lesion formation. METHODS AND RESULTS: We generated CD137-deficient apolipoprotein E-knockout mice (ApoE(-/-) CD137(-/-)) and LDL-receptor-knockout mice (Ldlr(-/-)CD137(-/-)) to investigate the role of CD137 in atherogenesis. The deficiency of CD137 induced a reduction in atherosclerotic plaque lesions in both atherosclerosis mouse models, which was attributed to the downregulation of cytokines such as interferon-gamma, monocyte chemoattractant protein-1, and tumor necrosis factor-alpha. CD137 signaling promoted the production of inflammatory molecules, including monocyte chemoattractant protein-1, interleukin-6, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1, in endothelial cells. Stimulation of CD137 ligand signaling activated monocytes/macrophages and augmented the production of proinflammatory cytokines in atherosclerotic vessels. CONCLUSIONS: CD137/CD137 ligand signaling plays multiple roles in the progression of atherosclerosis, and thus, blockade of this pathway is a promising therapeutic target for the disease.
Asunto(s)
Ligando 4-1BB/fisiología , Aterosclerosis/prevención & control , Hipercolesterolemia/complicaciones , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/fisiología , Animales , Animales Congénicos , Apolipoproteínas E/deficiencia , Apolipoproteínas E/genética , Aterosclerosis/etiología , Aterosclerosis/inmunología , Cruzamientos Genéticos , Citocinas/biosíntesis , Citocinas/genética , Dieta Aterogénica , Modelos Animales de Enfermedad , Endotelio Vascular/metabolismo , Endotelio Vascular/patología , Retroalimentación Fisiológica , Femenino , Hipercolesterolemia/genética , Mediadores de Inflamación/metabolismo , Interferón gamma/inmunología , Activación de Linfocitos , Activación de Macrófagos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de LDL/deficiencia , Receptores de LDL/genética , Transducción de Señal , Linfocitos T/inmunología , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/deficiencia , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/genéticaRESUMEN
BACKGROUND: Programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) immune checkpoint inhibitors (ICIs) significantly affect outcomes in non-small cell lung cancer (NSCLC) patients. However, differences in reactions toward PD-1/PD-L1 ICI among patients impose inefficient treatment. Therefore, developing a reliable biomarker to predict PD-1/PD-L1 ICI reaction is highly necessary for predictive, preventive, and personalized (3P) medicine. MATERIALS AND METHODS: We recruited 63 patients from the National Cancer Center (NCC) and classified them into the training and validation sets. Next, 99 patients were recruited for inclusion into the external validation set at the Samsung Medical Center (SMC). Proteomic analysis enabled us to identify plasma C7 levels, which were significantly different among groups classified by their overall response to the RECIST V 1.1-based assessment. Analytical performance was evaluated to predict the PD-1/PD-L1 ICI response for each type of immunotherapy, and NSCLC histology was evaluated by determining the C7 levels via ELISA. RESULTS: Plasma C7 levels were significantly different between patients with and without clinical benefits (PFS ≥ 6 months). Among the groups sorted by histology and PD-1/PD-L1 immunotherapy type, only the predicted accuracy for pembrolizumab-treated patients from both NCC and SMC was greater than 73%. In patients treated with pembrolizumab, C7 levels were superior to those of the companion diagnostics 22C3 (70.3%) and SP263 (62.1%). Moreover, for pembrolizumab-treated patients for whom the PD-L1 tumor proportion score (TPS) was < 50%, the predictive accuracy of C7 was nearly 20% higher than that of 22C3 and SP263. CONCLUSION: Evaluation of plasma C7 levels shows an accurate prediction of NSCLC patient reactions on pembrolizumab. It demonstrates plasma C7 is an alternative and supportive biomarker to overcome the predictive limitation of previous 22C3 and SP263. Thus, it is clear that clinical use of plasma C7 allows predictive diagnosis on lung cancer patients who have not been successfully treated with current CDx and targeted prevention on metastatic diseases in secondary care caused by a misdiagnosis of current CDx. Reduction of patients' financial burden and increased efficacy of cancer treatment would also enable prediction, prevention, and personalization of medical service on NSCLC patients. In other words, plasma C7 provides efficient medical service and an optimized medical economy followed which finally promotes the prosperity of 3P medicine. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13167-021-00266-x.
RESUMEN
Most members of the tumor-necrosis factor superfamily have been reported to mediate reverse signaling in T cells, macrophages, and/or dendritic cells. BAFF has been reported to have important functions in B-cell survival through forward signaling, but the presence of reverse signaling has not been explored. To investigate the possibility of BAFF-mediated reverse signaling, the expression patterns and functions of BAFF were analyzed in monocytic cell lines including the human macrophage-like cell line, THP-1. The expression of BAFF and its receptors was detected in monocytic cell lines, either before or after activation. The stimulation of BAFF induced the expression of matrix metalloproteinase (MMP)-9, interleukin -8, and transforming growth factor-beta-induced gene product (beta ig-h3) and the upregulation of intercellular adhesion molecule-1 in THP-1 cells. The activation of mitogen-activated protein kinase extracellular signal-regulated kinase1/2 and nuclear factor-kappaB was required for these responses. In addition to these stimulatory effects, BAFF-mediated signaling inhibited processes involving cytoskeletal movement such as phagocytosis and transmigration through blocking the activation of phosphatidylinositol 3-kinase/AKT and Rac-1. Furthermore, murine primary macrophage culture such as peritoneal macrophages expressed BAFF and stimulation of it induced the expression of MMP-9. These observations show that the reverse signaling initiated from BAFF induces the expression of inflammatory mediators while suppressing the cytoskeletal movements associated with phagocytosis and transmigration.
Asunto(s)
Factor Activador de Células B/metabolismo , Citoesqueleto/metabolismo , Mediadores de Inflamación/metabolismo , Macrófagos/metabolismo , Transducción de Señal , Animales , Receptor del Factor Activador de Células B/metabolismo , Línea Celular , Movimiento Celular , Activación Enzimática , Proteínas de la Matriz Extracelular/metabolismo , Humanos , Macrófagos/citología , Macrófagos/enzimología , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , FN-kappa B/metabolismo , Fagocitosis , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación , Procesamiento Proteico-Postraduccional , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Zimosan/metabolismo , Proteína de Unión al GTP rac1/metabolismoRESUMEN
Glucocorticoid-induced TNF receptor family related protein ligand (GITRL) is known to interact with its cognate receptor GITR. In order to investigate the potential role of GITRL in the pro-inflammatory activation of macrophages and the signaling pathway induced by GITRL, we stimulated the macrophage cell line, THP-1, and primary macrophages with an anti-GITRL monoclonal antibody or a GITR:Fc fusion protein and analyzed the cellular responses. The stimulation of GITRL induced the expression of pro-inflammatory cytokines and matrix metalloproteinase (MMP)-9 and up-regulated ICAM-1 expression levels, which was responsible for enhanced cellular aggregation and adhesion to extracellular matrix proteins. The activation of these pro-inflammatory mediators required the activation of ERK1/2 mitogen-activated protein kinase (MAPK) and negatively regulated by p38 MAPK and JNK. Immunofluorescence analysis detected nuclear translocation of the NF-kappaB p50 subunit and this was blocked by ERK inhibitor, indicating that GITRL stimulation induced ERK1/2 phosphorylation and subsequent activation of NF-kappaB. Furthermore, the expression of GITRL and GITR was detected in macrophages in inflammatory disease specimens such as atherosclerotic plaques and synovial tissues of rheumatoid arthritis. These observations raise the possibility that the GITRL-mediated inflammatory activation of macrophages is involved in the pathogenesis of inflammatory diseases.
Asunto(s)
Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Inflamación/enzimología , Activación de Macrófagos/inmunología , FN-kappa B/metabolismo , Transducción de Señal , Factores de Necrosis Tumoral/metabolismo , Anciano , Anciano de 80 o más Años , Adhesión Celular , Agregación Celular , Células Cultivadas , Quimiocinas/metabolismo , Proteína Relacionada con TNFR Inducida por Glucocorticoide/metabolismo , Humanos , Mediadores de Inflamación/metabolismo , Molécula 1 de Adhesión Intercelular/genética , Macrófagos/citología , Macrófagos/enzimología , Metaloproteinasa 9 de la Matriz/metabolismo , Persona de Mediana Edad , Regulación hacia Arriba/genéticaRESUMEN
Herpetic stromal keratitis (HSK) is an inflammatory disorder induced by HSV-1 infection and characterized by T cell-dependent destruction of corneal tissues. It is not known what triggers CD4(+) T cell migration into the stroma of HSV-1-infected corneas. The keratocyte is a fibroblast-like cell that can function as an antigen-presenting cell in the mouse cornea by expressing MHC class II and costimulatory molecules after HSV-1 infection. We hypothesized that chemokines produced by stromal keratocytes are involved in CD4(+) T cell infiltration into the cornea. We found that keratocytes produce several cytokines and chemokines, including MCP-1, RANTES, and T cell activation (TCA)-3. HSV-1 infection increased the production of MCP-1 and RANTES by keratocytes, and these acted as chemoattractants for HSV-1-primed CD4(+) T cells expressing CCR2 and CCR5. Expression of MCP-1 in the corneal stroma was confirmed in vivo. Finally, when HSV-1-primed CD4(+) T cells were adoptively transferred into wild type and MCP-1-deficient mice that had been sublethally irradiated to minimize chemokine production from immune cells, infiltration of CD4(+) T cells was markedly reduced in the MCP-1-deficient mice, suggesting that it is the MCP-1 from HSV-1-infected keratocytes that attracts CD4(+) T cells into the cornea.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Quimiocina CCL2/fisiología , Sustancia Propia/inmunología , Queratitis Herpética/inmunología , Traslado Adoptivo , Animales , Linfocitos T CD8-positivos/inmunología , Movimiento Celular , Células Cultivadas , Quimiocina CCL1/genética , Quimiocina CCL1/metabolismo , Quimiocina CCL5/genética , Quimiocina CCL5/metabolismo , Quimiocinas/genética , Quimiocinas/metabolismo , Sustancia Propia/virología , Citocinas/genética , Citocinas/metabolismo , Ensayo de Inmunoadsorción Enzimática , Epitelio Corneal/citología , Epitelio Corneal/metabolismo , Fibroblastos/inmunología , Fibroblastos/virología , Citometría de Flujo , Herpesvirus Humano 1/fisiología , Humanos , Técnicas para Inmunoenzimas , Ratones , Ratones Endogámicos BALB C , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores de Quimiocina/genética , Receptores de Quimiocina/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Z39Ig is a transmembrane protein containing two Ig homology domains with unknown functions. Immunohistochemical analyses of human carotid atherosclerotic plaques detected Z39Ig staining in areas rich in foamy macrophages. Z39Ig staining was also observed in macrophages in the lining layers and sublining areas of rheumatoid arthritis synovium. Z39Ig staining in the osteoarthritis synovium was restricted to macrophages in the lining layers. To identify the role(s) of Z39Ig in the function of macrophages, we used human monocytic cell lines TF-1A (Z39Ig-negative) and THP-1 (Z39Ig-positive). The expression of Z39Ig was induced in TF-1A cells ,when they were differentiated into macrophages by treatment with PMA. The stimulation of PMA-treated TF-1A or THP-1 cells with immobilized anti-Z39Ig mAb induced the secretion of IL-8 and matrix metalloproteinase (MMP)-9, which was dependent on NF-kappaB activation. These data indicate that the macrophage Z39Ig is involved in the pathogenesis of inflammatory diseases through chemokine induction, which will promote the migration of inflammatory cells into the lesion area, and MMP-9 induction, which will contribute to cartilage destruction or extracellular matrix degradation.
Asunto(s)
Artritis/inmunología , Aterosclerosis/inmunología , Macrófagos/inmunología , Receptores de Complemento/biosíntesis , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacología , Reacciones Antígeno-Anticuerpo , Línea Celular , Humanos , Inmunohistoquímica , Inflamación , Interleucina-8/metabolismo , Macrófagos/efectos de los fármacos , Metaloproteinasa 9 de la Matriz/metabolismo , FN-kappa B/inmunología , Receptores de Complemento/efectos de los fármacos , Receptores de Complemento/inmunología , Acetato de Tetradecanoilforbol/farmacologíaRESUMEN
Aptamers have recently emerged as reliable and promising targeting agents in the field of biology. However, their therapeutic potential has yet to be completely assessed due to their poor pharmacokinetics for systemic administration. Here, we describe a novel aptamer-antibody complex, designated an "oligobody" (oligomer+antibody) that may overcome the therapeutic limitations of aptamers. To provide proof-of-principle study, we investigated the druggability of oligobody in vivo using cotinine conjugated t44-OMe aptamer, which is specific for the sequence of pegaptanib, and an anti-cotinine antibody. The antibody part of oligobody resulted in extended in vivo pharmacokinetics of the aptamer without influencing its binding affinity. Moreover, the aptamer of oligobody penetrated deeply into the tumor tissues whereas the anti-VEGF antibody did not. Finally, the systemic administration of this oligobody reduced the tumor burden in a xenograft mouse model. Together, these results suggested that our oligobody strategy may represent a novel platform for rapid, low-cost and high-throughput cancer therapy.