RESUMEN
Acetate, a precursor of acetyl-CoA, is instrumental in energy production, lipid synthesis and protein acetylation. However, whether acetate reprogrammes tumour metabolism and plays a role in tumour immune evasion remains unclear. Here, we show that acetate is the most abundant short-chain fatty acid in human non-small cell lung cancer tissues, with increased tumour-enriched acetate uptake. Acetate-derived acetyl-CoA induces c-Myc acetylation, which is mediated by the moonlighting function of the metabolic enzyme dihydrolipoamide S-acetyltransferase. Acetylated c-Myc increases its stability and subsequent transcription of the genes encoding programmed death-ligand 1, glycolytic enzymes, monocarboxylate transporter 1 and cell cycle accelerators. Dietary acetate supplementation promotes tumour growth and inhibits CD8+ T cell infiltration, whereas disruption of acetate uptake inhibits immune evasion, which increases the efficacy of anti-PD-1-based therapy. These findings highlight a critical role of acetate promoting tumour growth beyond its metabolic role as a carbon source by reprogramming tumour metabolism and immune evasion, and underscore the potential of controlling acetate metabolism to curb tumour growth and improve the response to immune checkpoint blockade therapy.
Asunto(s)
Acetatos , Antígeno B7-H1 , Proteínas Proto-Oncogénicas c-myc , Animales , Humanos , Ratones , Acetatos/metabolismo , Acetatos/farmacología , Acetilcoenzima A/metabolismo , Acetilación , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Evasión Inmune/efectos de los fármacos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/inmunología , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Escape del Tumor , Regulación hacia Arriba/efectos de los fármacosRESUMEN
BACKGROUND: The novel coronavirus disease-2019 (COVID-19) that emerged in China, is an extremely contagious and pathogenic viral infection caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) that has sparked a global pandemic. The few and limited availability of approved therapeutic agents or vaccines is of great concern. Urgently, Remdesivir, Nirmatrelvir, Molnupiravir, and some phytochemicals including polyphenol, flavonoid, alkaloid, and triterpenoid are applied to develop as repurposing drugs against the SARS-CoV-2 invasion. METHODS: This study was conducted to perform molecular docking and absorption, distribution, metabolism, excretion and toxicity (ADMET) analysis of the potential phytocompounds and repurposing drugs against three targets of SARS-CoV-2 proteins (RNA dependent RNA polymerase, RdRp, Endoribonclease, S-protein of ACE2-RBD). RESULTS: The docking data illustrated Arachidonic acid, Rutin, Quercetin, and Curcumin were highly bound with coronavirus polyprotein replicase and Ebolavirus envelope protein. Furthermore, anti- Ebolavirus molecule Remedesivir, anti-HIV molecule Chloroquine, and Darunavir were repurposed with coronavirus polyprotein replicase as well as Ebolavirus envelope protein. The strongest binding interaction of each targets are Rutin with RdRp, Endoribonclease with Amentoflavone, and ACE2-RBD with Epigallocatechin gallate. CONCLUSIONS: Taken altogether, these results shed a light on that phytocompounds have a therapeutic potential for the treatment of anti-SARS-CoV-2 may base on multi-target effects or cocktail formulation for blocking viral infection through invasion/activation, transcription/reproduction, and posttranslational cleavage to battle COVID-19 pandemic.
Asunto(s)
Tratamiento Farmacológico de COVID-19 , COVID-19 , Fitoquímicos , Humanos , Enzima Convertidora de Angiotensina 2 , Antivirales/farmacología , Antivirales/uso terapéutico , Antivirales/química , Evasión Inmune/efectos de los fármacos , Simulación del Acoplamiento Molecular , Pandemias , ARN Polimerasa Dependiente del ARN , Rutina/farmacología , SARS-CoV-2 , Internalización del Virus/efectos de los fármacos , Replicación Viral/efectos de los fármacos , Fitoquímicos/química , Fitoquímicos/farmacología , Fitoquímicos/uso terapéutico , Ácido Araquidónico/química , Ácido Araquidónico/farmacología , Quercetina/química , Quercetina/farmacología , Curcumina/química , Curcumina/farmacologíaRESUMEN
SARS-CoV-2 is a highly pathogenic virus that evades antiviral immunity by interfering with host protein synthesis, mRNA stability, and protein trafficking. The SARS-CoV-2 nonstructural protein 1 (Nsp1) uses its C-terminal domain to block the messenger RNA (mRNA) entry channel of the 40S ribosome to inhibit host protein synthesis. However, how SARS-CoV-2 circumvents Nsp1-mediated suppression for viral protein synthesis and if the mechanism can be targeted therapeutically remain unclear. Here, we show that N- and C-terminal domains of Nsp1 coordinate to drive a tuned ratio of viral to host translation, likely to maintain a certain level of host fitness while maximizing replication. We reveal that the stem-loop 1 (SL1) region of the SARS-CoV-2 5' untranslated region (5' UTR) is necessary and sufficient to evade Nsp1-mediated translational suppression. Targeting SL1 with locked nucleic acid antisense oligonucleotides inhibits viral translation and makes SARS-CoV-2 5' UTR vulnerable to Nsp1 suppression, hindering viral replication in vitro at a nanomolar concentration, as well as providing protection against SARS-CoV-2-induced lethality in transgenic mice expressing human ACE2. Thus, SL1 allows Nsp1 to switch infected cells from host to SARS-CoV-2 translation, presenting a therapeutic target against COVID-19 that is conserved among immune-evasive variants. This unique strategy of unleashing a virus' own virulence mechanism against itself could force a critical trade-off between drug resistance and pathogenicity.
Asunto(s)
Regiones no Traducidas 5'/genética , Evasión Inmune/genética , Biosíntesis de Proteínas , SARS-CoV-2/genética , Proteínas no Estructurales Virales/genética , Animales , Secuencia de Bases , Chlorocebus aethiops , Células HEK293 , Interacciones Huésped-Patógeno/efectos de los fármacos , Interacciones Huésped-Patógeno/genética , Humanos , Evasión Inmune/efectos de los fármacos , Ratones Transgénicos , Modelos Biológicos , Oligonucleótidos Antisentido/farmacología , Biosíntesis de Proteínas/efectos de los fármacos , SARS-CoV-2/efectos de los fármacos , Células Vero , Replicación Viral/efectos de los fármacosRESUMEN
Lipopolysaccharide (LPS) as an important inflammatory mediator activates the innate/adaptive immune system. The existence of LPS in pancreatic ductal adenocarcinoma (PDAC) has been reported, however, its biological function in PDAC remains unclear. Here, we demonstrated that circulating and tumoral LPS was significantly increased by intestinal leakage in the orthotopic murine PDAC model, and LPS administration promoted T cell infiltration but exhaustion paradoxically in the subcutaneous murine PDAC model. By bioinformatic analysis, Toll-like receptor 4 (TLR4), LPS receptor, was further found to enrich in immune tolerance signaling in PDAC tissues. Then, a significant positive correlation was found between TLR4 and programmed death ligand-1 (PD-L1) in clinical PDAC tissues, as well as serum LPS and tumoral PD-L1. Meanwhile, LPS stimulation in vitro and in vivo obviously upregulated tumor PD-L1 expression, and effectively promoted cancer cells resistance to T cell cytotoxicity. Mechanistically, the activation of TLR4/MyD88/AKT/NF-κB cascade was found to participate in LPS mediated PD-L1 transcription via binding to its promoter regions, which was enhanced by crosstalk between NF-κB and AKT pathways. Finally, PD-L1 blockade could significantly reverse LPS-induced immune escape, and synergized with LPS treatment. Taken together, LPS can remodel tumor microenvironment, and synergize with PD-L1 blockade to suppress tumor growth, which may be a promising comprehensive strategy for PDAC.
Asunto(s)
Antígeno B7-H1/metabolismo , Tracto Gastrointestinal/metabolismo , Factor 88 de Diferenciación Mieloide/metabolismo , FN-kappa B/metabolismo , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptor Toll-Like 4/metabolismo , Microambiente Tumoral , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Anciano , Animales , Antígeno B7-H1/genética , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Modelos Animales de Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Evasión Inmune/efectos de los fármacos , Tolerancia Inmunológica/efectos de los fármacos , Lipopolisacáridos , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Masculino , Ratones Endogámicos BALB C , Modelos Biológicos , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Transducción de Señal , Transcripción Genética/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunologíaRESUMEN
Kinase inhibitors suppress the growth of oncogene driven cancer but also enforce the selection of treatment resistant cells that are thought to promote tumor relapse in patients. Here, we report transcriptomic and functional genomics analyses of cells and tumors within their microenvironment across different genotypes that persist during kinase inhibitor treatment. We uncover a conserved, MAPK/IRF1-mediated inflammatory response in tumors that undergo stemness- and senescence-associated reprogramming. In these tumor cells, activation of the innate immunity sensor RIG-I via its agonist IVT4, triggers an interferon and a pro-apoptotic response that synergize with concomitant kinase inhibition. In humanized lung cancer xenografts and a syngeneic Egfr-driven lung cancer model these effects translate into reduction of exhausted CD8+ T cells and robust tumor shrinkage. Overall, the mechanistic understanding of MAPK/IRF1-mediated intratumoral reprogramming may ultimately prolong the efficacy of targeted drugs in genetically defined cancer patients.
Asunto(s)
Proteína 58 DEAD Box/metabolismo , Inmunidad Innata , Inflamación/patología , Sistema de Señalización de MAP Quinasas , Neoplasias/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Receptores Inmunológicos/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Puntos de Control del Ciclo Celular/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Citocinas/metabolismo , Receptores ErbB/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Evasión Inmune/efectos de los fármacos , Inmunidad Innata/efectos de los fármacos , Factor 1 Regulador del Interferón/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Neoplasias/patología , Oncogenes , Transducción de Señal/efectos de los fármacosRESUMEN
Cyclic GMP-AMP synthase (cGAS) is a key DNA sensor that detects aberrant cytosolic DNA arising from pathogen invasions or genotoxic stresses. Upon binding to DNA, cGAS is activated and catalyzes the synthesis of cyclic GMP-AMP (cGAMP), which induces potent antimicrobial and antitumor responses. Kaposi sarcoma-associated herpesvirus (KSHV) is a human DNA tumor virus that causes Kaposi sarcoma and several other malignancies. We previously reported that KSHV inhibitor of cGAS (KicGAS) encoded by ORF52, inhibits cGAS enzymatic activity, but the underlying mechanisms remained unclear. To define the inhibitory mechanisms, here we performed in-depth biochemical and functional characterizations of KicGAS, and mapped its functional domains. We found KicGAS self-oligomerizes and binds to double stranded DNA cooperatively. This self-oligomerization is essential for its DNA binding and cGAS inhibition. Interestingly, KicGAS forms liquid droplets upon binding to DNA, which requires collective multivalent interactions with DNA mediated by both structured and disordered domains coordinated through the self-oligomerization of KicGAS. We also observed that KicGAS inhibits the DNA-induced phase separation and activation of cGAS. Our findings reveal a novel mechanism by which DNA viruses target the host protein phase separation for suppression of the host sensing of viral nucleic acids.
Asunto(s)
Herpesvirus Humano 8/genética , Interacciones Huésped-Patógeno/genética , Nucleotidiltransferasas/genética , Sarcoma de Kaposi/genética , Citosol/enzimología , Citosol/microbiología , Roturas del ADN de Doble Cadena/efectos de los fármacos , Daño del ADN/genética , ADN Viral/genética , Proteínas de Unión al ADN/genética , Herpesvirus Humano 8/patogenicidad , Humanos , Evasión Inmune/efectos de los fármacos , Inmunidad Innata/genética , Nucleótidos Cíclicos/genética , Nucleotidiltransferasas/antagonistas & inhibidores , Sarcoma de Kaposi/tratamiento farmacológico , Sarcoma de Kaposi/virología , Proteínas Virales/genéticaRESUMEN
T cell exhaustion plays critical roles in tumor immune evasion. Novel strategies to suppress immune evasion are in urgent need. We aimed to identify potential compounds to target T cell exhaustion and increase response to immune checkpoint inhibitors (ICIs). Differentially expressed genes (DEGs) were identified between tumors with different immune evasion potential by comparing the transcriptome data. DEGs were then analyzed in the Connectivity Map (CMap) platform to identify potential compounds to increase response to ICIs. Gene set enrichment analysis, LDH release assay, Chromatin immunoprecipitation (ChIP), and Co-IP were performed to explore the potential mechanisms in vitro. Patients derived organoids and humanized xenograft mouse model were utilized to validate the finding ex vivo and in vivo. We identified 25 potential compounds that may play critical roles in regulating tumor immune evasion. We further pinpointed a specific compound, dexamethasone, which shows potent anti-tumor effect in multiple cancer cell lines when cocultured with T cells. Dexamethasone can suppress T cell exhaustion by decreasing the activity of two immune checkpoints simultaneously, including PD-L1 and IDO1. Functional study shows dexamethasone can increase the sensitivity of ICIs in coculture system, 3D organoid model and humanized mouse model. Mechanism study shows dexamethasone mediated transcriptional suppression of PD-L1 and IDO1 depends on the nuclear translocation of GR/STAT3 complex. These findings demonstrate dexamethasone can suppress immune evasion by inducing GR/STAT3 mediated downregulation of PD-L1 and IDO1 pathways.
Asunto(s)
Antígeno B7-H1/metabolismo , Dexametasona/farmacología , Evasión Inmune/efectos de los fármacos , Inmunosupresores/farmacología , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Bases de Datos Genéticas , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Xenoinjertos , Humanos , Recuento de Linfocitos , Ratones , Modelos Biológicos , Unión Proteica , Transporte de Proteínas , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismoRESUMEN
The outbreak of coronavirus disease 2019 (COVID-19) has not only affected human health but also diverted the focus of research and derailed the world economy over the past year. Recently, vaccination against COVID-19 has begun, but further studies on effective therapeutic agents are still needed. The severity of COVID-19 is attributable to several factors such as the dysfunctional host immune response manifested by uncontrolled viral replication, type I interferon suppression, and release of impaired cytokines by the infected resident and recruited cells. Due to the evolving pathophysiology and direct involvement of the host immune system in COVID-19, the use of immune-modulating drugs is still challenging. For the use of immune-modulating drugs in severe COVID-19, it is important to balance the fight between the aggravated immune system and suppression of immune defense against the virus that causes secondary infection. In addition, the interplaying events that occur during virus-host interactions, such as activation of the host immune system, immune evasion mechanism of the virus, and manifestation of different stages of COVID-19, are disjunctive and require thorough streamlining. This review provides an update on the immunotherapeutic interventions implemented to combat COVID-19 along with the understanding of molecular aspects of the immune evasion of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which may provide opportunities to develop more effective and promising therapeutics.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Antivirales/uso terapéutico , COVID-19/terapia , Evasión Inmune/efectos de los fármacos , Factores Inmunológicos/uso terapéutico , Replicación Viral/efectos de los fármacos , COVID-19/inmunología , COVID-19/patología , COVID-19/prevención & control , Vacunas contra la COVID-19/administración & dosificación , Ensayos Clínicos como Asunto , Citocinas/antagonistas & inhibidores , Citocinas/biosíntesis , Dexametasona/uso terapéutico , Combinación de Medicamentos , Humanos , Inmunidad Innata/efectos de los fármacos , Inmunización Pasiva/métodos , Proteína Antagonista del Receptor de Interleucina 1/uso terapéutico , Péptidos/uso terapéutico , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/inmunología , SARS-CoV-2/patogenicidad , Replicación Viral/inmunología , Sueroterapia para COVID-19RESUMEN
T-2 toxin and deoxynivalenol (DON) are type A and B trichothecenes, respectively. They widely occur as pollutants in food and crops and cause a series of toxicities, including immunotoxicity, hepatotoxicity, and neurotoxicity. Oxidative stress is the primary mechanistic basis of these toxic effects. Increasing amounts of evidence have shown that mitochondria are significant targets of apoptosis caused by T-2 toxin- and DON-induced oxidative stress via regulation of Bax/B-cell lymphoma-2 and caspase-3/caspase-9 signaling. DNA methylation and autophagy are involved in oxidative stress related to apoptosis, and hypoxia and immune evasion are related to oxidative stress in this context. Hypoxia induces oxidative stress by stimulating mitochondrial reactive oxygen species production and regulates the expression of cytokines, such as interleukin-1ß and tumor necrosis factor-α. Programmed cell death-ligand 1 is upregulated by these cytokines and by hypoxia-inducible factor-1, which allows it to bind to programmed cell death-1 to enable escape of immune cell surveillance and achievement of immune evasion. This review concentrates on novel findings regarding the oxidative stress mechanisms of the trichothecenes T-2 toxin and DON. Importantly, we discuss the new evidence regarding the connection of hypoxia and immune evasion with oxidative stress in this context. Finally, the trinity of hypoxia, oxidative stress and immune evasion is highlighted. This work will be conducive to an improved understanding of the oxidative stress caused by trichothecene mycotoxins.
Asunto(s)
Estrés Oxidativo/efectos de los fármacos , Toxina T-2/toxicidad , Tricotecenos/toxicidad , Animales , Apoptosis/efectos de los fármacos , Humanos , Hipoxia/inducido químicamente , Evasión Inmune/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/patología , Especies Reactivas de Oxígeno/metabolismoRESUMEN
The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for virus infection through the engagement of the human ACE2 protein1 and is a major antibody target. Here we show that chronic infection with SARS-CoV-2 leads to viral evolution and reduced sensitivity to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma, by generating whole-genome ultra-deep sequences for 23 time points that span 101 days and using in vitro techniques to characterize the mutations revealed by sequencing. There was little change in the overall structure of the viral population after two courses of remdesivir during the first 57 days. However, after convalescent plasma therapy, we observed large, dynamic shifts in the viral population, with the emergence of a dominant viral strain that contained a substitution (D796H) in the S2 subunit and a deletion (ΔH69/ΔV70) in the S1 N-terminal domain of the spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype were reduced in frequency, before returning during a final, unsuccessful course of convalescent plasma treatment. In vitro, the spike double mutant bearing both ΔH69/ΔV70 and D796H conferred modestly decreased sensitivity to convalescent plasma, while maintaining infectivity levels that were similar to the wild-type virus.The spike substitution mutant D796H appeared to be the main contributor to the decreased susceptibility to neutralizing antibodies, but this mutation resulted in an infectivity defect. The spike deletion mutant ΔH69/ΔV70 had a twofold higher level of infectivity than wild-type SARS-CoV-2, possibly compensating for the reduced infectivity of the D796H mutation. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy, which is associated with the emergence of viral variants that show evidence of reduced susceptibility to neutralizing antibodies in immunosuppressed individuals.
Asunto(s)
Tratamiento Farmacológico de COVID-19 , COVID-19/terapia , COVID-19/virología , Evolución Molecular , Mutagénesis/efectos de los fármacos , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/genética , Adenosina Monofosfato/análogos & derivados , Adenosina Monofosfato/farmacología , Adenosina Monofosfato/uso terapéutico , Anciano , Alanina/análogos & derivados , Alanina/farmacología , Alanina/uso terapéutico , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , COVID-19/inmunología , Enfermedad Crónica , Genoma Viral/efectos de los fármacos , Genoma Viral/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Evasión Inmune/efectos de los fármacos , Evasión Inmune/genética , Evasión Inmune/inmunología , Tolerancia Inmunológica/efectos de los fármacos , Tolerancia Inmunológica/inmunología , Inmunización Pasiva , Terapia de Inmunosupresión , Masculino , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/inmunología , Mutación , Filogenia , SARS-CoV-2/inmunología , SARS-CoV-2/metabolismo , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/inmunología , Factores de Tiempo , Carga Viral/efectos de los fármacos , Esparcimiento de Virus , Sueroterapia para COVID-19RESUMEN
PURPOSE: Although the neutrophil membrane (NM)-based nanoparticulate delivery system has exhibited rapid advances in tumor targeting stemmed from the inherited instinct, the antitumor effect requires further improvement due to inefficient cellular internalization in the absence of specific interactions between NM-coated nanoparticles and tumor cells. METHODS: Herein, we fabricated drug-paclitaxel loaded NM camouflaging nanoparticles (TNM-PN) modified with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), favorable for the cellular internalization. RESULTS: The results showed that TNM-PN exerted a significant cytotoxicity to tumor cells by TRAIL-mediated endocytosis and strong adhesion to inflamed endothelial cells in vitro. Due to TRAIL modification as well as the adhesive interactions between neutrophil and inflamed tumor vascular endothelial cells, tumors in TNM-PN group exhibited almost 2-fold higher fluorescence intensities than that of NM camouflaging nanoparticles and 3-fold higher than that of bare nanoparticles, respectively. Significant tumor inhibition and survival rates of mice were achieved in TNM-PN group as a consequence of prolonged blood circulations to 48 h and preferential tumor accumulations, which was ascribed to targeting adhesion originated from NM to immune evasion and subsequent excellent cellular internalization. CONCLUSION: The research unveiled a novel strategy of amplifying cellular internalization based on NM coating nanotechnology to boost antitumor efficacy.
Asunto(s)
Membrana Celular/metabolismo , Sistemas de Liberación de Medicamentos , Nanopartículas/química , Nanotecnología/métodos , Neoplasias/tratamiento farmacológico , Neutrófilos/citología , Albúminas/farmacología , Albúminas/uso terapéutico , Animales , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Membrana Celular/efectos de los fármacos , Endocitosis/efectos de los fármacos , Células Endoteliales/efectos de los fármacos , Células Endoteliales/patología , Humanos , Evasión Inmune/efectos de los fármacos , Inflamación/patología , Ratones , Nanopartículas/administración & dosificación , Nanopartículas/ultraestructura , Neoplasias/patología , Neutrófilos/efectos de los fármacos , Paclitaxel/farmacología , Paclitaxel/uso terapéutico , Células RAW 264.7 , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología , Distribución Tisular/efectos de los fármacosRESUMEN
Checkpoint inhibitors (CPIs) augment adaptive immunity. Systematic pan-tumor analyses may reveal the relative importance of tumor-cell-intrinsic and microenvironmental features underpinning CPI sensitization. Here, we collated whole-exome and transcriptomic data for >1,000 CPI-treated patients across seven tumor types, utilizing standardized bioinformatics workflows and clinical outcome criteria to validate multivariable predictors of CPI sensitization. Clonal tumor mutation burden (TMB) was the strongest predictor of CPI response, followed by total TMB and CXCL9 expression. Subclonal TMB, somatic copy alteration burden, and histocompatibility leukocyte antigen (HLA) evolutionary divergence failed to attain pan-cancer significance. Dinucleotide variants were identified as a source of immunogenic epitopes associated with radical amino acid substitutions and enhanced peptide hydrophobicity/immunogenicity. Copy-number analysis revealed two additional determinants of CPI outcome supported by prior functional evidence: 9q34 (TRAF2) loss associated with response and CCND1 amplification associated with resistance. Finally, single-cell RNA sequencing (RNA-seq) of clonal neoantigen-reactive CD8 tumor-infiltrating lymphocytes (TILs), combined with bulk RNA-seq analysis of CPI-responding tumors, identified CCR5 and CXCL13 as T-cell-intrinsic markers of CPI sensitivity.
Asunto(s)
Inhibidores de Puntos de Control Inmunológico/farmacología , Neoplasias/inmunología , Linfocitos T/inmunología , Biomarcadores de Tumor/metabolismo , Antígenos CD8/metabolismo , Quimiocina CXCL13/metabolismo , Cromosomas Humanos Par 9/genética , Estudios de Cohortes , Ciclina D1/genética , Variaciones en el Número de Copia de ADN/genética , Exoma/genética , Amplificación de Genes , Humanos , Evasión Inmune/efectos de los fármacos , Análisis Multivariante , Mutación/genética , Neoplasias/patología , Polimorfismo de Nucleótido Simple/genética , Receptores CCR5/metabolismo , Linfocitos T/efectos de los fármacos , Carga Tumoral/genéticaRESUMEN
BACKGROUND: Progranulin (PGRN), as a multifunctional growth factor, is overexpressed in multiple tumors, but the role of PGRN on tumor immunity is still unclear. Here, we studied the effect of PGRN on breast cancer tumor immunity and its possible molecular mechanism. METHODS: The changes of macrophage phenotypes after PGRN treatment were detected by western blot, quantitative polymerase chain reaction (PCR) and flow cytometry. Western blot was used to study the signal molecular mechanism of PGRN regulating this process. The number and localization of immune cells in Wild-type (WT) and PGRN-/- breast cancer tissues were analyzed by immunohistochemical staining and immunofluorescence techniques. The activation and proliferation of CD8+ T cells were measured by flow cytometry. RESULTS: After being treated with PGRN, the expressions of M2 markers and programmed death ligand 1 (PD-L1) on macrophages increased significantly. Signal transducer and activator of transcription 3 (STAT3) signaling pathway inhibitor Stattic significantly inhibited the expression of PD-L1 and M2 related markers induced by PGRN. In WT group, CD8 were co-localized with macrophages and PD-L1, but not tumor cells. The number of immune cells in PGRN-/- breast cancer tissue increased, and their infiltration into tumor parenchyma was also enhanced. Moreover, in the co-culture system, WT peritoneal macrophages not only reduced the ratio of activated CD8+ T cells but also reduced the proportion of proliferating CD8+ T cells. The addition of programmed death receptor 1 (PD-1) and PD-L1 neutralizing antibodies effectively reversed this effect and restored the immune function of CD8+ T cells. CONCLUSION: These results demonstrate that PGRN promotes M2 polarization and PD-L1 expression by activating the STAT3 signaling pathway. Furthermore, through PD-1/PD-L1 interaction, PGRN can promote the breast tumor immune escape. Our research may provide new ideas and targets for clinical breast cancer immunotherapy.
Asunto(s)
Antígeno B7-H1/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Linfocitos T CD8-positivos/efectos de los fármacos , Macrófagos/efectos de los fármacos , Progranulinas/farmacología , Macrófagos Asociados a Tumores/metabolismo , Animales , Antígeno B7-H1/biosíntesis , Antígeno B7-H1/inmunología , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Linfocitos T CD8-positivos/inmunología , Línea Celular Tumoral , Femenino , Humanos , Evasión Inmune/efectos de los fármacos , Macrófagos/inmunología , Ratones , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Chagas' disease is a zoonotic parasitic ailment now affecting more than 6 million people, mainly in Latin America. Its agent, the protozoan Trypanosoma cruzi, is primarily transmitted by endemic hematophagous triatomine insects. Transplacental transmission is also important and a main source for the emerging global expansion of this disease. In the host, the parasite undergoes intra (amastigotes) and extracellular infective (trypomastigotes) stages, both eliciting complex immune responses that, in about 70% of the cases, culminate in permanent immunity, concomitant with the asymptomatic presence of the parasite. The remaining 30% of those infected individuals will develop a syndrome, with variable pathological effects on the circulatory, nervous, and digestive systems. Herein, we review an important number of T. cruzi molecules, mainly located on its surface, that have been characterized as immunogenic and protective in various experimental setups. We also discuss a variety of parasite strategies to evade the complement system - mediated immune responses. Within this context, we also discuss the capacity of the T. cruzi infective trypomastigote to translocate the ER-resident chaperone calreticulin to its surface as a key evasive strategy. Herein, it is described that T. cruzi calreticulin inhibits the initial stages of activation of the host complement system, with obvious benefits for the parasite. Finally, we speculate on the possibility to experimentally intervene in the interaction of calreticulin and other T. cruzi molecules that interact with the complement system; thus resulting in significant inhibition of T. cruzi infectivity.
Asunto(s)
Antiprotozoarios/farmacología , Enfermedad de Chagas/tratamiento farmacológico , Interacciones Huésped-Parásitos/inmunología , Evasión Inmune/efectos de los fármacos , Trypanosoma cruzi/inmunología , Antiprotozoarios/uso terapéutico , Calreticulina/metabolismo , Enfermedad de Chagas/inmunología , Enfermedad de Chagas/parasitología , Activación de Complemento/efectos de los fármacos , Activación de Complemento/inmunología , Proteínas del Sistema Complemento/metabolismo , Humanos , Unión Proteica/efectos de los fármacos , Unión Proteica/inmunología , Proteínas Protozoarias/metabolismo , Trypanosoma cruzi/metabolismoRESUMEN
Many diverse strategies allow and facilitate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to evade antiviral innate immune mechanisms. Although the type I interferon (IFN) system has a critical role in restricting the dissemination of viral infection, suppression of IFN receptor signals by SARS-CoV-2 constitutes a checkpoint that plays an important role in the immune escape of the virus. Environmental pollution not only facilitates SARS-CoV-2 infection but also increases infection-associated fatality risk, which arises due to Systemic Aryl hydrocarbon Receptor (AhR) Activation Syndrome. The intracellular accumulation of endogenous kynurenic acid due to overexpression of the indoleamine 2,3-dioxygenase (IDO) by AhR activation induces AhR-interleukin-6 (IL-6)-signal transducers and activators of the transcription 3 (STAT3) signaling pathway. The AhR-IDO1-Kynurenine pathway is an important checkpoint, which leads to fatal consequences in SARS-CoV-2 infection and immune evasion in the context of Treg/Th17 imbalance and cytokine storm.
Asunto(s)
COVID-19/inmunología , Contaminación Ambiental/efectos adversos , Evasión Inmune/inmunología , Inmunidad Innata/inmunología , Mediadores de Inflamación/inmunología , Animales , Antivirales/farmacología , Antivirales/uso terapéutico , COVID-19/metabolismo , Humanos , Evasión Inmune/efectos de los fármacos , Inmunidad Innata/efectos de los fármacos , Mediadores de Inflamación/metabolismo , Receptores de Hidrocarburo de Aril/inmunología , Receptores de Hidrocarburo de Aril/metabolismo , Tratamiento Farmacológico de COVID-19RESUMEN
PURPOSE: Nanoparticle (NP)-based chemo-photothermal therapy (CPT) has been shown to be a promising non-invasive approach for antitumor treatment. However, NPs must overcome the limitations of opsonization, clearance of the reticuloendothelial system, and ineffective targeting of tumor tissue sites. To solve these problems, stem cell membrane (SCM)-camouflaged polydopamine nanoparticles (PDA@SCM NPs) carrying the hydrophobic anticancer drug 7-ethyl-10-hydroxycamptothecin (SN38) were constructed for CPT of malignant bone tumors. METHODS: We developed umbilical-cord mesenchymal stem cell membrane-coated polydopamine nanoparticles encapsulating SN38 (PDA-SN38@SCM NPs) as an efficient tumor-targeting drug-delivery platform for CPT of malignant bone tumors. We characterized PDA@SCM NPs and evaluated the biocompatibility and anti-phagocytosis properties of PDA@SCM NPs. The antitumor activity of PDA-SN38@SCM NPs was evaluated in MG63 lines and an MG63 xenograft model in mice. RESULTS: Synthesized PDA-SN38@SCM NPs retained an excellent photothermal effect after SN38 loading. The drug release of PDA-SN38@SCM NPs could be triggered by near-infrared irradiation and an acidic stimulus. PDA@SCM NPs exhibited lower nonspecific macrophage uptake, longer retention in blood, and more effective accumulation at tumor sites than that shown by PDA NPs. Confocal laser scanning microscopy (CLSM) and flow cytometry showed that MG63 cells took up more PDA-SN38@SCM NPs than PDA-SN38 NPs. In vitro and in vivo antitumor studies demonstrated the outstanding performance of PDA-SN38@SCM NPs in synergistic CPT for bone tumors. CONCLUSION: PDA-SN38@SCM NPs demonstrated an extraordinary synergistic CPT effect and could be a promising strategy for the treatment of malignant bone tumors.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Óseas/terapia , Membrana Celular/metabolismo , Indoles/química , Nanopartículas/química , Terapia Fototérmica , Polímeros/química , Células Madre/metabolismo , Animales , Antineoplásicos/farmacología , Materiales Biocompatibles/química , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/patología , Línea Celular Tumoral , Liberación de Fármacos , Femenino , Humanos , Evasión Inmune/efectos de los fármacos , Irinotecán/farmacocinética , Irinotecán/farmacología , Irinotecán/uso terapéutico , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Nanopartículas/ultraestructura , Células RAW 264.7 , Distribución Tisular/efectos de los fármacosRESUMEN
Virus infection may induce excessive interferon (IFN) responses that can lead to host tissue injury or even death. ß-arrestin 2 regulates multiple cellular events through the G protein-coupled receptor (GPCR) signaling pathways. Here we demonstrate that ß-arrestin 2 also promotes virus-induced production of IFN-ß and clearance of viruses in macrophages. ß-arrestin 2 interacts with cyclic GMP-AMP synthase (cGAS) and increases the binding of dsDNA to cGAS to enhance cyclic GMP-AMP (cGAMP) production and the downstream stimulator of interferon genes (STING) and innate immune responses. Mechanistically, deacetylation of ß-arrestin 2 at Lys171 facilitates the activation of the cGAS-STING signaling and the production of IFN-ß. In vitro, viral infection induces the degradation of ß-arrestin 2 to facilitate immune evasion, while a ß-blocker, carvedilol, rescues ß-arrestin 2 expression to maintain the antiviral immune response. Our results thus identify a viral immune-evasion pathway via the degradation of ß-arrestin 2, and also hint that carvedilol, approved for treating heart failure, can potentially be repurposed as an antiviral drug candidate.
Asunto(s)
Carvedilol/farmacología , Evasión Inmune/inmunología , Proteínas de la Membrana/metabolismo , Nucleotidiltransferasas/metabolismo , Virosis/inmunología , Arrestina beta 2/metabolismo , Animales , Carvedilol/uso terapéutico , Modelos Animales de Enfermedad , Reposicionamiento de Medicamentos , Células HEK293 , Herpesvirus Humano 1/inmunología , Humanos , Evasión Inmune/efectos de los fármacos , Interferón beta/metabolismo , Macrófagos Peritoneales/inmunología , Macrófagos Peritoneales/metabolismo , Masculino , Ratones , Cultivo Primario de Células , Proteolisis/efectos de los fármacos , Células RAW 264.7 , RNA-Seq , Virus Sendai/inmunología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Vesiculovirus/inmunología , Virosis/tratamiento farmacológico , Virosis/virología , Arrestina beta 2/agonistas , Arrestina beta 2/genéticaRESUMEN
Drug resistance and immune escape of tumor cells severely compromise the treatment efficiency of hepatocellular carcinoma (HCC). Long noncoding RNA KCNQ1 overlapping transcript 1 (lncRNA KCNQ1OT1) has been shown to be involved in drug resistance in several cancers. The aim of the present study was to investigate the role of KCNQ1OT1 in sorafenib resistance and immune escape of HCC cells. Reverse transcriptionquantitative PCR analysis, western blotting and immunohistochemistry were performed to detect the expression of KCNQ1OT1, miR506 and programmed deathligand1 (PDL1). Cell Counting Kit8 assay, flow cytometry and Transwell assays were used to evaluate IC50 value, cell apoptosis and metastasis. ELISA was performed to detect the secretion of cytokines. Dualluciferase reporter assay was conducted to verify the targeting relationships between miR506 and KCNQ1OT1 or PDL1. KCNQ1OT1 and PDL1 were found to be upregulated and miR506 was downregulated in sorafenibresistant HCC tissues and cells. Furthermore, KCNQ1OT1 knockdown reduced the IC50 value of sorafenib, suppressed cell metastasis and promoted apoptosis in sorafenibresistant HCC cells. Moreover, KCNQ1OT1 knockdown changed the tumor microenvironment and Tcell apoptosis in a sorafenibresistant HCC/Tcell coculture model. In addition, it was demonstrated that KCNQ1OT1 functioned as a competing endogenous RNA of miR506 and increased PDL1 expression in sorafenibresistant HCC cells. miR506 inhibition abolished the effects of KCNQ1OT1 knockdown on sorafenib sensitivity, tumor growth, the tumor microenvironment and Tcell apoptosis. In conclusion, KCNQ1OT1 knockdown inhibited sorafenib resistance and PDL1mediated immune escape by sponging miR506 in sorafenibresistant HCC cells.
Asunto(s)
Antígeno B7-H1/metabolismo , Carcinoma Hepatocelular/genética , Resistencia a Antineoplásicos , Evasión Inmune , Neoplasias Hepáticas/genética , MicroARNs/metabolismo , Sorafenib/uso terapéutico , Apoptosis/efectos de los fármacos , Apoptosis/genética , Secuencia de Bases , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Movimiento Celular/genética , Citocinas/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Evasión Inmune/efectos de los fármacos , Evasión Inmune/genética , MicroARNs/genética , Modelos Biológicos , Invasividad Neoplásica , Canales de Potasio con Entrada de Voltaje/metabolismo , Sorafenib/farmacología , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo , Microambiente Tumoral/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genéticaRESUMEN
PURPOSE OF REVIEW: Symptomatic cerebrospinal fluid (CSF) HIV escape defines the presence of neurological disease in combination antiretroviral therapy (cART)-treated persons due to HIV replication in CSF despite systemic suppression or to higher viral replication in CSF than in plasma. The aim was to search for cases of recurrent symptomatic CSF escape and to define their characteristics. RECENT FINDINGS: By review of the literature, we identified symptomatic CSF escape relapses in three patients who had shown clinical remission of a first escape episode following cART optimization. By examination of our cohort of 21 patients with symptomatic CSF escape, we identified five additional patients. In the latter, viral escape relapsed over a median follow-up of 108 months because of low adherence or upon treatment simplification of a previously optimized regimen. cART reoptimization based on resistance profile and potential drug neuropenetration and efficacy led to relapse resolution with no further episodes after a median follow-up of 50 months from relapse. The observation that CSF escape may relapse highlights the importance of long-term neuro-suppressive regimens after a first episode and supports the role of the brain as a reservoir for HIV.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Líquido Cefalorraquídeo/virología , Infecciones por VIH/líquido cefalorraquídeo , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , VIH-1/inmunología , Adulto , Enfermedad Crónica , Femenino , Infecciones por VIH/patología , Humanos , Evasión Inmune/efectos de los fármacos , Evasión Inmune/inmunología , Masculino , ARN Viral/sangre , Recurrencia , Carga Viral/efectos de los fármacos , Replicación ViralRESUMEN
The outbreak of coronavirus disease 2019 (COVID-19) and pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a major concern globally. As of 14 April 2020, more than 1.9 million COVID-19 cases have been reported in 185 countries. Some patients with COVID-19 develop severe clinical manifestations, while others show mild symptoms, suggesting that dysregulation of the host immune response contributes to disease progression and severity. In this review, we have summarized and discussed recent immunological studies focusing on the response of the host immune system and the immunopathology of SARS-CoV-2 infection as well as immunotherapeutic strategies for COVID-19. Immune evasion by SARS-CoV-2, functional exhaustion of lymphocytes, and cytokine storm have been discussed as part of immunopathology mechanisms in SARS-CoV-2 infection. Some potential immunotherapeutic strategies to control the progression of COVID-19, such as passive antibody therapy and use of interferon αß and IL-6 receptor (IL-6R) inhibitor, have also been discussed. This may help us to understand the immune status of patients with COVID-19, particularly those with severe clinical presentation, and form a basis for further immunotherapeutic investigations.