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1.
Medicine (Baltimore) ; 100(12): e25234, 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33761715

RESUMO

ABSTRACT: This study investigated the expression change, prognostic values, and potential regulatory mechanisms of mortality factor on chromosome 4 (MORF4)-related gene-binding protein (MRGBP) in hepatocellular carcinoma (HCC).MRGBP expression and clinical data from The Cancer Genome Atlas were used to evaluate the associations between MRGBP expression and clinicopathological characteristics. Kaplan-Meier and Cox regression analyses were performed to assess the factors contributing to prognosis. Gene set enrichment analysis (GSEA) was used to identify pathways associated with MRGBP expression. Single-sample gene set enrichment analysis (ssGSEA) was used to comprehensively analyze the relative immune infiltration levels.High MRGBP expression was significantly associated with a higher T stage, pathologic stage, histologic grade, vascular invasion, tumor protein p53 status, and worse overall survival. MRGBP exhibited high diagnostic accuracy with an area under the receiver operating characteristic curve value of 0.980. GSEA revealed the enrichment of pathways related to tumorigenesis in the MRGBP high-expression phenotype, such as cell cycle and DNA replication pathways. ssGSEA revealed that MRGBP expression was significantly correlated with 15 types of immune cell infiltration levels. The Wilcoxon rank sum test revealed significantly high T helper (Th), T follicular helper, CD56 bright natural killer, and Th2 cell enrichment scores in the high MRGBP expression group and significantly low neutrophil, Th17, dendritic cell (DC), gamma delta T, cytotoxic cell, regulatory T cell, plasmacytoid DC, and immature DC enrichment scores.MRGBP may be a novel prognostic biomarker and a therapeutic target correlated with immune infiltrates in HCC.


Assuntos
Carcinoma Hepatocelular , Histona Acetiltransferases , Neoplasias Hepáticas , Fígado , Proteínas Nucleares , Biomarcadores Tumorais/análise , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Biologia Computacional/métodos , Feminino , Regulação Neoplásica da Expressão Gênica , Histona Acetiltransferases/análise , Histona Acetiltransferases/genética , Humanos , Estimativa de Kaplan-Meier , Fígado/imunologia , Fígado/patologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica , Estadiamento de Neoplasias , Proteínas Nucleares/análise , Proteínas Nucleares/genética , Prognóstico
2.
Int J Nanomedicine ; 16: 1553-1564, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33658783

RESUMO

Purpose: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Most current therapeutic strategies primarily include localized treatment, lacking effective systemic strategies. Meanwhile, recent studies have suggested that RNA vaccines can effectively activate antigen-presenting cells (APCs) and lymphocytes to produce a strong systemic immune response and inhibit tumor growth. However, tumor vaccines loaded with a single tumor antigen may induce immunosuppression and immune evasion, while identifying tumor-specific antigens can require expensive and laborious procedures. Therefore, the use of whole tumor cell antigens are currently considered to be promising, potentially effective, methods. Previously, we developed a targeted liposome-polycation-DNA (LPD) complex nanoparticle that possess a small size, high RNA encapsulation efficiency, and superior serum stability. These particles were found to successfully deliver RNA to tumor sites. In the current study, we encapsulated total tumor-derived RNA in lipid nanoparticles (LNPs) to target dendritic cells (DCs) to incite expeditious and robust anti-tumor immunity. Methods: Total tumor-derived RNA was extracted from liver cancer cells (Hepa1-6 cells). LNPs loaded with tumor RNA were then prepared thin-film hydration method. The ability of RNA LNPs to induce DC maturation, cytotoxicity, and anti-tumor activity, was investigated in vitro and in vivo. Results: The average particle size of LNPs and RNA LNPs was 102.22 ± 4.05 nm and 209.68 ± 6.14 nm, respectively, while the zeta potential was 29.97 ± 0.61 mV and 42.03 ± 0.42 mV, respectively. Both LNPs and RNA LNP vaccines exhibited good distribution and stability. In vitro, RNA LNP vaccines were capable of promoting DC maturation and inducing T lymphocytes to kill Hepa1-6 cells. In vivo, RNA LNP vaccines effectively prevent and inhibit HCC growth. Conclusion: RNA LNPs may serve as an effective antigen specific vaccine to induce anti-tumor immunity for HCC.


Assuntos
Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/terapia , Imunoterapia , Lipídeos/química , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/terapia , Nanopartículas/química , RNA Neoplásico/metabolismo , Animais , Vacinas Anticâncer/imunologia , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Humanos , Ativação Linfocitária/imunologia , Masculino , Camundongos Endogâmicos C57BL , Nanopartículas/administração & dosagem , Tamanho da Partícula , Linfócitos T/imunologia
3.
Medicine (Baltimore) ; 100(10): e24683, 2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33725827

RESUMO

BACKGROUND: Increasing evidence has indicated immune-related genes (IRGs) play a key role in the development of hepatocellular carcinoma (HCC). Whereas, there have been no investigations proposing a reliable prognostic signature in terms of IRGs. This study aimed to develop a robust signature based on IRGs in HCC. A total of 597 HCC patients from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases were enrolled in this study. METHODS: The TCGA cohort was utilized for discovery, and the ICGC cohort was utilized for validation. Multiple algorithms were implemented to identify key prognostic IRGs and establish an immune-related risk signature. Bioinformatics analysis and R soft tools were utilized to annotate underlying biological functions. RESULTS: A total of 1416 differentially expressed mRNAs (DEMs) were screened, of which 90 were differentially expressed IRGs (DEIRGs). Using univariate Cox regression analysis, we identified 33 prognostically relevant DEIRGs. Using least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox regression analysis, we extracted 8 optimal DEIRGs to construct a risk signature in the TCGA cohort, and the signature was verified in the ICGC cohort. We also built a nomogram to increase the accuracy of predicting HCC prognosis. By investigating the relationship of the risk score and 8 risk genes from our signature with clinical traits, we found that the aberrant expression of the immune-related risk genes is correlated with the development of HCC. Moreover, the high-risk group was higher than the low-risk group in terms of tumor mutation burden (TMB), immune cell infiltration, and the expression of immune checkpoints (programmed cell death protein 1 [PD-1], programmed cell death ligand 1 [PD-L1], and cytotoxic T-lymphocyte-related protein 4 [CTLA-4]), and functional enrichment analysis indicated the signature enriched an intensive immune phenotype. CONCLUSION: This study developed a robust immune-related risk signature and built a predictive nomogram that reliably predict overall survival in HCC, which may be helpful for clinical management and personalized immunotherapy decisions.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/imunologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/imunologia , Regulação Neoplásica da Expressão Gênica , Humanos , Mutação , Nomogramas , Prognóstico , RNA Mensageiro/genética , Medição de Risco/métodos , Carga Tumoral/genética
4.
Nat Commun ; 12(1): 1455, 2021 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-33674593

RESUMO

T-cell exhaustion denotes a hypofunctional state of T lymphocytes commonly found in cancer, but how tumor cells drive T-cell exhaustion remains elusive. Here, we find T-cell exhaustion linked to overall survival in 675 hepatocellular carcinoma (HCC) patients with diverse ethnicities and etiologies. Integrative omics analyses uncover oncogenic reprograming of HCC methionine recycling with elevated 5-methylthioadenosine (MTA) and S-adenosylmethionine (SAM) to be tightly linked to T-cell exhaustion. SAM and MTA induce T-cell dysfunction in vitro. Moreover, CRISPR-Cas9-mediated deletion of MAT2A, a key SAM producing enzyme, results in an inhibition of T-cell dysfunction and HCC growth in mice. Thus, reprogramming of tumor methionine metabolism may be a viable therapeutic strategy to improve HCC immunity.


Assuntos
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Metionina/metabolismo , Linfócitos T/metabolismo , Animais , Biomarcadores Tumorais , Linfócitos T CD8-Positivos , Sistemas CRISPR-Cas , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Inativação de Genes , Humanos , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/imunologia , Metionina Adenosiltransferase/sangue , Metionina Adenosiltransferase/genética , Metionina Adenosiltransferase/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , S-Adenosilmetionina/metabolismo , Transcriptoma
5.
Medicine (Baltimore) ; 100(3): e24153, 2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33546030

RESUMO

BACKGROUND: Previous studies have reported that lymphocyte-to-monocyte ratio (LMR) had novel prognostic value in hepatocellular carcinoma (HCC). The purpose of this meta-analysis was to synthetically evaluate the prognostic role of preoperative LMR in HCC patients following curative resection. METHODS: Eligible studies were acquired through searching Pubmed, Web of Science, Cochrane Library and EMbase update to September 2019. Merged hazard ratios (HRs) and 95% confidence intervals (CIs) were applied as effect sizes. RESULTS: A total of ten studies containing 4,092 patients following liver resection were enrolled in this meta-analysis. The pooled results demonstrated that preoperative elevated LMR indicated superior survival outcome (HR: 0.58, 95% CI: 0.34-0.96, P = .035) and recurrence-free survival (RFS)/disease-free survival/time to recurrence (HR = 0.76, 95% CI: 0.58-0.98, P = .034). The significant prognostic role of preoperative LMR was detected in the subgroup of all publication year, country of origin, sample sizes <300, TNM stage of I-IV and LMR cut-off value ≤4. Furthermore, high LMR was significantly associated with male, high AFP, large tumor size, incomplete tumor capsule, advanced TNM stage and BCLC stage, and presence of PVTT. CONCLUSION: Elevated preoperative LMR indicated superior survival outcome in HCC patients following curative resection, and might serve as a novel prognostic biomarker.


Assuntos
Carcinoma Hepatocelular/imunologia , Neoplasias Hepáticas/imunologia , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Hepatectomia , Humanos , Fígado/patologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Contagem de Linfócitos
6.
Nat Commun ; 12(1): 227, 2021 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-33431814

RESUMO

The clinical relevance of immune landscape intratumoural heterogeneity (immune-ITH) and its role in tumour evolution remain largely unexplored. Here, we uncover significant spatial and phenotypic immune-ITH from multiple tumour sectors and decipher its relationship with tumour evolution and disease progression in hepatocellular carcinomas (HCC). Immune-ITH is associated with tumour transcriptomic-ITH, mutational burden and distinct immune microenvironments. Tumours with low immune-ITH experience higher immunoselective pressure and escape via loss of heterozygosity in human leukocyte antigens and immunoediting. Instead, the tumours with high immune-ITH evolve to a more immunosuppressive/exhausted microenvironment. This gradient of immune pressure along with immune-ITH represents a hallmark of tumour evolution, which is closely linked to the transcriptome-immune networks contributing to disease progression and immune inactivation. Remarkably, high immune-ITH and its transcriptomic signature are predictive for worse clinical outcome in HCC patients. This in-depth investigation of ITH provides evidence on tumour-immune co-evolution along HCC progression.


Assuntos
Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Progressão da Doença , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , DNA/genética , Edição de Genes , Redes Reguladoras de Genes , Humanos , Leucócitos Mononucleares/metabolismo , Filogenia , Prognóstico , RNA/genética , Análise de Sobrevida , Transcriptoma/genética , Resultado do Tratamento , Microambiente Tumoral/imunologia
7.
Nat Med ; 27(1): 152-164, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33398162

RESUMO

Metastasis is the primary cause of cancer mortality, and cancer frequently metastasizes to the liver. It is not clear whether liver immune tolerance mechanisms contribute to cancer outcomes. We report that liver metastases diminish immunotherapy efficacy systemically in patients and preclinical models. Patients with liver metastases derive limited benefit from immunotherapy independent of other established biomarkers of response. In multiple mouse models, we show that liver metastases siphon activated CD8+ T cells from systemic circulation. Within the liver, activated antigen-specific Fas+CD8+ T cells undergo apoptosis following their interaction with FasL+CD11b+F4/80+ monocyte-derived macrophages. Consequently, liver metastases create a systemic immune desert in preclinical models. Similarly, patients with liver metastases have reduced peripheral T cell numbers and diminished tumoral T cell diversity and function. In preclinical models, liver-directed radiotherapy eliminates immunosuppressive hepatic macrophages, increases hepatic T cell survival and reduces hepatic siphoning of T cells. Thus, liver metastases co-opt host peripheral tolerance mechanisms to cause acquired immunotherapy resistance through CD8+ T cell deletion, and the combination of liver-directed radiotherapy and immunotherapy could promote systemic antitumor immunity.


Assuntos
Imunoterapia , Neoplasias Hepáticas Experimentais/secundário , Neoplasias Hepáticas Experimentais/terapia , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Macrófagos/imunologia , Linfócitos T/imunologia , Animais , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/secundário , Carcinoma Pulmonar de Células não Pequenas/terapia , Linhagem Celular Tumoral , Estudos de Coortes , Terapia Combinada , Feminino , Humanos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas Experimentais/imunologia , Ativação Linfocitária , Masculino , Melanoma/imunologia , Melanoma/secundário , Melanoma/terapia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Radioterapia Adjuvante , Linfócitos T/classificação , Linfócitos T/patologia , Falha de Tratamento , Resultado do Tratamento , Microambiente Tumoral/imunologia , Microambiente Tumoral/efeitos da radiação
8.
Mol Immunol ; 131: 13-22, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33453658

RESUMO

Glypican-3 (GPC3) is a highly specific diagnostic marker for hepatocellular carcinoma (HCC) diagnosis and a potential target in HCC therapy. Nanobodies (Nbs) are promising targeting molecules due to their high specificity and strong affinities to antigens, high stability, deep tissue penetration, and low immunogenicity. In this study, we isolated Nbs against GPC3 marker protein from a synthetic Nb library by phage display. To characterize these Nbs, we performed enzyme-linked immunosorbent assay, immunoprecipitation assay, and immunofluorescent assay to demonstrate that four (G8, G10, G11, and G64) of them bound specifically to recombinant as well as endogenous GPC3, and epitope mapping showed they all bound to N-terminal subunit of GPC3. Furthermore, we found that G64 exhibited high protein stability and GPC3 binding activity in serum at 37℃ for at least 96 h, and G64 did not affect the proliferation of HEK293T cells and HCC cell line HepG2. Our study provides four anti-GPC3 Nbs as promising targeting molecules for HCC diagnostic and therapeutic drugs.


Assuntos
Biomarcadores Tumorais/imunologia , Carcinoma Hepatocelular/imunologia , Glipicanas/imunologia , Neoplasias Hepáticas/imunologia , Anticorpos de Domínio Único/imunologia , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Células HEK293 , Células Hep G2 , Humanos
9.
Nat Commun ; 12(1): 174, 2021 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-33420030

RESUMO

The immunosuppressive microenvironment that is shaped by hepatic metastatic pancreatic ductal adenocarcinoma (PDAC) is essential for tumor cell evasion of immune destruction. Neutrophils are important components of the metastatic tumor microenvironment and exhibit heterogeneity. However, the specific phenotypes, functions and regulatory mechanisms of neutrophils in PDAC liver metastases remain unknown. Here, we show that a subset of P2RX1-negative neutrophils accumulate in clinical and murine PDAC liver metastases. RNA sequencing of murine PDAC liver metastasis-infiltrated neutrophils show that P2RX1-deficient neutrophils express increased levels of immunosuppressive molecules, including PD-L1, and have enhanced mitochondrial metabolism. Mechanistically, the transcription factor Nrf2 is upregulated in P2RX1-deficient neutrophils and associated with PD-L1 expression and metabolic reprogramming. An anti-PD-1 neutralizing antibody is sufficient to compromise the immunosuppressive effects of P2RX1-deficient neutrophils on OVA-activated OT1 CD8+ T cells. Therefore, our study uncovers a mechanism by which metastatic PDAC tumors evade antitumor immunity by accumulating a subset of immunosuppressive P2RX1-negative neutrophils.


Assuntos
Imunossupressores/farmacologia , Neoplasias Hepáticas/imunologia , Neutrófilos/metabolismo , Neoplasias Pancreáticas/imunologia , Microambiente Tumoral/imunologia , Animais , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/imunologia , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/patologia , Modelos Animais de Doenças , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Knockout , Mitocôndrias/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Pâncreas/imunologia , Pâncreas/patologia , Neoplasias Pancreáticas/patologia , Receptores Purinérgicos P2X/genética , Receptores Purinérgicos P2X/imunologia , Receptores Purinérgicos P2X/metabolismo
10.
Nat Commun ; 12(1): 187, 2021 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-33420074

RESUMO

The gut microbiota is reported to modulate the immune response in hepatocellular carcinoma (HCC). Here, we employ metagenomic and metabolomic studies to characterise gut microbiota in patients with non-alcoholic fatty liver disease (NAFLD) related cirrhosis, with or without HCC, and evaluate its effect on the peripheral immune response in an ex vivo model. We find that dysbiosis characterises the microbiota of patients with NAFLD-cirrhosis, with compositional and functional shifts occurring with HCC development. Gene function of the microbiota in NAFLD-HCC supports short chain fatty acid production, and this is confirmed by metabolomic studies. Ex vivo studies show that bacterial extracts from the NAFLD-HCC microbiota, but not from the control groups, elicit a T cell immunosuppressive phenotype, characterised by expansion of regulatory T cells and attenuation of CD8 + T cells. Our study suggest that the gut microbiota in NAFLD-HCC is characterised by a distinctive microbiome/metabolomic profile, and can modulate the peripheral immune response.


Assuntos
Carcinoma Hepatocelular/imunologia , Microbioma Gastrointestinal/imunologia , Microbioma Gastrointestinal/fisiologia , Imunidade , Neoplasias Hepáticas/imunologia , Hepatopatia Gordurosa não Alcoólica/imunologia , Idoso , Bactérias/genética , Linfócitos T CD8-Positivos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Citocinas , Fibras na Dieta , Disbiose/imunologia , Ácidos Graxos Voláteis/sangue , Ácidos Graxos Voláteis/metabolismo , Fezes/química , Feminino , Humanos , Fígado/patologia , Cirrose Hepática , Neoplasias Hepáticas/patologia , Masculino , Metabolômica , Metagenômica , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Fenótipo
11.
Phytomedicine ; 80: 153356, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33039729

RESUMO

BACKGROUND: Using natural polysaccharides from Traditional Chinese Medicine as nanodrug delivery systems have considerable potential for tumor diagnostics and therapeutics. PURPOSE: On the basis of targeted therapy and combining the advantages of natural polysaccharides (angelica polysaccharide, APS) and natural Chinese medicine (curcumin, Cur) to design functionalized nanoparticles to improve the therapeutic through cell membrane encapsulation and immunotherapy. STUDY DESIGN AND METHODS: Cur-loaded, glycyrrhetic acid (GA)-APS-disulfide bond (DTA)-Cur nanomicelle (GACS-Cur), which were prepared by the dialysis method. GACS-Cur was encapsulated with the membranes from red blood cells (RBCm) termed GACS-Cur@RBCm, which were prepared by the principle of extrusion using a miniature extruder. The developed formulations were subjected to various in vitro and in vivo evaluation tests. RESULTS: The resulting APS nanocarriers supported a favorable drug-loading capacity, biocompatibility, and enhanced synergistic anti-hepatoma effects both in vitro and in vivo. After administration in mice, in vivo imaging results showed that the GACS-Cur and RBCm-coated groups had an obvious stronger tumor tissue targeting ability than the control treatment groups. Additionally, the immunomodulatory effect increased IL-12, TNF-α and IFN-γ expression and CD8+ T cell infiltration (1.9-fold) than that of the saline group. Notably, in comparison with hyaluronic acid (HA) nanocarriers, APS nanocarriers possess higher anti-hepatoma efficiency and targeting capabilities and, thus, should be further studied for a wide range of anti-cancer applications. CONCLUSION: Our data demonstrated that APS nanocarriers encapsulated with erythrocyte membrane mighty be a promising clinical method in the development of efficacy, safety and targeting of liver cancer therapy.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Curcumina/administração & dosagem , Neoplasias Hepáticas/tratamento farmacológico , Polissacarídeos/química , Angelica/química , Animais , Antineoplásicos Fitogênicos/imunologia , Antineoplásicos Fitogênicos/farmacologia , Biomimética , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Curcumina/farmacologia , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Feminino , Células Hep G2 , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/farmacologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Camundongos Nus , Micelas , Nanopartículas/administração & dosagem , Nanopartículas/química , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Int J Mol Sci ; 21(24)2020 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-33371259

RESUMO

The lysyl oxidase (LOX) family members are secreted copper-dependent amine oxidases, comprised of five paralogues: LOX and LOX-like l-4 (LOXL1-4), which are characterized by catalytic activity contributing to the remodeling of the cross-linking of the structural extracellular matrix (ECM). ECM remodeling plays a key role in the angiogenesis surrounding tumors, whereby a corrupt tumor microenvironment (TME) takes shape. Primary liver cancer includes hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), ranked as the seventh most common cancer globally, with limited therapeutic options for advanced stages. In recent years, a growing body of evidence has revealed the key roles of LOX family members in the pathogenesis of liver cancer and the shaping of TME, indicating their notable potential as therapeutic targets. We herein review the clinical value and novel biological roles of LOX family members in tumor progression and the TME of liver cancers. In addition, we highlight recent insights into their mechanisms and their potential involvement in the development of target therapy for liver cancer.


Assuntos
Neoplasias Hepáticas/patologia , Proteína-Lisina 6-Oxidase/metabolismo , Microambiente Tumoral/imunologia , Animais , Progressão da Doença , Humanos , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/imunologia , Proteína-Lisina 6-Oxidase/classificação
13.
Int J Mol Sci ; 21(24)2020 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-33352757

RESUMO

Tumor-associated (TA) autoantibodies have been identified at the early tumor stage before developing clinical symptoms, which holds hope for early cancer diagnosis. We identified a TA autoantibody from HBx-transgenic (HBx-tg) hepatocellular carcinoma (HCC) model mouse, characterized its target antigen, and examined its relationship to human HCC. The mimotopes corresponding to the antigenic epitope of TA autoantibody were screened from a random cyclic peptide library and used for the detection of serum TA autoantibody. The target antigen of the TA autoantibody was identified as an oncogenic bi-functional purine biosynthesis protein, ATIC. It was upregulated in liver cancer tissues of HBx-tg mouse as well as human HCC tissues. Over-expressed ATIC was also secreted extracellularly via the cancer-derived exosomes, which might cause auto-immune responses. The cyclic peptide mimotope with a high affinity to anti-ATIC autoantibody, CLPSWFHRC, distinguishes between serum samples from HCC patients and healthy subjects with 70.83% sensitivity, 90.68% specificity (AUC = 0.87). However, the recombinant human ATIC protein showed a low affinity to anti-ATIC autoantibody, which may be incompatible as a capture antigen for serum TA autoantibody. This study indicates that anti-ATIC autoantibody can be a potential HCC-associated serum biomarker and suggests that autoantibody biomarker's efficiency can be improved by using antigenic mimicry to native antigens present in vivo.


Assuntos
Autoanticorpos/sangue , Biomarcadores Tumorais/sangue , Carcinoma Hepatocelular/diagnóstico , Epitopos/imunologia , Hidroximetil e Formil Transferases/imunologia , Neoplasias Hepáticas/diagnóstico , Complexos Multienzimáticos/imunologia , Nucleotídeo Desaminases/imunologia , Peptídeos Cíclicos/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Autoanticorpos/imunologia , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/imunologia , Feminino , Humanos , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/imunologia , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Biblioteca de Peptídeos , Prognóstico , Adulto Jovem
14.
J Vasc Interv Radiol ; 31(11): 1729-1738.e1, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33012649

RESUMO

PURPOSE: To assess the safety of locoregional treatment (LRT) combined with nivolumab for intermediate and advanced hepatocellular carcinoma (HCC). MATERIALS AND METHODS: A single-center retrospective review included 29 patients undergoing 41 LRTs-transarterial chemoembolization or yttrium-90 transarterial radioembolization-60 days before or concurrently with nivolumab. Demographic, clinical, and laboratory values and adverse events were reviewed before and after nivolumab initiation and after each LRT. Treatment response and time to progression were assessed using Modified Response Evaluation Criteria in Solid Tumors. Clinical events, including nivolumab termination, death, and time of last follow-up, were assessed. RESULTS: Over a median nivolumab course of 8.1 months (range, 1.0-30) with a median of 14.2 2-week cycles (range, 1-53), predominantly Child-Pugh A (22/29) patients-12 Barcelona Clinic Liver Cancer (BCLC) B and 17 BCLC C-underwent 20 transarterial chemoembolization and 21 transarterial radioembolization LRTs at a median of 67 days (range, 48-609) after nivolumab initiation. Ten patients underwent multiple LRTs. During a median follow-up of 11.5 months (range, 1.8-35.1), no grade III/IV adverse events attributable to nivolumab were observed. There were five instances of grade III/IV hypoalbuminemia or hyperbilirubinemia within 3 months after LRT. There were no nivolumab-related deaths, and 30-day mortality after LRT was 0%. CONCLUSIONS: LRTs performed concurrently with nivolumab immunotherapy demonstrate an acceptable safety profile in patients with intermediate and advanced HCC.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Hepatocelular/terapia , Embolização Terapêutica , Neoplasias Hepáticas/terapia , Nivolumabe/uso terapêutico , Adulto , Idoso , Antineoplásicos Imunológicos/efeitos adversos , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/mortalidade , Quimioembolização Terapêutica , Quimioterapia Adjuvante , Progressão da Doença , Embolização Terapêutica/efeitos adversos , Embolização Terapêutica/mortalidade , Feminino , Humanos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Nivolumabe/efeitos adversos , Compostos Radiofarmacêuticos/administração & dosagem , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Radioisótopos de Ítrio/administração & dosagem
15.
Medicine (Baltimore) ; 99(41): e22568, 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33031305

RESUMO

The effect of intraoperative blood transfusion on the immune function and prognosis of hepatocellular carcinoma (HCC) has not been fully investigated. The aim of this study was to evaluate the effects of intraoperative autologous blood transfusion and allogeneic blood transfusion on immune function and prognosis in surgically treated HCC patients. One hundred fourteen primary hepatic carcinoma patients who would undergo selective operations were divided into two groups, 35 patients in the experimental group received intraoperative autologous blood transfusion and 79 patients in the control group received allogeneic blood transfusion. The amount of serum T lymphocyte subsets, natural killer (NK) cells and immunoglobulin before and after operation, as well as the recurrence-free survival (RFS) were compared. Results shown that, there was no significant difference in the level of immunocytes and immunoglobulin between the two groups before treatment (P > .05). At 1 day after surgery, there were significant differences in T lymphocyte, NK cells and immunoglobulin levels before and after transfusion. CD3+, CD4+, CD4+/CD8+, and NK cells in autologous transfusion group were significantly higher than those in allogeneic transfusion group (P < .05); the level of IgG, IgM, and IgA in allogeneic transfusion group were significantly lower than those before operation (P < .05), the level of IgG, IgM, and IgA in autologous transfusion group did not significantly fluctuate, and significantly higher than those of allogeneic transfusion group (P < .05). At 5 days after surgery, all indexes of autologous transfusion group recovered to the preoperative level, the levels of CD3+, CD4+, CD4+/CD8+, NK cells, IgG, IgM, and IgA were significantly higher than those of allogeneic transfusion group (P < .05). The follow-up results showed that the RFS of autologous transfusion group was significantly higher than that of allogeneic transfusion group (P < .05). In conclusion, compared with allogeneic blood transfusion, intraoperative autologous blood transfusion possessed less impact on immune function, it may even improve immune function and RFS in HCC patients after surgery. Therefore, HCC patients should be recommended to receive autologous blood transfusion instead of allogeneic blood transfusion when they need blood transfusion during the perioperative period.


Assuntos
Transfusão de Sangue , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/cirurgia , Cuidados Intraoperatórios , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/cirurgia , Transfusão de Sangue Autóloga , Feminino , Humanos , Imunoglobulinas/imunologia , Células Matadoras Naturais/imunologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Subpopulações de Linfócitos T/imunologia
16.
Anticancer Res ; 40(11): 6367-6373, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33109574

RESUMO

BACKGROUND/AIM: The presence of TLS (tertiary lymphoid structures) is detectable in the microenvironment of human cancers and linked to better patient outcomes. The role of TLS in colorectal cancer liver metastases (CRCLM) is unclear. PATIENTS AND METHODS: Medical records of patients with CRCLM were reviewed (n=33) and corresponding tissue samples (n=21) were obtained. Whole slide imaging analyses on immunohistochemical staining of immune cell infiltrates and TLS were correlated to clinical outcomes (including chemotherapy response) and other parameters. RESULTS: Neither the size (p=0.6) nor the quantity (p=0.47) of TLS was associated with the clinical course. When considering spatial differences, TLS in the invasive margin (IM) were associated with progression-free survival (p=0.03), while TLS in the LM (liver metastasis) were not. Also, TLS in the IM were associated with the presence of CD3+ T cells, which itself was prognostically favorable (p<0.001). CONCLUSION: TLS in the IM are associated with good prognosis in CRCLM, but not chemotherapy response.


Assuntos
Neoplasias Colorretais/patologia , Neoplasias Hepáticas/patologia , Prognóstico , Estruturas Linfoides Terciárias/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Complexo CD3/imunologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/imunologia , Feminino , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/imunologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Intervalo Livre de Progressão , Linfócitos T/imunologia , Linfócitos T/patologia , Estruturas Linfoides Terciárias/diagnóstico por imagem , Estruturas Linfoides Terciárias/imunologia , Microambiente Tumoral/imunologia
17.
Life Sci ; 260: 118476, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32971102

RESUMO

Hepatocellular carcinoma (HCC) is the sixth most common malignancy and has the third highest mortality rate among all tumors. Previous studies found that phosphatidylinositol glycan anchor biosynthesis class U (PIGU) was highly expressed in hepatocellular carcinoma (HCC), while the function of PIGU in HCC remains unknown. Here, we deeply investigated this issue. The expression levels of PIGU in HCC cells were measured by Western blotting. The functions of PIGU in HCC cells were assessed in vitro, followed by assessing the nuclear factor-kappa B (NF-κB) pathway-related protein levels. The xenograft mouse models were conducted to investigate the effects of PIGU in vivo. Moreover, the effects of PIGU downregulation on natural killer (NK)-92 cell-mediated cell killing were detected. The results showed that PIGU was highly expressed in HCC cells compared with normal liver cells. Functional studies showed that PIGU promoted viability, cell cycle progression, migration, and invasion and suppressed apoptosis in HCC cells. Mechanism studies indicated that PIGU silencing blocked the NF-κB pathway and the blockade of the NF-κB pathway reversed the effects of PIGU overexpression on HCC cell function, including cell viability, migration, invasion, and apoptosis. In vivo studies further verified the effects of PIGU on HCC cell function, and demonstrated that PIGU knockdown suppressed tumorigenesis. Additionally, we proved that PIGU downregulation significantly enhanced the sensitivity of HCC cells to NK-92 cell cytolysis. Collectively, PIGU may promote HCC progression through activating the NF-κB pathway and promoting immune escape, indicating that PIGU may serve as a promising therapeutic target for HCC treatment.


Assuntos
Aciltransferases/metabolismo , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , NF-kappa B/metabolismo , Aciltransferases/genética , Aciltransferases/imunologia , Animais , Apoptose/genética , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidade , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidade , Masculino , Camundongos Nus , Evasão Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Scand J Immunol ; 92(5): e12971, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32892401

RESUMO

With an increase in sedentary lifestyle and dietary over nutrition, obesity has become one of the major public health problems worldwide and is a prevalent predisposing risk factor to non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease in Western developed countries. NAFLD represents a series of diseased states ranging from non-alcoholic fatty liver (NAFL) to steatohepatitis (NASH), which can lead to fibrosis and eventually to cirrhosis and hepatocellular carcinoma. Currently, the only effective treatment to cure end-stage liver disease is liver transplantation. Macrophages have been reported to play a crucial role in the progression of NAFLD, thereby are a potential target for therapy. In this review, we discuss the current knowledge on the role of macrophages and inflammatory signalling pathways associated with obesity and chronic liver inflammation, and their contribution to NAFLD development and progression.


Assuntos
Fígado Gorduroso/imunologia , Cirrose Hepática/imunologia , Macrófagos/imunologia , Hepatopatia Gordurosa não Alcoólica/imunologia , Obesidade/imunologia , Receptores Depuradores/imunologia , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/metabolismo , Progressão da Doença , Fígado Gorduroso/complicações , Fígado Gorduroso/metabolismo , Humanos , Cirrose Hepática/complicações , Cirrose Hepática/metabolismo , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/metabolismo , Macrófagos/metabolismo , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/complicações , Obesidade/metabolismo , Receptores Depuradores/metabolismo
19.
DNA Cell Biol ; 39(10): 1838-1849, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32876480

RESUMO

The breast cancer gene 1 (BRCA1) is a tumor suppressor, and mutations or epigenetic inactivation will increase the risk of breast cancer oncogenesis. The current research aimed to explore the relationship between BRCA1 expression, prognosis, and tumor immunity in hepatocellular carcinoma (HCC). In this study, BRCA1 expression was analyzed via multiple online databases and its association with clinical characteristics, prognosis and genetic alterations was identified using the original The Cancer Genome Atlas-liver hepatocellular carcinoma cohorts. DNA methylation sites and their prognostic values were analyzed using MethSurv. The correlations between BRCA1 and immune infiltration were investigated via Tumor Immune Estimation Resource. As results, BRCA1 was significantly upregulated in tumor tissues in multiple HCC cohorts. Besides, high BRCA1 expression was correlated with race, advanced T stage, clinical stage, poor tumor grade, MSI status, and worse prognosis. Notably, BRCA1 expression was positively correlated with infiltration levels of B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages, and dendritic cells. The current findings imply that BRCA1 is associated with prognosis and immune infiltration, laying foundations for in-depth research on the role of BRCA1 in HCC.


Assuntos
Proteína BRCA1/genética , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Proteína BRCA1/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Movimento Celular , Metilação de DNA , Células Dendríticas/imunologia , Humanos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Linfócitos/imunologia , Macrófagos/imunologia
20.
J Vasc Interv Radiol ; 31(8): 1233-1241, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32741550

RESUMO

PURPOSE: To assess the safety and effectiveness of yttrium-90 radioembolization and checkpoint inhibitor immunotherapy within a short interval for the treatment of unresectable hepatic metastases. MATERIALS AND METHODS: This single-institution retrospective study included 22 patients (12 men; median age, 65 y ± 11) with unresectable hepatic metastases and preserved functional status (Eastern Cooperative Oncology Group performance status 0/1) who received immunotherapy and radioembolization within a 15-month period (median, 63.5 d; interquartile range, 19.7-178.2 d) from February 2013 to March 2018. Primary malignancies were uveal melanoma (12 of 22; 54.5%), soft tissue sarcoma (3; 13.6%), cutaneous melanoma (3; 14%), and others (4; 18.2%). Studies were reviewed to March 2019 to assess Common Terminology Criteria for Adverse Events grade 3/4 toxicities, disease progression, and death. RESULTS: There were no grade 4 toxicities within 6 mo of radioembolization. Grade 3 hepatobiliary toxicities occurred in 3 patients (13.6%) within 6 months, 2 from rapid disease progression and 1 from a biliary stricture. Two patients (9.1%) experienced clinical toxicities, including grade 4 colitis at 6 months and hepatic abscess at 3 months. Median overall survival (OS) from first radioembolization was 20 mo (95% confidence interval [CI], 12.5-27.5 mo), and median OS from first immunotherapy was 23 months (95% CI, 15.9-30.1 mo). Within the uveal melanoma subgroup, the median OS from first radioembolization was 17.0 months (95% CI, 14.2-19.8 mo). Median time to progression was 7.8 months (95% CI, 3.3-12.2 mo), and median progression-free survival was 7.8 mo (95% CI, 3.1-12.4 mo). CONCLUSIONS: Checkpoint immunotherapy around the time of radioembolization is safe, with a low incidence of toxicity independent of primary malignancy.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Embolização Terapêutica , Neoplasias Hepáticas/terapia , Compostos Radiofarmacêuticos/administração & dosagem , Radioisótopos de Ítrio/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/efeitos adversos , Progressão da Doença , Embolização Terapêutica/efeitos adversos , Feminino , Humanos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Segurança do Paciente , Intervalo Livre de Progressão , Compostos Radiofarmacêuticos/efeitos adversos , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Radioisótopos de Ítrio/efeitos adversos
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