Hepatic macrophages in liver homeostasis and diseases-diversity, plasticity and therapeutic opportunities

Cellular and Molecular Immunology, Journal Year: 2020, Volume and Issue: 18(1), P. 45 - 56

Published: Oct. 12, 2020

Language: Английский

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IMbrave 050: A Phase III Trial of Atezolizumab Plus Bevacizumab in High-Risk Hepatocellular Carcinoma after Curative Resection or Ablation

Future Oncology, Journal Year: 2020, Volume and Issue: 16(15), P. 975 - 989

Published: April 30, 2020

Hepatocellular carcinoma recurs in 70–80% of cases following potentially curative resection or ablation and the immune component liver microenvironment plays a key role recurrence. Many immunosuppressive mechanisms implicated HCC recurrence are modulated by VEGF and/or checkpoints such as PD-L1. Atezolizumab (PD-L1 inhibitor) plus bevacizumab (VEGF has been shown to significantly improve overall survival, progression-free survival response rate unresectable HCC. Dual PD-L1/VEGF blockade may be effective reducing creating more immune-favorable microenvironment. We describe rationale design IMbrave 050 (NCT04102098), randomized, open-label, Phase III study comparing atezolizumab versus active surveillance patients at high-risk ablation. The primary end point is recurrence-free survival. Clinical Trial Registration: NCT04102098

Language: Английский

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Long noncoding RNA LINC00662 promotes M2 macrophage polarization and hepatocellular carcinoma progression via activating Wnt/β‐catenin signaling

Molecular Oncology, Journal Year: 2019, Volume and Issue: 14(2), P. 462 - 483

Published: Dec. 2, 2019

Tumor‐associated macrophages have important roles in hepatocellular carcinoma (HCC) initiation and progression. Long noncoding RNAs (lncRNAs) also been reported to be involved HCC. In this study, we explored how lncRNA LINC00662 may influence HCC progression through both tumor cell‐dependent macrophage‐dependent mechanisms. was found upregulated HCC, high levels correlated with poor survival of patients. WNT3A expression secretion via competitively binding miR‐15a, miR‐16, miR‐107. Through inducing secretion, activated Wnt/β‐catenin signaling cells an autocrine manner further promoted cell proliferation, cycle, invasion, while repressing apoptosis. addition, acting a paracrine M2 macrophage polarization. Via activating polarization, significantly growth metastasis vivo . Hence, targeting provide novel therapeutic strategy against

Language: Английский

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New insights into the interplay between long non‐coding RNAs and RNA‐binding proteins in cancer

Cancer Communications, Journal Year: 2022, Volume and Issue: 42(2), P. 117 - 140

Published: Jan. 12, 2022

Abstract With the development of proteomics and epigenetics, a large number RNA‐binding proteins (RBPs) have been discovered in recent years, interaction between long non‐coding RNAs (lncRNAs) RBPs has also received increasing attention. It is extremely important to conduct in‐depth research on lncRNA‐RBP network, especially context its role occurrence cancer. Increasing evidence demonstrated that interactions play vital cancer progression; therefore, targeting these could provide new insights for drug discovery. In this review, we discussed how lncRNAs can interact with regulate their localization, modification, stability, activity effects transport, transcription, localization lncRNAs. Moreover, explored regulation influence lncRNAs, RBPs, downstream pathways are related development, such as N6‐methyladenosine (m6A) modification addition, network regulates cell phenotypes, proliferation, apoptosis, metastasis, resistance, immunity, tumor environment, metabolism. Furthermore, summarized therapeutic strategies target network. Although treatments still experimental stage various theories processes being studied, believe may ideas treatment.

Language: Английский

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Recent advances in systemic therapy for hepatocellular carcinoma

Biomarker Research, Journal Year: 2022, Volume and Issue: 10(1)

Published: Jan. 9, 2022

Hepatocellular carcinoma (HCC) is one of the most common and lethal malignant tumors in world. Therapeutic options for advanced HCC are limited. Systemic treatment, especially with conventional cytotoxic drugs, usually ineffective. For more than a decade, sorafenib has been only systemic drug that proven to be clinically effective treating HCC. However, over past three years, rapid progress molecular targeted therapies dramatically changed treatment landscape Immune checkpoint now being incorporated into therapies, their combination therapy emerging as tool enhance immune response. In this review, we summarize development agents immunotherapies

Language: Английский

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PD-1/PD-L1 checkpoint inhibitors in advanced hepatocellular carcinoma immunotherapy

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: Dec. 19, 2022

Hepatocellular carcinoma (HCC) has a high prevalence and mortality rate worldwide. Sorafenib monotherapy been the standard of first-line treatment for advanced HCC long time, but there are still many shortcomings. In recent years, with deepening research on tumor immune microenvironment, researchers have begun to explore new approaches in immunotherapy, introduction checkpoint inhibitors brought fundamental changes HCC. Programmed cell death protein 1 (PD-1) is an molecule that plays important role down-regulating system function promoting tolerance. ligand (PDL-1) involved evasion by binding PD-1, resulting failure treatment. Currently, immunotherapy targeting PD-1/PD-L1 axis achieved unprecedented success HCC, it also faces great challenges, its low remission be solved. For most patients pathway not only limiting factor antitumor immunity, blocking enough stimulate effective response; thus, combination therapy may better option. this study, microenvironment were reviewed clarify feasibility anti-PD-1/PD-L1 therapy, series clinical trials summarized verify safety efficacy newly developed Furthermore, we focused hyperprogressive disease drug resistance gain understanding blockade as promising

Language: Английский

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Cancer associated fibroblast–derived CCL5 promotes hepatocellular carcinoma metastasis through activating HIF1α/ZEB1 axis

Cell Death and Disease, Journal Year: 2022, Volume and Issue: 13(5)

Published: May 20, 2022

Cancer-associated fibroblasts (CAFs) are one of the most enriched components Hepatocellular carcinoma (HCC) microenvironment, which tightly related to metastasis and invasion HCC. We identified a mechanism by CAF-derived chemokine CCL5 enhanced HCC triggering HIF1α/ZEB1 axis. demonstrated that CAFs derived from tissues promoted migration cells facilitated lung NOD/SCID mice. Then antibody array elucidated higher level secreted than paracancerous tissue (PTFs). Mechanistically, we found inhibited ubiquitination degradation hypoxia-inducible factor 1 alpha (HIF1α) binding specific receptors, maintained HIF1α under normoxia, thereby up-regulated downstream gene zinc finger enhancer-binding protein (ZEB1) induced epithelial-mesenchymal transition (EMT), ultimately validating its ability promote And this novel may have association with poor prognosis. Taken together, targeting mediated cascade possibly propose new therapeutic route for

Language: Английский

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Bufalin stimulates antitumor immune response by driving tumor-infiltrating macrophage toward M1 phenotype in hepatocellular carcinoma

Journal for ImmunoTherapy of Cancer, Journal Year: 2022, Volume and Issue: 10(5), P. e004297 - e004297

Published: May 1, 2022

Background Immunotherapy for hepatocellular carcinoma (HCC) exhibits limited clinical efficacy due to immunosuppressive tumor microenvironment (TME). Tumor-infiltrating macrophages (TIMs) account the major component in TME, and dominance of M2 phenotype over M1 TIMs plays pivotal role sustaining character. We thus investigate effect bufalin on promoting polarization toward improve HCC immunotherapy. Methods The impact evoking antitumor immune response was evaluated immunocompetent mouse model. expression profiling macrophage-associated genes, surface markers cytokines treatment vitro vivo were detected using flow cytometry, immunofluorescence, western blot analysis, ELISA RT-qPCR. Cell signaling involved macrophage identified via analysis gene sequencing, bufalin-governed target explored by immunoprecipitation, gain-and-loss response. combination antiprogrammed cell death protein 1 (anti-PD-1) antibody also assessed orthotopic Results In this study, we showed that can function as an modulator governs from tumor-promoting tumor-inhibitory M1, which induces suppression through activation effector T Mechanistically, inhibits overexpression p50 nuclear factor kappa B (NF-κB) factor, leading predominance p65-p50 heterodimers homodimers nuclei. accumulation activates NF-κB signaling, is responsible production immunostimulatory cytokines, resulting Moreover, enhances activity anti-PD-1 antibody, exerts synergistic suppression. Conclusions These data expound a novel mechanism bufalin, facilitate exploitation new potential macrophage-based immunotherapeutic modality.

Language: Английский

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ALKBH5/MAP3K8 axis regulates PD-L1+ macrophage infiltration and promotes hepatocellular carcinoma progression

International Journal of Biological Sciences, Journal Year: 2022, Volume and Issue: 18(13), P. 5001 - 5018

Published: Jan. 1, 2022

Hepatocellular carcinoma is one of the most common malignant tumors.M6A a novel epigenetic modification that have been emerged as vital regulators for progression HCC.However, regulatory role, clinical significance and details modification, such impact on local tumor environment, remain largely unclear.Our study showed ALKBH5 was highly expressed in HCC high expression predicted worse prognosis patients.Prediction function by tissue samples single cell sequencing Gene Set Variation Analysis.Primary CD3 + T lymphocytes bone marrow-derived macrophages were used to evaluate effect immune microenvironment.The results indicated promote proliferation, metastasis PD-L1+macrophage recruitment.Mechanistically regulates MAP3K8 m6A dependent manner which mediates proliferation cells.ALKBH5 also promotes activation JNK ERK pathways through upregulating MAP3K8, thus regulating IL-8 promoting macrophage recruitment.Taken together, these data show growth, recruitment ALKBH5/MAP3K8 axis it may serve potential diagnostic marker target treatment patients.

Language: Английский

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Decoding the spatiotemporal heterogeneity of tumor-associated macrophages

Molecular Cancer, Journal Year: 2024, Volume and Issue: 23(1)

Published: July 27, 2024

Abstract Tumor-associated macrophages (TAMs) are pivotal in cancer progression, influencing tumor growth, angiogenesis, and immune evasion. This review explores the spatial temporal heterogeneity of TAMs within microenvironment (TME), highlighting their diverse subtypes, origins, functions. Advanced technologies such as single-cell sequencing multi-omics have elucidated intricate interactions between other TME components, revealing mechanisms behind recruitment, polarization, distribution. Key findings demonstrate that support vascularization, promote epithelial-mesenchymal transition (EMT), modulate extracellular matrix (ECM) remodeling, etc., thereby enhancing invasiveness metastasis. Understanding these complex dynamics offers new therapeutic targets for disrupting TAM-mediated pathways overcoming drug resistance. underscores potential targeting to develop innovative therapies, emphasizing need further research into characteristics functional roles TME.

Language: Английский

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