Pan-cancer immunogenic death analysis identifies key roles of CXCR3 and CCL18 in hepatocellular carcinoma
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ABSTRACT:
SUBMITTER: Guo J
PROVIDER: S-EPMC10491906 | biostudies-literature | 2023 May
REPOSITORIES: biostudies-literature
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Project description:The treatment and prognosis of liver cancer remain the focus of medical research. Studies have shown that SPP1 and CSF1 play important roles in cell proliferation, invasion, and metastasis. Therefore, this study analyzed the oncogenic and immunologic roles of SPP1 and CSF1 in hepatocellular carcinoma (HCC). We found that the expression levels of SPP1 and CSF1 in HCC were markedly increased and positively correlated. High SPP1 expression was significantly associated with poor OS, DSS, PFS, and RFS. It was not affected by gender, alcohol use, HBV, or race, whereas CSF1 was affected by these factors. Higher expression levels of SPP1 and CSF1 indicated higher levels of immune cell infiltration and a higher immune score with the R software package ESTIMATE. Further analysis revealed that many genes work co-expressed between SPP1 and CSF1 with the LinkedOmics database, which were mainly involved in signal transduction, the integral components of the membrane, protein binding, and osteoclast differentiation. In addition, we screened ten hub genes using cytoHubba, among which the expression of four genes was significantly associated with the prognosis of HCC patients. Finally, we demonstrated the oncogenic and immunologic roles of SPP1 and CSF1 using the vitro experiments. Reducing the expression of either SPP1 or CSF1 could significantly reduce the proliferation of HCC cells and the expression of CSF1, SPP1, and the other four hub genes. This study suggested that SPP1 and CSF1 interact with each other and have the potential to be therapeutic and prognostic targets for HCC.
| S-EPMC10129977 | biostudies-literature
Project description:Some chemotherapeutic agents have been found to enhance the antitumor immunity by inducing immunogenic cell death (ICD). The combination of disulfiram (DSF) and copper (Cu) has demonstrated anti-tumor effects in a range of malignancies including hepatocellular carcinoma (HCC). However, the potential of DSF/Cu as an ICD inducer and whether it could enhance the efficacy of immune checkpoint blockade in HCC remains unknown. Here, we showed that DSF/Cu-treated HCC cells exhibited characteristics of ICD in vitro, such as calreticulin (CRT) exposure, ATP secretion, high mobility group box 1 (HMGB1) release. DSF/Cu treated HCC cells elicited significant immune memory in a vaccination assay. DSF/Cu treatment promoted dendritic cell activation and maturation. The combination of DSF/Cu and CD47 blockade further facilitated DC maturation and subsequently enhanced CD8+ T cell cytotoxicity. Mechanically, DSF/Cu promoted the nuclear accumulation and aggregation of nuclear protein localization protein 4 (NPL4) to inhibit the ubiquitin-proteasome system, thus induced endoplasmic reticulum (ER) stress. Inhibition of NPL4 induced ICD-associated damage-associated molecular patterns. Collectively, our findings demonstrated that DSF/Cu induced ICD-mediated immune activation in HCC and enhanced the efficacy of CD47 blockade.
2022-10-19 | GSE211734 | GEO
Project description:The nonnegligible reason for the poor prognosis of hepatocellular carcinoma (HCC) is resistance to conventional chemotherapy. Immunogenic cell death (ICD) is a rare immunostimulatory form of cell death that can reengage the tumor-specific immune system. ICD can improve the clinical outcomes of chemotherapeutics by promoting a long-term cancer immunity. The discovery of potential ICD inducers is emerging as a promising direction. In the present study, micheliolide (MCL), a natural guaianolide sesquiterpene lactone, was screened out by the virtual screening strategies, identified as an inhibitor of thioredoxin reductase (TrxR) and was evaluated to have high potential to induce ICD. Here, we showed that MCL induced ICD-associated DAMPs (damage-associated molecular patterns, such as CRT exposure, ATP secretion and HMGB1 release). MCL significantly triggered the regression of established tumors in an immunocompetent mouse vaccine model, and induced ICD (DCs maturation, the stimulation of CD4+, and CD8+ T-cells responses) in vivo. Mechanistically, we found that the magnitude of ICD-associated effects induced upon exposure of HCC cells to MCL was dependent on the generation of reactive oxygen species (ROS)-mediated endoplasmic reticulum stress (ERS). In addition, the suppression of ROS normalized MCL-induced ERS, in contrast, the downregulation of TrxR synergized with the ERS driven by MCL. We also systematically detected the H2O2 generation using Hyper7 sensors in HCC cells exposed to MCL. Notably, MCL inhibited the development of HCC organoids. Collectively, our results reveal a potential association between the TrxR inhibitors and ICD, presenting valuable insights into the MCL-activated ICD in HCC cells.
| S-EPMC9168183 | biostudies-literature
Project description:IntroductionCytotoxic agents have shown limited benefits in hepatocellular carcinoma (HCC), mediated in part by the lack of targeting. As cell-penetrating peptides (CPPs) are capable of delivering various biologically active molecules into cells, including protein, peptides, small chemo-drugs, and nucleic acid with or without targeting, we developed T22-PE24, a CXCR4-targeted self-assembling cytotoxic nanotoxin, to effectively induce HCC pyroptosis.MethodsT22 incorporating enhanced green fluorescent protein (EGFP) or PE24 was purified from DE3 bacterial cells and characterized using transmission electron microscopy, the Zetasizer Nano®, and SEC-HPLC. The internalization effect of T22-EGFP was detected by flow cytometry system (FCS) in CXCR4+/LM3(CXCR4-) HCC cells. The CCK8, lactate dehydrogenase (LDH) release, Western blot, and nude mice HCC models were used to estimate the cell viability of T22-PE24. The complete-immunity HCC tumor-bearing mice model was used to assess the immune response of T22-PE24.ResultsThe round shape under transmission electron microscopy, 49.4 nm hydrodynamic diameter, and -33.33 mV zeta potential indicated that T22-PE24 self-assembled into nanoparticles. T22 incorporating EGFP selectively internalized in CXCR4+ HCC cells and showed no accumulation in CXCR4-knockout HCC cells. The T22-PE24 nanotoxin induced HCC pyroptosis via the caspase-3/GSDME signaling pathway and suppressed tumor growth in the absence of histological alterations in normal organs. Using the complete-immunity HCC tumor-bearing mice model, we found that T22-PE24 nanotoxin effectively induces the global reprogramming of cell components of the immune tumor microenvironment, leading to enhanced antitumor effects compared to those observed in immunodeficient mice.ConclusionOur findings demonstrate the activation of the innate immune response in HCC by inducing pyroptosis with T22-PE24 nanotoxin treatment and support an implementation of this strategy for HCC treatment.
| S-EPMC11570815 | biostudies-literature
Project description:Some chemotherapeutic agents have been found to enhance antitumor immunity by inducing immunogenic cell death (ICD). The combination of disulfiram (DSF) and copper (Cu) has demonstrated anti-tumor effects in a range of malignancies including hepatocellular carcinoma (HCC). However, the potential of DSF/Cu as an ICD inducer and whether it can enhance the efficacy of the immune checkpoint blockade in HCC remains unknown. Here, we showed that DSF/Cu-treated HCC cells exhibited characteristics of ICD in vitro, such as calreticulin (CRT) exposure, ATP secretion, and high mobility group box 1 (HMGB1) release. DSF/Cu-treated HCC cells elicited significant immune memory in a vaccination assay. DSF/Cu treatment promoted dendritic cell activation and maturation. The combination of DSF/Cu and CD47 blockade further facilitated DC maturation and subsequently enhanced CD8+ T cell cytotoxicity. Mechanically, DSF/Cu promoted the nuclear accumulation and aggregation of nuclear protein localization protein 4 (NPL4) to inhibit the ubiquitin-proteasome system; thus, inducing endoplasmic reticulum (ER) stress. The inhibition of NPL4 induced ICD-associated damage-associated molecular patterns. Collectively, our findings demonstrated that DSF/Cu-induced ICD-mediated immune activation in HCC enhanced the efficacy of CD47 blockade.
| S-EPMC9564202 | biostudies-literature
Project description:BackgroundImmunogenic cell death (ICD) can elicit an adaptive immune response with significant antitumor effects. Percutaneous ethanol injection therapy has been applied as tumor ablation for small hepatocellular carcinoma (HCC). However, it was not clear whether ethanol can elicit ICD. The aim of this study is to investigate the role of ethanol as an ICD inducer.MethodsHCC cell lines were treated with low-concentration ethanol and ICD markers, such as calreticulin, high-mobility group box 1, and ATP were assayed. The mouse vaccination-rechallenge assay was used to further confirm ethanol as an ICD inducer. Western blot and real-time PCR were used to investigate ICD-related endoplasmic reticulum (ER) stress and signaling pathways. The genes with differential expression levels between primary and distant tumors were analyzed by nCounter gene expression. Intratumoral injection of ethanol was done to investigate the abscopal effect.ResultsThe low-concentration ethanol could induce ICD in HCC cell lines through unfolded protein responses initiated by ER stress and multiple cell-death pathways. Intratumoral injections of low-concentration ethanol had significantly direct and abscopal antitumor effects in mouse models of both subcutaneous and orthotopic HCC. nCounter gene expression analysis in primary and distant tumors revealed the activation of various immune-response pathways, notably those mediated by CD8 T cells and the interferon pathway. Vaccinating mice with low-concentration ethanol-treated HCC cells successfully inhibited metastasis in both intravenous and intrasplenic metastasis models.ConclusionsOur results suggest that low-concentration ethanol could serve as an inducer of ICD. Low-concentration ethanol could potentially improve therapeutic antitumor immunity by inducing substantial ICD.
| S-EPMC11843001 | biostudies-literature
Project description:In hepatocellular carcinoma (HCC), the signal transducer and activator of transcription 3 (STAT3) is present in an overactive state that is closely related to tumour development and immune escape. STAT3 inhibition reshapes the tumour immune microenvironment, but the underlying mechanisms have not been fully clarified. We found that STAT3 inhibition could induce immunogenic cell death (ICD) of HCC cells via translocation of the "eat me" molecule calreticulin to the cell surface and a significant reduction in the expression of the "don't eat me" molecule leucocyte surface antigen CD47. STAT3 inhibition promoted dendritic cell (DC) activation and enhanced the recognition and phagocytosis of HCC cells by macrophages. Furthermore, STAT3 inhibition prevented the expression of key glycolytic enzymes, facilitating the induction of ICD in HCC. Interestingly, STAT3 directly regulated the transcription of CD47 and solute carrier family 2 member 1 (SLC2A1; also known as GLUT1). In subcutaneous and orthotopic transplantation mouse tumour models, the STAT3 inhibitor napabucasin prevented tumour growth and induced the expression of calreticulin and the protein disulfide isomerase family A member 3 (PDIA3; also known as ERp57) but suppressed that of CD47 and GLUT1. Meanwhile, the amount of tumour-infiltrated DCs and macrophages increased, along with the expression of costimulatory molecules. More CD4+ and CD8+ T cells accumulated in tumour tissues, and CD8+ T cells had lower expression of checkpoint molecules such as lymphocyte activation gene 3 protein (LAG-3) and programmed cell death protein 1 (PD-1). Significantly, the antitumour immune memory response was induced by treatment targeting STAT3. These findings provide a new mechanism for targeting STAT3-induced ICD in HCC, and confirms STAT3 as a potential target for the treatment of HCC via reshaping the tumour immune microenvironment.
| S-EPMC9348600 | biostudies-literature
Project description:BackgroundBoth immunogenic cell death (ICD) and long noncoding RNAs (lncRNAs) are strongly associated with tumor development, but the mechanism of action of ICD-associated lncRNAs in hepatocellular carcinoma (HCC) remains unclear.MethodsWe collected data from 365 HCC patients from The Cancer Genome Atlas (TCGA) database. We formulated a prognostic signature of ICD-associated lncRNAs and a nomogram to predict prognosis. To explore the potential mechanisms and provide clinical guidance, survival analysis, enrichment analysis, tumor microenvironment analysis, tumor mutation burden (TMB), and drug sensitivity prediction were conducted based on the subgroups obtained from the risk score.ResultsA prognostic signature of seven ICD-associated lncRNAs was constructed. Kaplan-Meier (K-M) survival curves showed a more unfavorable outcome in high-risk patients. The nomogram had a higher predictive value than the nomogram constructed without the risk model. Enrichment analysis confirmed that risk lncRNAs were closely associated with cell proliferation and mitosis. Most of the immune checkpoints currently used in therapy (e.g., PDCD1 and CTLA4) appeared to be elevated in high-risk patients. Tumor microenvironment analysis showed differential expression of lymphocytes (including natural killer cells, regulatory T cells, etc.) in the high-risk group. TMB had a higher incidence of mutations in the high-risk group (P=0.004). Chemotherapy drug sensitivity prediction provides effective guidelines for individual therapy. RT-qPCR of human HCC tissues verified the accuracy of the model.ConclusionWe constructed an effective prognostic signature for patients with HCC using seven ICD-lncRNAs, which provides guidance for the prognostic assessment and personalized treatment of patients.
| S-EPMC10500227 | biostudies-literature
Project description:BackgroundHepatocellular carcinoma (HCC) is considered one of the most common cancers, characterized by low early detection and high mortality rates, and is a global health challenge. Immunogenic cell death (ICD) is defined as a specific type of regulated cell death (RCD) capable of reshaping the tumor immune microenvironment by releasing danger signals that trigger immune responses, which would contribute to immunotherapy.MethodsThe ICD gene sets were collected from the literature. We collected expression data and clinical information from public databases for the HCC samples in our study. Data processing and mapping were performed using R software to analyze the differences in biological characteristics between different subgroups. The expression of the ICD representative gene in clinical specimens was assessed by immunohistochemistry, and the role of the representative gene in HCC was evaluated by various in vitro assays, including qRT-PCR, colony formation, and CCK8 assay. Lasso-Cox regression was used to screen prognosis-related genes, and an ICD-related risk model (ICDRM) was constructed. To improve the clinical value of ICDRM, Nomograms and calibration curves were created to predict survival probabilities. Finally, the critical gene of ICDRM was further investigated through pan-cancer analysis and single-cell analysis.ResultsWe identified two ICD clusters that differed significantly in terms of survival, biological function, and immune infiltration. As well as assessing the immune microenvironment of tumors in HCC patients, we demonstrate that ICDRM can differentiate ICD clusters and predict the prognosis and effectiveness of therapy. High-risk subpopulations are characterized by high TMB, suppressed immunity, and poor survival and response to immunotherapy, whereas the opposite is true for low-risk subpopulations.ConclusionsThis study reveals the potential impact of ICDRM on the tumor microenvironment (TME), immune infiltration, and prognosis of HCC patients, but also a potential tool for predicting prognosis.
| S-EPMC10249577 | biostudies-literature
Project description:Family with sequence similarity 49, member B (FAM49B) is highly expressed in many tumors, its role in malignant tumors especially in hepatocellular carcinoma (HCC) remains uncertain. We first evaluated the expression, clinical features, and prognostic value of FAM49B using RNA-seq and clinical data from The Cancer Genome Atlas. We further assessed the role of FAM49B in the tumor immune microenvironment. The correlation of FAM49B with the sensitivity of 192 anti-cancer drugs was analyzed using data from Genomics of Drug Sensitivity in Cancer database. qRT-PCR assay was used to validate the expression of FAM49B in HCC. FAM49B was expressed at high levels in most tumor types, including HCC. High FAM49B expression predicted poor survival in patients with HCC. We also found that FAM49B expression was negatively associated with the infiltration levels of immune killer cells, including NK cells, and positively associated with immunosuppressive cells, including Tregs and Central Memory T cell (Tcm), in HCC. In addition, FAM49B expression was positively associated with immune checkpoints, immune regulation genes, MHC genes, chemokines and chemokine receptors. Patients with evaluated expression of FAM49B might be resistant to several anti-cancer drugs. Our results suggest that FAM49B is a potential prognostic biomarker for HCC. FAM49B play a potential key role in regulating tumor immune microenvironment and anti-tumor drug tolerance.
| S-EPMC8692685 | biostudies-literature