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BACKGROUND: Epstein-Barr virus (EBV) is a double-stranded DNA oncogenic virus. Several types of solid tumors, such as nasopharyngeal carcinoma, EBV-associated gastric carcinoma, and lymphoepithelioma-like carcinoma of the lung, have been linked to EBV infection. Currently, several TCR-T-cell therapies for EBV-associated tumors are in clinical trials, but due to the suppressive immune microenvironment of solid tumors, the clinical application of TCR-T-cell therapy for EBV-associated solid tumors is limited. Figuring out the mechanism by which EBV participates in the formation of the tumor immunosuppressive microenvironment will help T cells or TCR-T cells break through the limitation and exert stronger antitumor potential. METHODS: Flow cytometry was used for analyzing macrophage differentiation phenotypes induced by EBV-infected and EBV-uninfected tumors, as well as the function of T cells co-cultured with these macrophages. Xenograft model in mice was used to explore the effects of M2 macrophages, TCR-T cells, and matrix metalloprotein 9 (MMP9) inhibitors on the growth of EBV-infected tumors. RESULTS: EBV-positive tumors exhibited an exhaustion profile of T cells, despite the presence of a large T-cell infiltration. EBV-infected tumors recruited a large number of mononuclear macrophages with CCL5 and induced CD163+M2 macrophages polarization through the secretion of CSF1 and the promotion of autocrine IL10 production by mononuclear macrophages. Massive secretion of MMP9 by this group of CD163+M2 macrophages induced by EBV infection was an important factor contributing to T-cell exhaustion and TCR-T-cell therapy resistance in EBV-positive tumors, and the use of MMP9 inhibitors improved the function of T cells cocultured with M2 macrophages. Finally, the combination of an MMP9 inhibitor with TCR-T cells targeting EBV-positive tumors significantly inhibited the growth of xenografts in mice. CONCLUSIONS: MMP9 inhibitors improve TCR-T cell function suppressed by EBV-induced M2 macrophages. TCR-T-cell therapy combined with MMP9 inhibitors was an effective therapeutic strategy for EBV-positive solid tumors.
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Antígenos CD , Infecções por Vírus Epstein-Barr , Herpesvirus Humano 4 , Macrófagos , Metaloproteinase 9 da Matriz , Receptores de Superfície Celular , Animais , Camundongos , Humanos , Metaloproteinase 9 da Matriz/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/virologia , Receptores de Superfície Celular/metabolismo , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Microambiente Tumoral , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Feminino , Linfócitos T/imunologia , Linfócitos T/metabolismo , Imunoterapia Adotiva/métodosRESUMO
Fluoropyrimidine-based combination chemotherapy plus targeted therapy is the standard initial treatment for unresectable metastatic colorectal cancer (mCRC), but the prognosis remains poor. This phase 3 trial (ClinicalTrials.gov: NCT03950154) assessed the efficacy and adverse events (AEs) of the combination of PD-1 blockade-activated DC-CIK (PD1-T) cells with XELOX plus bevacizumab as a first-line therapy in patients with mCRC. A total of 202 participants were enrolled and randomly assigned in a 1:1 ratio to receive either first-line XELOX plus bevacizumab (the control group, n = 102) or the same regimen plus autologous PD1-T cell immunotherapy (the immunotherapy group, n = 100) every 21 days for up to 6 cycles, followed by maintenance treatment with capecitabine and bevacizumab. The main endpoint of the trial was progression-free survival (PFS). The median follow-up was 19.5 months. Median PFS was 14.8 months (95% CI, 11.6-18.0) for the immunotherapy group compared with 9.9 months (8.0-11.8) for the control group (hazard ratio [HR], 0.60 [95% CI, 0.40-0.88]; p = 0.009). Median overall survival (OS) was not reached for the immunotherapy group and 25.6 months (95% CI, 18.3-32.8) for the control group (HR, 0.57 [95% CI, 0.33-0.98]; p = 0.043). Grade 3 or higher AEs occurred in 20.0% of patients in the immunotherapy group and 23.5% in the control groups, with no toxicity-associated deaths reported. The addition of PD1-T cells to first-line XELOX plus bevacizumab demonstrates significant clinical improvement of PFS and OS with well tolerability in patients with previously untreated mCRC.
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Neoplasias do Colo , Neoplasias Colorretais , Oxaloacetatos , Humanos , Bevacizumab/uso terapêutico , Capecitabina/uso terapêutico , Oxaliplatina , Neoplasias Colorretais/tratamento farmacológico , Fluoruracila/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , ImunoterapiaRESUMO
Neutrophil extracellular traps (NET), formed by the extracellular release of decondensed chromatin and granules, have been shown to promote tumor progression and metastasis. Tumor-associated neutrophils in hepatocellular carcinoma (HCC) are prone to NET formation, highlighting the need for a more comprehensive understanding of the mechanisms of action of NETs in liver cancer. Here, we showed that DNA of NETs (NET-DNA) binds transmembrane and coiled-coil domains 6 (TMCO6) on CD8+ T cells to impair antitumor immunity and thereby promote HCC progression. TGFß1 induced NET formation, which recruited CD8+ T cells. Binding to NET-DNA inhibited CD8+ T cells function while increasing apoptosis and TGFß1 secretion, forming a positive feedback loop to further stimulate NET formation and immunosuppression. Mechanistically, the N-terminus of TMCO6 interacted with NET-DNA and suppressed T-cell receptor signaling and NFκB p65 nuclear translocation. Blocking NET formation by inhibiting PAD4 induced potent antitumor effects in wild-type mice but not TMCO6-/- mice. In clinical samples, CD8+ T cells expressing TMCO6 had an exhausted phenotype. TGFß1 signaling inhibition or TMCO6 deficiency combined with anti-PD-1 abolished NET-driven HCC progression in vivo. Collectively, this study unveils the role of NET-DNA in impairing CD8+ T-cell immunity by binding TMCO6 and identifies targeting this axis as an immunotherapeutic strategy for blocking HCC progression. SIGNIFICANCE: TMCO6 is a receptor for DNA of NETs that mediates CD8+ T-cell dysfunction in HCC, indicating that the NET-TMCO6 axis is a promising target for overcoming immunosuppression in liver cancer.
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Linfócitos T CD8-Positivos , Carcinoma Hepatocelular , Armadilhas Extracelulares , Neoplasias Hepáticas , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Animais , Humanos , Camundongos , Armadilhas Extracelulares/imunologia , Armadilhas Extracelulares/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Neutrófilos/imunologia , Neutrófilos/metabolismo , DNA/imunologia , DNA/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linhagem Celular Tumoral , MasculinoRESUMO
T/NK cell-based immunotherapy has achieved remarkable success in adult cancers but has limited efficacy in pediatric malignancies including high-risk neuroblastoma (NB). Immune defects of NB tumor microenvironment are poorly understood compared with adults. Here, we described the unique characteristics of NB immune contexture and determined the phenotype signatures of PD-L1-expressing CD8+ T and NK cells in NB tumors by systemically analyzing the spatial distribution of T and NK cells and the distinct expression of programmed death 1 (PD-1) and its ligand (PD-L1) in patients with NB. We found that PD-L1-expressing CD8+ T and NK cells in NB tumors were highly activated and functionally competent and associated with better clinical outcomes. Intratumoral NK cells were a favorable prognostic biomarker independent of CD8+ T cells, PD-1/PD-L1 expression, tumor stage, MYCN amplification, and risk classification. NK cells combined with anti-PD-1/PD-L1 antibodies showed potent antitumor activity against both MYCN-amplified and non-amplified NBs in vitro and in vivo, and PD-L1-expressing NK cells associated with improved antitumor efficacy. Collectively, we raise novel insights into the role of PD-L1 expression on CD8+ T-cell and NK-cell activation. We highlight the great potential of intratumoral NK cells in better defining risk stratification, and predicting survival and response to anti-PD-1/PD-L1 therapy in NB. These findings explain why single anti-PD-1/PD-L1 therapy may not be successful in NB, suggesting its combination with NK cell-adoptive cellular therapy as a promising strategy for relapsing/refractory NB. This study provides a potential prospect that patients with PD-L1-expressing NK cells may respond to anti-PD-1/PD-L1 therapy.
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Antígeno B7-H1 , Neuroblastoma , Criança , Adulto , Humanos , Receptor de Morte Celular Programada 1/genética , Linfócitos T CD8-Positivos/metabolismo , Proteína Proto-Oncogênica N-Myc/genética , Proteína Proto-Oncogênica N-Myc/metabolismo , Células Matadoras Naturais/metabolismo , Prognóstico , Neuroblastoma/terapia , Neuroblastoma/genética , Neuroblastoma/metabolismo , Microambiente TumoralRESUMO
PURPOSE: The safety and objective clinical responses were observed in the phase I study using adjuvant autologous tumour-infiltrating lymphocytes (TILs) following concurrent chemoradiotherapy (CCRT) in nasopharyngeal carcinoma (NPC) patients. METHODS AND MATERIALS: One hundred fifty-six patients with stage III-IVb and pretreatment Epstein-Barr virus DNA levels of ≥4000 copies/ml were randomly assigned to receive CCRT combined with TIL infusion (n = 78) or CCRT alone (n = 78). All patients received CCRT and patients assigned to the TIL group received TIL infusion within 1 week after CCRT. The primary endpoint was investigator-assessed progression-free survival (PFS) at 3 years. RESULTS: After a median follow-up of 62.3 months, no significant difference was observed in the 3-year PFS rate between the CCRT plus TIL infusion group and CCRT alone group (75.6% versus 74.4%, hazard ratios, 1.08; 95% confidence intervals, 0.62-1.89). TIL infusion was safe without grade 3 or 4 adverse events and all the high-grade adverse effects were associated with myelosuppression caused by CCRT. Exploratory analysis showed that a potential survival benefit was observed with TILs in patients with lower levels of circulating CD8+TIM3+ cells, serum IL-8 or PD-L1. The infused TIL products in patients with favourable outcomes were associated with increased transcription of interferon-γ and a series of inflammatory related genes and a lower exhausted score. CONCLUSION: The primary objective of prolonging PFS with CCRT plus TILs in high-risk NPC patients was not met. These findings may provide evidence for the design of future trials investigating the combination of TILs plus immune checkpoint inhibitors based on CCRT in high-risk NPC patients. TRIAL REGISTRATION NUMBER: NCT02421640.
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Infecções por Vírus Epstein-Barr , Neoplasias Nasofaríngeas , Humanos , Adjuvantes Imunológicos , Quimiorradioterapia/métodos , Intervalo Livre de Doença , DNA , Infecções por Vírus Epstein-Barr/complicações , Herpesvirus Humano 4 , Linfócitos do Interstício Tumoral , Carcinoma Nasofaríngeo/terapia , Neoplasias Nasofaríngeas/patologiaRESUMO
Rationale: Resistance to 5-fluorouracil (5-FU) chemotherapy remains the main barrier to effective clinical outcomes for patients with colorectal cancer (CRC). A better understanding of the detailed mechanisms underlying 5-FU resistance is needed to increase survival. Interleukin (IL)-33 is a newly discovered alarmin-like molecule that exerts pro- and anti-tumorigenic effects in various cancers. However, the precise role of IL-33 in CRC progression, as well as in the development of 5-FU resistance, remains unclear. Methods: High-quality RNA-sequencing analyses were performed on matched samples from patients with 5-FU-sensitive and 5-FU-resistant CRC. The clinical and biological significance of IL-33, including its effects on both T cells and tumor cells, as well as its relationship with 5-FU chemotherapeutic activity were examined in ex vivo, in vitro and in vivo models of CRC. The molecular mechanisms underlying these processes were explored. Results: IL-33 expressed by tumor cells was a dominant mediator of antitumoral immunity in 5-FU-sensitive patients with CRC. By binding to its ST2 receptor, IL-33 triggered CD4+ (Th1 and Th2) and CD8+ T cell responses by activating annexin A1 downstream signaling cascades. Mechanistically, IL-33 enhanced the sensitivity of CRC cells to 5-FU only in the presence of T cells, which led to the activation of both tumor cell-intrinsic apoptotic and immune killing-related signals, thereby synergizing with 5-FU to induce apoptosis of CRC cells. Moreover, injured CRC cells released more IL-33 and the T cell chemokines CXCL10 and CXCL13, forming a positive feedback loop to further augment T cell responses. Conclusions: Our results identified a previously unrecognized connection between IL-33 and enhanced sensitivity to 5-FU. IL-33 created an immune-active tumor microenvironment by orchestrating antitumoral T cell responses. Thus, IL-33 is a potential predictive biomarker for 5-FU chemosensitivity and favorable prognosis and has potential as a promising adjuvant immunotherapy to improve the clinical benefits of 5-FU-based therapies in the treatment of CRC.
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Neoplasias Colorretais , Fluoruracila , Humanos , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Alarminas/uso terapêutico , Neoplasias Colorretais/patologia , Interleucina-33 , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Microambiente TumoralRESUMO
Hepatocellular carcinoma is one of the most common malignancies and has a poor prognosis. The ubiquitin-proteasome pathway is required for the degradation of most short-lived proteins. CMTM6 has been implicated in the progression of various tumors, but its biological function and the underlying molecular mechanisms in HCC are still unknown. In this study, we found that the expression of CMTM6 was significantly reduced in HCC and predicted better prognosis of HCC patients. Through in vitro and in vivo experiments, CMTM6 was shown to inhibit the proliferation of HCC cells by blocking the G1/S phase transition. Mechanistically, CMTM6 interacted with p21 and prevented its ubiquitination mediated by SCFSKP2, CRL4CDT2 and APC/CCDC20 in a cell-cycle-independent manner. As a result, CMTM6 stabilized p21 protein, leading to the inactivation of pRB/E2F pathway. Additionally, CMTM6 sensitized HCC cells to doxorubicin and cisplatin, positively correlated with better clinical outcomes of the transarterial chemoembolization (TACE) treatment for postoperative recurrence. Taken together, our study reports a novel mechanism by which p21 can be stabilized by CMTM6 and pinpoints a crucial role of the CMTM6-p21 axis in suppressing the progression of HCC and sensitizing patients with postoperative recurrence to TACE treatment.
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Carcinoma Hepatocelular , Quimioembolização Terapêutica , Neoplasias Hepáticas , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , UbiquitinaçãoRESUMO
BACKGROUND: Platinum resistance is a major challenge in the clinical treatment of advanced ovarian cancer (OC). Accumulating evidence shows that the tumor-promotive M2 macrophage is linked to the limiting chemotherapy efficacy of multiple malignancies including OC. Circular RNAs (circRNAs) are a novel class of non-coding RNAs which function as the critical regulator in biological process of cancer. However, their impact on macrophage polarization and chemoresistance of OC remain unclear. METHODS: Platinum-resistant circRNAs were screened using circRNA deep sequencing and validated using in situ hybridization in OC tissues with or without platinum resistance. The role of circITGB6 in inducing cisplatin (CDDP) resistance was evaluated by clone formation, immunofluorescence and annexin V assays in vitro, and by intraperitoneal tumor model in vivo. The mechanism underlying circITGB6-mediated tumor-associated macrophage (TAM) polarization into M2 phenotype was investigated using RNA pull-down, luciferase reporter, electrophoretic mobility shift, RNA binding protein immunoprecipitation (RIP), ELISA and immunofluorescence assays. RESULTS: We identified that a novel circRNA, circITGB6, robustly elevated in tumor tissues and serums from patients with OC with platinum resistance, was correlated with poor prognosis. circITGB6 overexpression promoted an M2 macrophage-dependent CDDP resistance in both vivo and vitro. Mechanistic research determined that circITGB6 directly interacted with IGF2BP2 and FGF9 mRNA to form a circITGB6/IGF2BP2/FGF9 RNA-protein ternary complex in the cytoplasm, thereby stabilizing FGF9 mRNA and inducing polarization of TAMs toward M2 phenotype. Importantly, blocking M2 macrophage polarization with an antisense oligonucleotide targeting circITGB6 markedly reversed the circITGB6-induced CDDP resistance of OC in vivo. CONCLUSIONS: This study reveals a novel mechanism for platinum resistance in OC and demonstrates that circITGB6 may serve as a potential prognostic marker and a therapeutic target for patients with OC.
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Neoplasias Ovarianas , Macrófagos Associados a Tumor , Carcinoma Epitelial do Ovário , Linhagem Celular Tumoral , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Feminino , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Fenótipo , RNA , RNA Circular/genética , RNA Mensageiro , Proteínas de Ligação a RNARESUMO
OBJECTIVES: Although axitinib has achieved a preferable response rate for advanced renal cell carcinoma (RCC), patient survival remains unsatisfactory. In this study, we evaluated the efficacy and safety of a combination treatment of axitinib and a low dose of pembrolizumab-activated autologous dendritic cells-co-cultured cytokine-induced killer cells in patients with advanced RCC. METHODS: All adult patients, including treatment-naive or pretreated with VEGF-targeted agents, were enrolled from May 2016 to March 2019. Patients received axitinib 5 mg twice daily and pembrolizumab-activated dendritic cells-co-cultured cytokine-induced killer cells intravenously weekly for the first four cycles, every 2 weeks for the next four cycles, and every month thereafter. RESULTS: The 43 patients (22 untreated and 21 previously treated) showed a median progression-free survival (mPFS) of 14.7 months (95% CI, 11.16-18.30). mPFS in treatment-naive patients was 18.2 months, as compared with 14.4 months in pretreated patients (log-rank P-value = 0.07). Overall response rates were 25.6% (95% CI, 13.5-41.2%). Grade 3 or higher adverse events occurred in 5% of patients included hypertension (11.6%) and palmar-plantar erythrodysesthesia (7.0%). Peripheral blood lymphocyte immunophenotype and serum cytokine profile analyses demonstrated increased antitumor immunity after combination treatment particularly in patients with a long-term survival benefit, while those with a minimal survival benefit demonstrated an elevated proportion of peripheral CD8+TIM3+ T cells and lower serum-level immunostimulatory cytokine profile. CONCLUSIONS: The combination therapy was active and well tolerated for treatment of advanced RCC, either as first- or second-line treatment following other targeted agents. Changes in immunophenotype and serum cytokine profile may be used as prognostic biomarkers.
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BACKGROUND AND AIMS: Cancer-associated fibroblasts (CAFs) are key players in multicellular, stromal-dependent alterations leading to HCC pathogenesis. However, the intricate crosstalk between CAFs and other components in the tumor microenvironment (TME) remains unclear. This study aimed to investigate the cellular crosstalk among CAFs, tumor cells, and tumor-associated neutrophils (TANs) during different stages of HCC pathogenesis. APPROACH AND RESULTS: In the HCC-TME, CAF-derived cardiotrophin-like cytokine factor 1 (CLCF1) increased chemokine (C-X-C motif) ligand 6 (CXCL6) and TGF-ß secretion in tumor cells, which subsequently promoted tumor cell stemness in an autocrine manner and TAN infiltration and polarization in a paracrine manner. Moreover, CXCL6 and TGF-ß secreted by HCC cells activated extracellular signal-regulated kinase (ERK) 1/2 signaling of CAFs to produce more CLCF1, thus forming a positive feedback loop to accelerate HCC progression. Inhibition of ERK1/2 or CLCF1/ciliary neurotrophic factor receptor signaling efficiently impaired CLCF1-mediated crosstalk among CAFs, tumor cells, and TANs both in vitro and in vivo. In clinical samples, up-regulation of the CLCF1-CXCL6/TGF-ß axis exhibited a marked correlation with increased cancer stem cells, "N2"-polarized TANs, tumor stage, and poor prognosis. CONCLUSIONS: This study reveals a cytokine-mediated cellular crosstalk and clinical network involving the CLCF1-CXCL6/TGF-ß axis, which regulates the positive feedback loop among CAFs, tumor stemness, and TANs, HCC progression, and patient prognosis. These results may support the CLCF1 cascade as a potential prognostic biomarker and suggest that selective blockade of CLCF1/ciliary neurotrophic factor receptor or ERK1/2 signaling could provide an effective therapeutic target for patients with HCC.
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Fibroblastos Associados a Câncer/patologia , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Fibroblastos Associados a Câncer/metabolismo , Carcinoma Hepatocelular/metabolismo , Quimiocina CXCL6/metabolismo , Citocinas/metabolismo , Progressão da Doença , Feminino , Humanos , Neoplasias Hepáticas/metabolismo , Sistema de Sinalização das MAP Quinases , Masculino , Pessoa de Meia-Idade , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Microambiente TumoralRESUMO
Bladder cancer (BC) is the ninth most common lethal malignancy worldwide. Great efforts have been devoted to clarify the pathogenesis of BC, but the underlying molecular mechanisms remain unclear. To screen for the genes associated with the progression and carcinogenesis of BC, three datasets were obtained from the Gene Expression Omnibus. A total of 37 tumor and 16 non-cancerous samples were analyzed to identify differentially expressed genes (DEGs). Subsequently, 141 genes were identified, including 55 upregulated and 86 downregulated genes. The protein-protein interaction network was established using the Search Tool for Retrieval of Interacting Genes database. Hub gene identification and module analysis were performed using Cytoscape software. Hierarchical clustering of hub genes was conducted using the University of California, Santa Cruz Cancer Genomics Browser. Among the hub genes, kinesin family member 11 (KIF11) was identified as one of the most significant prognostic biomarkers among all the candidates. The Kaplan Meier Plotter database was used for survival analysis of KIF11. The expression profile of KIF11 was analyzed using the ONCOMINE database. The expression levels of KIF11 in BC samples and bladder cells were measured using reverse transcription-quantitative pCR, immunohistochemistry and western blotting. In summary, KIF11 was significantly upregulated in BC and might act as a potential prognostic biomarker. The present identification of DEGs and hub genes in BC may provide novel insight for investigating the molecular mechanisms of BC.
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Accumulating evidence has indicated that inflammation is required for the initiation and progression of hepatocellular carcinoma (HCC). The annexin family protein, which has a highly similar structure, has been demonstrated to participate in pro- or anti-inflammatory regulation in the developing of tumours. However, the potential effects of ANXA3 in the immune microenvironment of HCC remain unknown. In present study, we found that increased ANXA3 expression is associated with a higher infiltrated neutrophil-lymphocyte ratio (iNLR) in HCC. Moreover, HCC patients with a high iNLR and high ANXA3 expression confer the highest risk of death. ANXA3 can be detected in both cell lysates and culture supernatants. However, the secretory ANXA3 did not directly regulate the iNLR. Further study demonstrated that ANXA3 upregulated the iNLR by inducing chemokine CXCL8 and CCL25 release from HCC cells. We further confirmed that ANXA3 promotes tumourigenesis and detected the same associations between ANXA3 and the iNLR or chemokines in vivo. Our findings indicate that ANXA3 regulates the chemokine to remodel the iNLR and promotes tumourigenicity in HCC. These results further expanded our understanding of ANXA3 in the microenvironment of HCC and might provide novel targets for the investigation of molecular treatments for HCC patients.
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Anexina A3/metabolismo , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Linfócitos/fisiologia , Neutrófilos/fisiologia , Microambiente Tumoral/imunologia , Linhagem Celular Tumoral , Movimento Celular , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Regulação para Cima/fisiologiaRESUMO
BACKGROUND: High probability of metastasis limited the long-term survival of patients with hepatocellular carcinoma (HCC). Our previous study revealed that Galectin-3 was closely associated with poor prognosis in HCC patients. METHODS: The effects of Galectin-3 on tumour metastasis were investigated in vitro and in vivo, and the underlying biological and molecular mechanisms involved in this process were evaluated. RESULTS: Galectin-3 showed a close correlation with vascular invasion and poor survival in a large-scale study in HCC patients from multiple sets. Galectin-3 was significantly involved in diverse metastasis-related processes in HCC cells, such as angiogenesis and epithelial-to-mesenchymal transition (EMT). Mechanistically, Galectin-3 activated the PI3K-Akt-GSK-3ß-ß-catenin signalling cascade; the ß-catenin/TCF4 transcriptional complex directly targeted IGFBP3 and vimentin to regulate angiogenesis and EMT, respectively. In animal models, Galectin-3 enhanced the tumorigenesis and metastasis of HCC cells via ß-catenin signalling. Moreover, molecular deletion of Galectin-3-ß-catenin signalling synergistically improved the antitumour effect of sorafenib. CONCLUSIONS: The Galectin-3-ß-catenin-IGFBP3/vimentin signalling cascade was determined as a central mechanism controlling HCC metastasis, providing possible biomarkers for predicating vascular metastasis and sorafenib resistance, as well as potential therapeutic targets for the treatment of HCC patients.
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Carcinoma Hepatocelular/patologia , Galectina 3/fisiologia , Neoplasias Hepáticas/patologia , beta Catenina/genética , Animais , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidade , Adesão Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Progressão da Doença , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidade , Camundongos Endogâmicos BALB C , Camundongos Nus , Metástase Neoplásica , Neoplasias de Tecido Vascular/genética , Neoplasias de Tecido Vascular/mortalidade , Neoplasias de Tecido Vascular/secundário , Análise de Sobrevida , Análise Serial de Tecidos , Via de Sinalização Wnt/genética , beta Catenina/metabolismoRESUMO
Adjuvant chemotherapy after surgery is the standard treatment modality for stage III and part of stage II or stage IV colorectal cancer (CRC) patients. However, the 5-year overall survival (OS) rate remains unsatisfactory. Thus, developing combination therapies is essential to improve the prognosis of patients with CRC. The present study aimed to determine the effect of a sequential combination of cytokine-induced killer cell (CIK) infusion and chemotherapy for patients with CRC. 122 patients with CRC treated with postoperative adjuvant chemotherapy were retrospectively included in this study. Among them, 62 patients received adjuvant chemotherapy only (control group), while the other 60 patients, with similar demographic and clinical characteristics, received adjuvant chemotherapy and sequential CIK cell immunotherapy (CIK group). Survival analysis showed significantly improved disease free survival (DFS) and OS rates in the CIK group compared with the control group (log-rank test, P = .0024; P = .008, respectively). Univariate and multivariate analyses indicated that sequential CIK cell treatment was an independent prognostic factor for patients' DFS and OS. Subgroup analyses showed that sequential CIK cell treatment significantly improved the DFS and OS of patients with high-risk T4 stage and insufficient chemotherapy duration. In conclusion, these data indicate that sequential adjuvant CIK cell treatment combined with chemotherapy is an effective therapeutic strategy to prevent disease recurrence and prolong survival of patients with CRC, particularly for patients with high-risk T4 stage and insufficient chemotherapy duration.
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Neoplasias Colorretais , Células Matadoras Induzidas por Citocinas , Quimioterapia Adjuvante , Neoplasias Colorretais/terapia , Terapia Combinada , Procedimentos Cirúrgicos do Sistema Digestório , Feminino , Humanos , Imunoterapia Adotiva , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estudos RetrospectivosRESUMO
OBJECT: This study aimed at investigating the clinical significance and biological function of ubiquitination factor E4B (UBE4B) in human renal cell carcinoma (RCC). METHODS: 19 paired clear cell renal cell carcinoma (ccRCC) tumor samples and the matched neighboring non-tumor samples were used to detect the expression of UBE4B in RCC tumor by Western blotting and RT-qPCR. UBE4B expression was also detected in 151 ccRCC paraffin-embedded tumor samples by using immunohistochemistry. Overall survival (OS) in different UBE4B expression groups were compared with Log rank test. The prognostic value of UBE4B expression in OS was evaluated with the univariate and multivariate Cox regression models. UBE4B was knocked down by small interfering RNA (siRNA) technology, and the effect of UBE4B on cell proliferation, colony formation, metastasis, apoptosis and cell cycle of RCC cells were examined in vitro. RESULTS: Both protein and mRNA levels of UBE4B were up-regulated in ccRCC tumor tissues in contrast to the corresponding adjacent nontumor ones. UBE4B expression was positively associated with tumor-node-metastasis (TNM) stage and distant metastasis in ccRCC patients. Survival analyses indicated that low expression of UBE4B was associated with increased OS in ccRCC patients. Functional analyses demonstrated that siRNA silencing of UBE4B expression in SKRC39 and ACHN cells further reduced the growth, motility and invasiveness of RCC cells. Moreover, siRNA silencing of UBE4B in the RCC cell lines did not induce apoptosis, and an increase in the cell population was observed during the G0/G1 phase of the cell cycle. CONCLUSION: UBE4B might act as an oncogene in regulating RCC development. Therefore it could be served as an effective indicator to predict OS and a potential biomarker for targeted therapy of RCC patients.
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Adjuvant cytokine-induced killer (CIK) cell immunotherapy has shown potential in improving the prognosis of hepatocellular carcinoma (HCC) patients after curative resection. However, whether an individual could obtain survival benefit from CIK cell treatment remains unknown. In the present study, we focused on the characteristics of CIK cells and aimed to identify the best predictive biomarker for adjuvant CIK cell treatment in patients with HCC after surgery. This study included 48 patients with HCC treated with postoperative adjuvant CIK cell immunotherapy. The phenotype activity and cytotoxic activity of CIK cells were determined by flow cytometry and xCELLigence™ Real-Time Cell Analysis (RTCA) system, respectively. Correlation analysis revealed that the cytotoxic activity of CIK cells was significantly negative correlated with the percentage of CD3+ CD4+ cell subsets, but significantly positive correlated with CD3-CD56+ and CD3+ CD56+ cell subsets. Survival analysis showed that there were no significant associations between patients' prognosis and the phenotype of CIK cells. By contrast, there was statistically significant improvement in recurrence-free survival (RFS) and overall survival (OS) for patients with high cytotoxic activity of CIK cells as compared with those with low cytotoxic activity of CIK cells. Univariate and multivariate analyses indicated that CIK cell cytotoxicity was an independent prognostic factor for RFS and OS. In conclusion, a high cytotoxic activity of CIK cells can serve as a valuable biomarker for adjuvant CIK cell immunotherapy of HCC patients after surgery.
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Carcinoma Hepatocelular/terapia , Células Matadoras Induzidas por Citocinas/transplante , Citotoxicidade Imunológica , Imunoterapia/métodos , Neoplasias Hepáticas/terapia , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/mortalidade , Técnicas de Cultura de Células , Células Cultivadas/imunologia , Células Cultivadas/transplante , Terapia Combinada/métodos , Células Matadoras Induzidas por Citocinas/imunologia , Testes Imunológicos de Citotoxicidade , Feminino , Citometria de Fluxo , Hepatectomia , Humanos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Prognóstico , Análise de Sobrevida , Transplante Autólogo/métodosRESUMO
OBJECTIVES: Fluoropyrimidine-based chemotherapy regimens are the current first-line treatment for metastatic colorectal cancer (mCRC); however, the outcome is often unsatisfactory. The present study aimed to determine the effect of combined cytokine-induced killer (CIK) cell immunotherapy and first-line chemotherapy in patients with mCRC. METHODS: This retrospective study included 252 patients with mCRC treated with first-line chemotherapy. Among them, 126 patients received first-line chemotherapy only (control group), while the other 126 patients, with similar demographic and clinical characteristics, received CIK cell immunotherapy combined with first-line chemotherapy (CIK group). Overall survival (OS) and progression-free survival (PFS) were compared between the two groups using the Kaplan-Meier method. RESULTS: The median OS for the CIK group was 54.7 versus 24.1 months for the controls, and the median PFS for the CIK group was 25.7 versus 14.6 months for the controls. Univariate and multivariate analyses indicated that CIK cell treatment was an independent prognostic factor for patients' OS and PFS. Subgroup analyses showed that CIK cell treatment significantly improved the OS and PFS of patients with metastatic colon cancer, but not those with metastatic rectal cancer. Additionally, the change in CD3+CD56+ subsets after the fourth treatment cycle might be an indicator of successful CIK cell treatment: Patients with increased CD3+CD56+ subsets had better survival than those with decreased CD3+CD56+ subsets. CONCLUSION: Cytokine-induced killer cell immunotherapy combined with first-line chemotherapy could significantly improve the OS and PFS of patients with mCRC, particularly for patients with metastatic colon cancer.
RESUMO
BACKGROUND: Clinically, the median survival in patients with metastatic renal cell carcinoma (RCC) was only 6-12 months and a 5-year survival rate of less than 20%. Therefore, an in-depth study of the molecular mechanisms involved in RCC is of great significance for improving the survival of patients with advanced RCC. Acylglycerol kinase (AGK) is a newly discovered lipid kinase that has been reported to be a potent oncogene that may be involved in the regulation of malignant progression in a variety of tumours. However, the expression and biological characteristics of the AGK gene in RCC remain unclear. METHODS: AGK expression was quantified by quantitative real-time PCR, Western blotting and immunohistochemistry in RCC cell lines and paired patient tissues. Kaplan-Meier method and Cox proportional hazards models were used to evaluate the prognostic value of AGK in human RCC tissue samples. Chi-squared test was performed to analyse the correlation between AGK expression and the clinicopathological features. Stable overexpression and knockdown of AGK in RCC cells was constructed with lentivirus. The oncogenic effects of AGK in human RCC progression were investigated using assays of colony formation, anchorage-independent growth, EdU assay, cell cycle analysis, wound-healing, trans-well analysis and xenograft tumour model. GSEA and KEGG analysis were conducted to detect the potential pathway of AGK involved in RCC. These results were further confirmed using the luciferase reporter assays, immunofluorescence and in vivo experiments. RESULTS: AGK expression is significantly elevated in RCC and closely related to the malignant development and poor prognosis in RCC patients. By in vitro and in vivo experiments, AGK was shown to enhance the proliferation of RCC cells by promoting the transition from the G1 phase to the S phase in the cell cycle and to enhance the migration and invasion by promoting epithelial-mesenchymal transition. By activating the PI3K/AKT/GSK3ß signalling pathway in RCC, AGK can increase nuclear accumulation of ß-catenin, which further upregulated TCF/LEF transcription factor activity. CONCLUSIONS: AGK promotes the progression of RCC via activating the PI3K/AKT/GSK3ß signalling pathway and might be a potential target for the further research of RCC.
Assuntos
Carcinoma de Células Renais/patologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Neoplasias Renais/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Carcinoma de Células Renais/metabolismo , Linhagem Celular Tumoral , Progressão da Doença , Ativação Enzimática , Feminino , Humanos , Neoplasias Renais/metabolismo , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/patologia , Transdução de SinaisRESUMO
The abnormal expression of noncoding RNAs has attracted increasing interest in the field of hepatocellular carcinoma progression. However, the underlying molecular mechanisms mediated by noncoding RNAs in these processes are unclear. Here, we obtained the expression profiles of long noncoding RNAs, microRNAs, and mRNAs from the Gene Expression Omnibus database and identified hepatocarcinogenesis-specific differentially expressed transcripts. Next, we identified significant Gene Ontology and pathway terms that the differentially expressed transcripts involved in. Using functional analysis and target prediction, we constructed a hepatocellular carcinoma-associated deregulated competitive endogenous RNA network to reveal the potential mechanisms underlying tumor progression. By analyzing The Cancer Genome Atlas dataset, six key long noncoding RNAs showed significant association with overall survival as well as strong correlation with some microRNAs and mRNAs in the competitive endogenous RNA network. We further validated the above results and determined their diagnostic and prognostic value in clinical samples. Importantly, by large-scale analyses, we identified a cluster of long noncoding RNAs, GBAP1, MCM3AP-AS1, SLC16A1-AS1, C3P1, DIO3OS, and HNF4A-AS1 as candidate biomarkers for the diagnosis and prognosis of hepatocellular carcinoma, which will improve our understanding of competitive endogenous RNA-mediated regulatory mechanisms underlying hepatocellular carcinoma development and will provide novel therapeutic targets in the future.