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1.
Acta Pharm Sin B ; 14(6): 2554-2566, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38828147

RESUMO

Oncolytic viruses (OVs), a group of replication-competent viruses that can selectively infect and kill cancer cells while leaving healthy cells intact, are emerging as promising living anticancer agents. Unlike traditional drugs composed of non-replicating compounds or biomolecules, the replicative nature of viruses confer unique pharmacokinetic properties that require further studies. Despite some pharmacokinetics studies of OVs, mechanistic insights into the connection between OV pharmacokinetics and antitumor efficacy remain vague. Here, we characterized the pharmacokinetic profile of oncolytic virus M1 (OVM) in immunocompetent mouse tumor models and identified the JAK‒STAT pathway as a key modulator of OVM pharmacokinetics. By suppressing the JAK‒STAT pathway, early OVM pharmacokinetics are ameliorated, leading to enhanced tumor-specific viral accumulation, increased AUC and Cmax, and improved antitumor efficacy. Rather than compromising antitumor immunity after JAK‒STAT inhibition, the improved pharmacokinetics of OVM promotes T cell recruitment and activation in the tumor microenvironment, providing an optimal opportunity for the therapeutic outcome of immune checkpoint blockade, such as anti-PD-L1. Taken together, this study advances our understanding of the pharmacokinetic-pharmacodynamic relationship in OV therapy.

2.
Oncogene ; 42(48): 3575-3588, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37864032

RESUMO

Oncolytic viruses are emerging as promising anticancer agents. Although the essential biological function of N-glycosylation on viruses are widely accepted, roles of N-glycan and glycan-processing enzyme in oncolytic viral therapy are remain elusive. Here, via cryo-EM analysis, we identified three distinct N-glycans on the envelope of oncolytic virus M1 (OVM) as being necessary for efficient receptor binding. E1-N141-glycan has immediate impact on the binding of MXRA8 receptor, E2-N200-glycan mediates the maturation of E2 from its precursor PE2 which is unable to bind with MXRA8, and E2-N262-glycan slightly promotes receptor binding. The necessity of OVM N-glycans in receptor binding make them indispensable for oncolysis in vitro and in vivo. Further investigations identified STT3A, a key catalytic subunit of oligosaccharyltransferase (OST), as the determinant of OVM N-glycosylation, and STT3A expression in tumor cells is positively correlated with OVM-induced oncolysis. Increased STT3A expression was observed in various solid tumors, pointing to a broad-spectrum anticancer potential of OVM. Collectively, our research supports the importance of STT3A-mediated N-glycosylation in receptor binding and oncolysis of OVM, thus providing a novel predictive biomarker for OVM.


Assuntos
Hexosiltransferases , Vírus Oncolíticos , Humanos , Glicosilação , Polissacarídeos/metabolismo , Hexosiltransferases/genética , Hexosiltransferases/metabolismo , Proteínas de Membrana/metabolismo
3.
Cell Rep Med ; 4(10): 101229, 2023 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-37820722

RESUMO

Although promising, dendritic cell (DC) vaccines still provide limited clinical benefits, mainly due to the immunosuppressive tumor microenvironment (TME) and the lack of tumor-associated antigens (TAAs). Oncolytic virus therapy is an ideal strategy to overcome immunosuppression and expose TAAs; therefore, they may work synergistically with DC vaccines. In this study, we demonstrate that oncolytic virus M1 (OVM) can enhance the antitumor effects of DC vaccines across diverse syngeneic mouse tumor models by increasing the infiltration of CD8+ effector T cells in the TME. Mechanically, we show that tumor cells counteract DC vaccines through the SIRPα-CD47 immune checkpoint, while OVM can downregulate SIRPα in DCs and CD47 in tumor cells. Since OVM upregulates PD-L1 in DCs, combining PD-L1 blockade with DC vaccines and OVM further enhances antitumor activity. Overall, OVM strengthens the antitumor efficacy of DC vaccines by targeting the SIRPα-CD47 axis, which exerts dominant immunosuppressive effects on DC vaccines.


Assuntos
Vírus Oncolíticos , Vacinas , Camundongos , Animais , Vírus Oncolíticos/genética , Antígeno CD47/genética , Antígeno B7-H1 , Linhagem Celular Tumoral , Antígenos de Neoplasias
4.
Cell Death Dis ; 14(3): 179, 2023 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-36872411

RESUMO

Cholesterol metabolism plays a critical role in the progression of hepatocellular carcinoma (HCC), but it is not clear how cholesterol metabolism is regulated. The tubulin beta class I genes (TUBBs) are associated with the prognosis of many different cancers. To confirm the function of TUBBs in HCC, the Kaplan-Meier method and Cox analyses were performed using TCGA and GSE14520 datasets. A higher expression of TUBB2B is an independent prognostic factor for shorter over survival in HCC patients. Deletion of TUBB2B in hepatocytes inhibits proliferation and promotes tumor cell apoptosis, while over-expression of TUBB2B has the opposite function. This result was confirmed in a mouse xenograft tumor model. Mechanistically, TUBB2B induces the expression of CYP27A1, an enzyme responsible for the conversion of cholesterol to 27-hydroxycholesterol, which leads to the up-regulation of cholesterol and the progression of HCC. In addition, TUBB2B regulates CYP27A1 via human hepatocyte nuclear factor 4alpha (HNF4A). These findings indicated that TUBB2B functions as an oncogene in HCC, and plays a role in promoting cell proliferation and anti-apoptosis through targeting HNF4A/CYP27A1/cholesterol.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Humanos , Camundongos , Apoptose , Colestanotriol 26-Mono-Oxigenase , Sistema Enzimático do Citocromo P-450 , Modelos Animais de Doenças , Fator 4 Nuclear de Hepatócito , Hepatócitos , Oncogenes , Tubulina (Proteína)
5.
Signal Transduct Target Ther ; 7(1): 100, 2022 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-35393389

RESUMO

Over the last decade, oncolytic virus (OV) therapy has shown its promising potential in tumor treatment. The fact that not every patient can benefit from it highlights the importance for defining biomarkers that help predict patients' responses. As particular self-amplifying biotherapeutics, the anti-tumor effects of OVs are highly dependent on the host factors for viral infection and replication. By using weighted gene co-expression network analysis (WGCNA), we found matrix remodeling associated 8 (MXRA8) is positively correlated with the oncolysis induced by oncolytic virus M1 (OVM). Consistently, MXRA8 promotes the oncolytic efficacy of OVM in vitro and in vivo. Moreover, the interaction of MXRA8 and OVM studied by single-particle cryo-electron microscopy (cryo-EM) showed that MXRA8 directly binds to this virus. Therefore, MXRA8 acts as the entry receptor of OVM. Pan-cancer analysis showed that MXRA8 is abundant in most solid tumors and is highly expressed in tumor tissues compared with adjacent normal ones. Further study in cancer cell lines and patient-derived tumor tissues revealed that the tumor selectivity of OVM is predominantly determined by a combinational effect of the cell membrane receptor MXRA8 and the intracellular factor, zinc-finger antiviral protein (ZAP). Taken together, our study may provide a novel dual-biomarker for precision medicine in OVM therapy.


Assuntos
Neoplasias , Terapia Viral Oncolítica , Vírus Oncolíticos , Microscopia Crioeletrônica , Humanos , Imunoglobulinas , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/terapia , Vírus Oncolíticos/genética
7.
Oncogene ; 40(29): 4783-4795, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34155344

RESUMO

Triple-negative breast cancer (TNBC) is the most aggressive molecular subtype among breast tumors and remains a challenge even for the most current therapeutic regimes. Here, we demonstrate that oncolytic alphavirus M1 effectively kills both TNBC and non-TNBC. ER-stress and apoptosis pathways are responsible for the cell death in non-TNBC as reported in other cancer types, yet the cell death in TNBC does not depend on these pathways. Transcriptomic analysis reveals that the M1 virus activates necroptosis in TNBC, which can be pharmacologically blocked by necroptosis inhibitors. By screening a library of clinically available compounds commonly used for breast cancer treatment, we find that Doxorubicin enhances the oncolytic effect of the M1 virus by up to 100-fold specifically in TNBC in vitro, and significantly stalls the tumor growth of TNBC in vivo, through promoting intratumoral virus replication and further triggering apoptosis in addition to necroptosis. These findings reveal a novel antitumor mechanism and a new combination regimen of the M1 oncolytic virus in TNBC, and highlight a need to bridge molecular diagnosis with virotherapy.


Assuntos
Neoplasias de Mama Triplo Negativas , Doxorrubicina , Terapia Viral Oncolítica
8.
Hum Gene Ther ; 32(3-4): 158-165, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33504253

RESUMO

Alphavirus M1 is a promising oncolytic virus for cancer therapy. Here, we constructed a fluorescent reporter virus for real-time visualization and quantification of M1 virus both in vitro and in vivo. The reporter-encoding M1 virus maintained the characteristics of parental virus in the aspects of structure, replication capacity, the feature to induce cytopathic cell death, and the property of tumor targeting. The fluorescence is positively correlated with virus replication both in vitro and in vivo. More importantly, the reporter can be stably expressed for at least 10 generations in a serial passage assay. In summary, we successfully constructed stable and authentic reporter viruses for studying M1 virus and provided a feasible technical route for gene modification of oncolytic virus M1.


Assuntos
Alphavirus , Neoplasias , Terapia Viral Oncolítica , Vírus Oncolíticos , Alphavirus/genética , Linhagem Celular Tumoral , Humanos , Neoplasias/genética , Neoplasias/terapia , Vírus Oncolíticos/genética , Replicação Viral
9.
Virol Sin ; 36(4): 655-666, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33481190

RESUMO

Oncolytic alphavirus M1 has been shown to selectively target and kill cancer cells, but cytopathic morphologies induced by M1 virus and the life cycle of the M1 strain in cancer cells remain unclear. Here, we study the key stages of M1 virus infection and replication in the M1 virus-sensitive HepG2 liver cancer cell line by transmission electron microscopy, specifically examining viral entry, assembly, maturation and release. We found that M1 virus induces vacuolization of cancer cells during infection and ultimately nuclear marginalization, a typical indicator of apoptosis. Specifically, our results suggest that the endoplasmic reticulum participates in the assembly of nucleocapsids. In the early and late stage of infection, three kinds of special cytopathic vacuoles are formed and appear to be involved in the replication, maturation and release of the virus. Taken together, our data displayed the process of M1 virus infection of tumor cells and provide the structural basis for the study of M1 virus-host interactions.


Assuntos
Alphavirus , Neoplasias , Terapia Viral Oncolítica , Vírus Oncolíticos , Animais , Linhagem Celular Tumoral , Estágios do Ciclo de Vida , Neoplasias/terapia , Replicação Viral
10.
Oncogene ; 39(37): 5995-6008, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32770142

RESUMO

Avoiding immune destruction is essential for tumorigenesis. Current research into the interaction between tumor and immunological niches complement tumor pathology beyond cancer genetics. Intrinsic host defense immunity is a specialized innate immunity component to restrict viral infection. However, whether intrinsic immunity participates in tumor pathology is unclear. Previously, we identified a zinc-finger antiviral protein ZAP that is commonly downregulated in a panel of clinical cancer specimens. However, whether ZAP has an impact on tumor development was unknown. Here we report ZAP as a genuine tumor suppressor. Pan-caner analysis with TCGA data from 712 patients and large-scale immunohistochemistry in tissue microarrays from 1552 patients reveal that ZAP is prevalently downregulated, and associated with poor survival in liver, colon, and bladder cancer patients. Ectopic over-expression of ZAP inhibits the malignant phenotypes of colorectal tumor by cell cycle arrest. Using RNA immunoprecipitation and RNA decay assays, we demonstrate that ZAP directly and specifically binds to and degrades the transcript of TRAILR4, which in turn represses TRAILR4 expression and inhibits the aggressiveness of colorectal cancer cells. Furthermore, our CRISPR-engineered mice models show that loss-of-function of ZAP synergizes with APC-deficiency to drive malignant colorectal cancer in vivo. Overall, we identify a previously unknown function of the antiviral factor ZAP in colorectal tumorigenesis, linking intrinsic immunity to tumor pathogenetics.


Assuntos
Neoplasias Colorretais/etiologia , Proteínas Supressoras de Tumor/genética , Dedos de Zinco/genética , Animais , Biomarcadores Tumorais , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Modelos Animais de Doenças , Feminino , Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Mutação com Perda de Função , Camundongos , Fenótipo , Prognóstico , Ligação Proteica , Estabilidade de RNA , RNA Mensageiro/genética , Proteínas de Ligação a RNA/genética , Proteínas Repressoras/genética , Receptores Chamariz do Fator de Necrose Tumoral/genética , Proteínas Supressoras de Tumor/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Sci Rep ; 6: 25491, 2016 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-27150638

RESUMO

Traditional Chinese Medicine (TCM) has been developed for thousands of years and has formed an integrated theoretical system based on a large amount of clinical practice. However, essential ingredients in TCM herbs have not been fully identified, and their precise mechanisms and targets are not elucidated. In this study, a new strategy combining comprehensive two-dimensional K562/cell membrane chromatographic system and in silico target identification was established to characterize active components from Indigo naturalis, a famous TCM herb that has been widely used for the treatment of leukemia in China, and their targets. Three active components, indirubin, tryptanthrin and isorhamnetin, were successfully characterized and their anti-leukemia effects were validated by cell viability and cell apoptosis assays. Isorhamnetin, with undefined cancer related targets, was selected for in silico target identification. Proto-oncogene tyrosine-protein kinase (Src) was identified as its membrane target and the dissociation constant (Kd) between Src and isorhamnetin was 3.81 µM. Furthermore, anti-leukemia effects of isorhamnetin were mediated by Src through inducing G2/M cell cycle arrest. The results demonstrated that the integrated strategy could efficiently characterize active components in TCM and their targets, which may bring a new light for a better understanding of the complex mechanism of herbal medicines.


Assuntos
Antineoplásicos/farmacologia , Membrana Celular/química , Membrana Celular/efeitos dos fármacos , Indigofera/química , Antineoplásicos/isolamento & purificação , Apoptose , Sobrevivência Celular/efeitos dos fármacos , China , Cromatografia , Biologia Computacional , Humanos , Células K562/química , Células K562/efeitos dos fármacos , Estruturas Vegetais/química , Proto-Oncogene Mas
12.
Sci Rep ; 5: 9202, 2015 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-25776856

RESUMO

The benefits of adjuvant cytokine-induced killer (CIK) cell immunotherapy for hepatocellular carcinoma (HCC) remain mixed among patients. Here, we constructed a prognostic nomogram to enable individualized predictions of survival benefit of adjuvant CIK cell treatment for HCC patients. Survival analysis showed that the median overall survival (OS) and progression-free survival (PFS) for patients in the hepatectomy/CIK combination group were 41 and 16 months, respectively, compared to 28 and 12 months for patients in the hepatectomy alone group (control). Based on multivariate analysis of the entire cohort, independent factors for OS were tumor size, tumor capsule, pathological grades, total bilirubin, albumin, prothrombin time, alpha-fetoprotein, and tumor number, which were incorporated into the nomogram. The survival prediction model performed well, as assessed by the c-index and calibration curve. Internal validation revealed a c-index of 0.698, which was significantly greater than the c-index value of the TNM (tumor-node-metastasis) staging systems of 0.634. The calibration curves fitted well. In conclusions, our developed nomogram resulted in more accurate individualized predictions of the survival benefit from adjuvant CIK cell treatment after hepatectomy. The model may provide valuable information to aid in the decision making regarding the application of adjuvant CIK cell immunotherapy.


Assuntos
Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/terapia , Células Matadoras Induzidas por Citocinas/imunologia , Imunoterapia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/mortalidade , Terapia Combinada , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Estudos Retrospectivos , Resultado do Tratamento , Carga Tumoral , Adulto Jovem
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