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1.
J Immunol ; 213(5): 559-566, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-38975727

RESUMO

Inactivating mutations of Foxp3, the master regulator of regulatory T cell development and function, lead to immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome in mice and humans. IPEX is a fatal autoimmune disease, with allogeneic stem cell transplant being the only available therapy. In this study, we report that a single dose of adeno-associated virus (AAV)-IL-27 to young mice with naturally occurring Foxp3 mutation (Scurfy mice) substantially ameliorates clinical symptoms, including growth retardation and early fatality. Correspondingly, AAV-IL-27 gene therapy significantly prevented naive T cell activation, as manifested by downregulation of CD62L and upregulation of CD44, and immunopathology typical of IPEX. Because IL-27 is known to induce IL-10, a key effector molecule of regulatory T cells, we evaluated the contribution of IL-10 induction by crossing IL-10-null allele to Scurfy mice. Although IL-10 deficiency does not affect the survival of Scurfy mice, it largely abrogated the therapeutic effect of AAV-IL-27. Our study revealed a major role for IL-10 in AAV-IL-27 gene therapy and demonstrated that IPEX is amenable to gene therapy.


Assuntos
Fatores de Transcrição Forkhead , Doenças Genéticas Ligadas ao Cromossomo X , Terapia Genética , Mutação em Linhagem Germinativa , Interleucina-10 , Linfócitos T Reguladores , Animais , Fatores de Transcrição Forkhead/genética , Camundongos , Interleucina-10/genética , Interleucina-10/imunologia , Terapia Genética/métodos , Linfócitos T Reguladores/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Interleucinas/imunologia , Interleucinas/genética , Diarreia/genética , Diarreia/terapia , Diarreia/imunologia , Enteropatias/imunologia , Enteropatias/genética , Enteropatias/terapia , Dependovirus/genética , Camundongos Endogâmicos C57BL , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/terapia , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/congênito , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/terapia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/congênito , Camundongos Knockout , Ativação Linfocitária/imunologia , Humanos , Interleucina-27/genética
2.
J Immunol ; 211(5): 895-902, 2023 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-37459051

RESUMO

IL-27 is a pleiotropic cytokine that exhibits stimulatory/regulatory functions on multiple lineages of immune cells and has a potential to be used as a therapeutic for cancer. We have recently demonstrated that administration of IL-27 producing adeno-associated virus (AAV-IL-27) exhibits potent inhibition of tumor growth in mouse models. In this study, we demonstrate that AAV-IL-27 treatment leads to significant expansion of CD11b+Gr1+ myeloid cells. AAV-IL-27-induced expansion of CD11b+Gr1+ cells is IL-27R-dependent and requires Stat3 signaling, but it is inhibited by Stat1 signaling. AAV-IL-27 treatment does not increase the self-renewal capacity of CD11b+Gr1+ cells but induces significant expansion of Lin-Sca1+c-Kit+ (LSK) and granulocyte-monocyte progenitor cells. Despite exhibiting significant suppression of T cells in vitro, IL-27-induced CD11b+Gr1+ cells lost the tumor-promoting activity in vivo and overall play an antitumor role. In tumors from AAV-IL-27-treated mice, CD11b+Gr1+ cells are largely F4/80+ and express high levels of MHC class I/II and M1 macrophage markers. Thus, IL-27 gene therapy induces Stat3-mediated expansion of CD11b+Gr1+ myeloid cells and promotes accumulation of M1 macrophages in the tumor microenvironment.


Assuntos
Interleucina-27 , Camundongos , Animais , Microambiente Tumoral , Macrófagos , Células Mieloides , Linfócitos T , Antígeno CD11b
3.
J Theor Biol ; 579: 111704, 2024 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-38104658

RESUMO

Interleukin-27 (IL-27) is known to play opposing roles in immunology. The present paper considers, specifically, the role IL-27 plays in cancer immunotherapy when combined with immune checkpoint inhibitor anti-PD-1. We first develop a mathematical model for this combination therapy, by a system of Partial Differential Equations, and show agreement with experimental results in mice injected with melanoma cells. We then proceed to simulate tumor volume with IL-27 injection at a variable dose F and anti-PD-1 at a variable dose g. We show that in some range of "small" values of g, as f increases tumor volume decreases as long as fFc(g), where Fc(g) is a monotone increasing function of g. This demonstrates that IL-27 can be both anti-cancer and pro-cancer, depending on the ranges of both anti-PD-1 and IL-27.


Assuntos
Interleucina-27 , Melanoma , Animais , Camundongos , Interleucina-27/uso terapêutico , Melanoma/patologia , Terapia Combinada , Modelos Teóricos , Imunoterapia/métodos
4.
J Immunol ; 208(9): 2239-2245, 2022 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-35418466

RESUMO

IL-27 is a pleiotropic cytokine that exhibits stimulatory/regulatory functions on multiple lineages of immune cells including T lymphocytes. In this study, we demonstrate that IL-27 directly induces CCL5 production by T lymphocytes, particularly CD8+ T cells in vitro and in vivo. IL-27-induced CCL5 production is IL-27R-dependent. In CD4+ T cells, IL-27-induced CCL5 production was primarily dependent on Stat1 activation, whereas in CD8+ T cells, Stat1 deficiency does not abrogate CCL5 induction. A chromatin immunoprecipitation assay revealed that in the CCL5 promoter region, both putative Stat3 binding sites exhibit significant binding to Stat3, whereas only one out of four Stat1 binding sites displays moderate binding to Stat1. In tumor-bearing mice, IL-27 induced dramatic production of CCL5 in tumor-infiltrating T cells. IL-27-induced CCL5 appears to contribute to an IL-27-mediated antitumor effect. This is signified by diminished tumor inhibition in anti-CCL5- and IL-27-treated mice. Additionally, intratumor delivery of CCL5 mRNA using lipid nanoparticles significantly inhibited tumor growth. Thus, IL-27 induces robust CCL5 production by T cells, which contributes to antitumor activity.


Assuntos
Interleucina-27 , Animais , Linfócitos T CD8-Positivos , Citocinas , Expressão Gênica , Lipossomos , Camundongos , Nanopartículas
5.
Nucleic Acids Res ; 49(D1): D1431-D1444, 2021 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-33095866

RESUMO

With the study of human diseases and biological processes increasing, a large number of non-coding variants have been identified and facilitated. The rapid accumulation of genetic and epigenomic information has resulted in an urgent need to collect and process data to explore the regulation of non-coding variants. Here, we developed a comprehensive variation annotation database for human (VARAdb, http://www.licpathway.net/VARAdb/), which specifically considers non-coding variants. VARAdb provides annotation information for 577,283,813 variations and novel variants, prioritizes variations based on scores using nine annotation categories, and supports pathway downstream analysis. Importantly, VARAdb integrates a large amount of genetic and epigenomic data into five annotation sections, which include 'Variation information', 'Regulatory information', 'Related genes', 'Chromatin accessibility' and 'Chromatin interaction'. The detailed annotation information consists of motif changes, risk SNPs, LD SNPs, eQTLs, clinical variant-drug-gene pairs, sequence conservation, somatic mutations, enhancers, super enhancers, promoters, transcription factors, chromatin states, histone modifications, chromatin accessibility regions and chromatin interactions. This database is a user-friendly interface to query, browse and visualize variations and related annotation information. VARAdb is a useful resource for selecting potential functional variations and interpreting their effects on human diseases and biological processes.


Assuntos
Doença de Alzheimer/genética , Bases de Dados Genéticas , Diabetes Mellitus Tipo 2/genética , Variação Genética , Genoma Humano , Locos de Características Quantitativas , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Cromatina , Montagem e Desmontagem da Cromatina , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Elementos Facilitadores Genéticos , Humanos , Internet , Anotação de Sequência Molecular , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Software
6.
Nano Lett ; 21(20): 8609-8618, 2021 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-34661419

RESUMO

Tumor heterogeneity, often leading to metastasis, limits the development of tumor therapy. Personalized therapy is promising to address tumor heterogeneity. Here, a vesicle system was designed to enhance innate immune response and amplify personalized immunotherapy. Briefly, the bacterial outer membrane vesicle (OMV) was hybridized with the cell membrane originated from the tumor (mT) to form new functional vesicles (mTOMV). In vitro experiments revealed that the mTOMV strengthened the activation of innate immune cells and increased the specific lysis ability of T cells in homogeneous tumors. In vivo experiments showed that the mTOMV effectively accumulated in inguinal lymph nodes, then inhibited lung metastasis. Besides, the mTOMV evoked adaptive immune response in homologous tumor rather than the heterogeneous tumor, reversibly demonstrating the effects of personalized immunotherapy. The functions to inhibit tumor growth and metastasis accompanying good biocompatibility and simple preparation procedure of mTOMV provide their great potential for clinical applications.


Assuntos
Membrana Externa Bacteriana , Imunoterapia , Membrana Celular , Imunidade Inata , Linfócitos T
7.
Nucleic Acids Res ; 47(W1): W248-W255, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31028388

RESUMO

Super-enhancers (SEs) have prominent roles in biological and pathological processes through their unique transcriptional regulatory capability. To date, several SE databases have been developed by us and others. However, these existing databases do not provide downstream or upstream regulatory analyses of SEs. Pathways, transcription factors (TFs), SEs, and SE-associated genes form complex regulatory networks. Therefore, we designed a novel web server, SEanalysis, which provides comprehensive SE-associated regulatory network analyses. SEanalysis characterizes SE-associated genes, TFs binding to target SEs, and their upstream pathways. The current version of SEanalysis contains more than 330 000 SEs from more than 540 types of cells/tissues, 5042 TF ChIP-seq data generated from these cells/tissues, DNA-binding sequence motifs for ∼700 human TFs and 2880 pathways from 10 databases. SEanalysis supports searching by either SEs, samples, TFs, pathways or genes. The complex regulatory networks formed by these factors can be interactively visualized. In addition, we developed a customizable genome browser containing >6000 customizable tracks for visualization. The server is freely available at http://licpathway.net/SEanalysis.


Assuntos
Bases de Dados Genéticas , Elementos Facilitadores Genéticos/genética , Regulação da Expressão Gênica/genética , Redes Reguladoras de Genes/genética , Software , Sítios de Ligação/genética , Humanos , Internet , Fatores de Transcrição/genética
8.
Cancer Immunol Immunother ; 69(11): 2333-2343, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32514618

RESUMO

Patients with pediatric cancers such as neuroblastoma (NB) are often unresponsive to checkpoint blockade immunotherapy. One major factor in pediatric tumor resistance to immunotherapy is considered to be the low mutation rate of pediatric tumors. Another factor may be the overexpression of additional inhibitory pathways. While analyzing the RNA-sequencing database TARGET, we found that human NB tumors overexpress immune checkpoint molecule CD200. To determine its significance and impact on tumor immune microenvironment, we analyzed 49 cases of previously untreated, surgically removed NB tumors using immunohistochemistry and multi-color flow cytometry (FACS). We found that CD200 is overexpressed in more than 90% of NB tumors. In the tumor microenvironment of NB, CD200 is mainly overexpressed in CD45- NB tumor cells, while its cognate receptor (CD200R) is mainly expressed in HLA-DR+CD14+ myeloid cells and CD11c+ dendritic cells. Low-level expression of CD200R is also observed in tumor-infiltrating CD4+ and CD8+ T cells. In NB tumors with higher CD200 expression (CD200high), we observed lower numbers of HLA-DR+CD14+ myeloid cells and less tumor-infiltrating CD4+ and CD8+ T cells. Moreover, we found that CD4+ and CD8+ T cells produced less IFN-γ and/or TNF-α in CD200high NB tumors. Thus, CD200-CD200R pathway appears to downregulate anti-tumor immunity in the tumor microenvironment of NB tumors, and blockade of this pathway may be beneficial for NB patients.


Assuntos
Antígenos CD/imunologia , Linfócitos do Interstício Tumoral/imunologia , Neuroblastoma/imunologia , Microambiente Tumoral/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Receptores de Orexina/imunologia , Evasão Tumoral/imunologia
9.
Adv Exp Med Biol ; 1223: 155-165, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32030689

RESUMO

Tumor-associated inflammation and immune responses are key components in the tumor microenvironment (TME) which regulate tumor growth, progression, and metastasis. Tumor-associated myeloid cells (TAMCs) are a group of cells that play multiple key roles including induction of tumor-associated inflammation/angiogenesis and regulation of tumor-specific T-cell responses. Thus, identification and characterization of key pathways that can regulate TAMCs are of critical importance for developing cancer immunotherapy. Recent studies suggest that CD200-CD200 receptor (CD200R) interaction may be important in regulating the TME via affecting TAMCs. In this chapter, we will give a brief overview of the CD200-CD200R axis, including the biology behind CD200-CD200R interaction and the role(s) it plays in tumor microenvironment and tumor growth, and activation/effector functions of T cells. We will also discuss CD200-CD200R's role as potential checkpoint molecules for cancer immunotherapy. Further investigation of the CD200-CD200R pathway will not only advance our understanding of tumor pathogenesis and immunity but also provide the rationale for CD200-CD200R-targeted immunotherapy of human cancer.


Assuntos
Antígenos CD/metabolismo , Imunoterapia , Neoplasias/terapia , Receptores de Orexina/metabolismo , Microambiente Tumoral/imunologia , Antígenos CD/imunologia , Humanos , Células Mieloides/imunologia , Células Mieloides/metabolismo , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias/patologia , Receptores de Orexina/imunologia
10.
Br J Cancer ; 118(11): 1476-1484, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29765149

RESUMO

BACKGROUND: Oesophageal squamous cell carcinoma (ESCC) is one of the most malignant cancers worldwide. Treatment of ESCC is in progress through accurate staging and risk assessment of patients. The emergence of potential molecular markers inspired us to construct novel staging systems with better accuracy by incorporating molecular markers. METHODS: We measured H scores of 23 protein markers and analysed eight clinical factors of 77 ESCC patients in a training set, from which we identified an optimal MASAN (MYC, ANO1, SLC52A3, Age and N-stage) signature. We constructed MASAN models using Cox PH models, and created MASAN-staging systems based on k-means clustering and minimum-distance classifier. MASAN was validated in a test set (n = 77) and an independent validation set (n = 150). RESULTS: MASAN possessed high predictive accuracies and stratified ESCC patients into three prognostic groups that were more accurate than the current pTNM-staging system for both overall survival and disease-free survival. To facilitate clinical utilisation, we also constructed MASAN-SI staging systems based on staining indices (SI) of protein markers, which possessed similar prognostic performance as MASAN. CONCLUSION: MASAN provides a good alternative staging system for ESCC prognosis with a high precision using a simple model.


Assuntos
Anoctamina-1/metabolismo , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/patologia , Proteínas de Membrana Transportadoras/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fatores Etários , Algoritmos , Biomarcadores Tumorais/metabolismo , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Sensibilidade e Especificidade , Análise de Sobrevida , Análise Serial de Tecidos
11.
Pediatr Blood Cancer ; 65(2)2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28921877

RESUMO

BACKGROUND: Infantile fibrosarcoma (IFS) is a rare pediatric malignancy with relatively good prognosis, but the risk of progression or recurrence after therapy exists. To understand the immune microenvironment of IFS and determine if immunotherapy is a potential treatment, we analyzed T-cell responses in IFS tumors. PROCEDURE: IFS tumors were analyzed by immunohistochemistry and multicolor flow cytometry to characterize immune cell infiltration and function. Tumor infiltrating lymphocytes (TILs) were expanded in vitro and evaluated for recognition of autologous tumor cells. Real-time PCR was applied to evaluate tumor expression of chemokines/cytokines and tumor antigens. RESULTS: Significant infiltration of both CD4+ and CD8+ T cells was found in seven of 10 IFS but rarely found in age- and sex-matched rhabdomyosarcoma tumors. The TILs from recurrent IFS tumors expressed high levels of costimulatory molecules such as CD28, 4-1BB, and OX40, but little or no coinhibitory molecules such as PD-1 and CTLA4, Tim3, Lag3, and CD39. Upon activation, large portions of TILs produced IFN-γ and TNF-α. Eighteen out of 40 T cell lines generated from surgically removed tumors could recognize autologous tumor cells. Moreover, we found that IFS tumors expressed high levels of T-cell chemokines such as CXCL10 and CXCL16, and also classic tumor antigens such as CTAG2, GAGE, and NY-ESO-1, whose expression could be further enhanced by treatment with epigenetic modulator decitabine. CONCLUSIONS: IFS tumors are highly immunogenic and expansion of TILs followed by adoptive cell transfer could be a potential immunotherapy for IFS patients undergoing tumor recurrence.


Assuntos
Antígenos de Diferenciação/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Citocinas/imunologia , Fibrossarcoma/imunologia , Proteínas de Neoplasias/imunologia , Adolescente , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Criança , Pré-Escolar , Feminino , Fibrossarcoma/patologia , Fibrossarcoma/terapia , Humanos , Imunoterapia , Lactente , Masculino
12.
J Immunol ; 197(4): 1489-97, 2016 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-27385779

RESUMO

CD200 is a cell surface glycoprotein that functions through engaging CD200R on cells of the myeloid lineage and inhibits their functions. Expression of CD200 was implicated in a variety of human cancer cells, including melanoma cells; however, its roles in tumor growth and immunity are not clearly understood. In this study, we used CD200R-deficient mice and the B16 tumor model to evaluate this issue. We found that CD200R-deficient mice exhibited accelerated growth of CD200(+), but not CD200(-), B16 tumors. Strikingly, CD200R-deficient mice receiving CD200(+) B16 cells i.v. exhibited massive tumor growth in multiple organs, including liver, lung, kidney, and peritoneal cavity, whereas the growth of the same tumors in wild-type mice was limited. CD200(+) tumors grown in CD200R-deficient mice contained higher numbers of CD11b(+)Ly6C(+) myeloid cells, exhibited increased expression of VEGF and HIF1α genes with increased angiogenesis, and showed significantly reduced infiltration of CD4(+) and CD8(+) T cells, presumably as the result of reduced expression of T cell chemokines, such as CXCL9 and CXCL16. The liver from CD200R-deficient mice, under metastatic growth of CD200(+) tumors, contained significantly increased numbers of CD11b(+)Gr1(-) myeloid cells and Foxp3(+) regulatory T cells and reduced numbers of NK cells. Liver T cells also had a reduced capacity to produce IFN-γ or TNF-α. Taken together, we revealed a critical role for CD200R signaling in limiting the growth and metastasis of CD200(+) tumors. Thus, targeting CD200R signaling may potentially interfere with the metastatic growth of CD200(+) tumors, like melanoma.


Assuntos
Antígenos CD/metabolismo , Melanoma Experimental/patologia , Invasividade Neoplásica/patologia , Transdução de Sinais/fisiologia , Animais , Antígenos CD/imunologia , Citometria de Fluxo , Imunofluorescência , Técnicas de Inativação de Genes , Humanos , Imuno-Histoquímica , Linfócitos do Interstício Tumoral/patologia , Melanoma Experimental/imunologia , Melanoma Experimental/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Invasividade Neoplásica/imunologia , Neovascularização Patológica/imunologia , Neovascularização Patológica/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Microambiente Tumoral/fisiologia
13.
Immunology ; 152(4): 638-647, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28758191

RESUMO

Stem cell antigen-1 (Sca-1/Ly6A/E) is a cell surface glycoprotein that is often used as a biomarker for stem cells and cell stemness. However, it is not clear what factors can directly induce the expression of Sca-1/Ly6A/E in T lymphocytes in vivo, and if induction of Sca-1 is associated with T cell stemness. In this study, we show that interleukin-27 (IL-27), a member of the IL-12 family of cytokines, directly induces Sca-1 expression in T cells in vivo. We found that mice-deficient for IL-27 (either P28 or EBI3) or its signalling (IL-27Rα) had profound reduction of Sca-1 expression in naive (CD62L+  CD44- ), memory (CD62L+  CD44+ ) and effector (CD62L-  CD44+ ) T cells. In contrast, in vivo delivery of IL-27 using adeno-associated viral vectors strongly induced the expression of Sca-1 in naive and memory/effector T-cell populations in an IL-27 receptor- or signal transducer and activator of transcription 1-dependent manner. Interestingly, IL-27-induced Sca-1+ T cells do not express or up-regulate classic stem cell-associated genes such as Nanog, Oct4, Sox2 and Ctnnb1. However, IL-27-induced Sca-1+ T cells had increased expression of effector/memory-associated transcription factor T-bet, Eomes and Blimp1. Hence, IL-27 signalling directly induces the expression of Sca-1/Ly6A/E expression in T cells. Direct expansion of Sca-1+  CD62L+  CD44- T memory stem cells may explain why IL-27 enhances T-cell memory.


Assuntos
Antígenos Ly/imunologia , Regulação da Expressão Gênica/imunologia , Memória Imunológica , Interleucinas/imunologia , Proteínas de Membrana/imunologia , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Animais , Antígenos CD/genética , Antígenos CD/imunologia , Antígenos Ly/genética , Interleucinas/genética , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Receptores de Citocinas/genética , Receptores de Citocinas/imunologia , Receptores de Interleucina , Transdução de Sinais/genética
14.
Mol Cancer ; 16(1): 9, 2017 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-28086904

RESUMO

BACKGROUND: With more than 600,000 mortalities each year, colorectal cancer (CRC) is the third most commonly diagnosed type of cancer worldwide. Recently, mechanisms involving noncoding RNAs have been implicated in the development of CRC. METHODS: We examined expression levels of lncRNA CRNDE and miR-181a-5p in 64 cases of CRC tissues and cell lines by qRT-PCR. Gain-of-function and loss-of-function assays were performed to examine the effect of CRNDE and miR-181a-5p on proliferation and chemoresistance of CRC cells. Using fluorescence reporter and western blot assays, we also explored the possible mechanisms of CRNDE in CRC cells. RESULTS: In this study, we found that the expression levels of the CRNDE were upregulated in CRC clinical tissue samples. We identified microRNA miR-181a-5p as an inhibitory target of CRNDE. Both CRNDE knockdown and miR-181a-5p overexpression in CRC cell lines led to inhibited cell proliferation and reduced chemoresistance. We also determined that ß-catenin and TCF4 were inhibitory targets of miR-181a-5p, and that Wnt/ß-catenin signaling was inhibited by both CRNDE knockdown and miR-181a-5p overexpression. Significantly, we found that the repression of cell proliferation, the reduction of chemoresistance, and the inhibition of Wnt/ß-catenin signaling induced by CRNDE knockdown would require the increased expression of miR-181a-5p. CONCLUSIONS: Our study demonstrated that the lncRNA CRNDE could regulate the progression and chemoresistance of CRC via modulating the expression levels of miR-181a-5p and the activity of Wnt/ß-catenin signaling.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , RNA Longo não Codificante/genética , Via de Sinalização Wnt , Adulto , Idoso , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Interferência de RNA , Fator de Transcrição 4 , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Carga Tumoral , beta Catenina/genética , beta Catenina/metabolismo
15.
Proc Natl Acad Sci U S A ; 111(7): 2704-9, 2014 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-24550298

RESUMO

Brain ischemia and reperfusion activate the immune system. The abrupt development of brain ischemic lesions suggests that innate immune cells may shape the outcome of stroke. Natural killer (NK) cells are innate lymphocytes that can be swiftly mobilized during the earliest phases of immune responses, but their role during stroke remains unknown. Herein, we found that NK cells infiltrated the ischemic lesions of the human brain. In a mouse model of cerebral ischemia, ischemic neuron-derived fractalkine recruited NK cells, which subsequently determined the size of brain lesions in a T and B cell-independent manner. NK cell-mediated exacerbation of brain infarction occurred rapidly after ischemia via the disruption of NK cell tolerance, augmenting local inflammation and neuronal hyperactivity. Therefore, NK cells catalyzed neuronal death in the ischemic brain.


Assuntos
Infarto Encefálico/imunologia , Infarto Encefálico/fisiopatologia , Isquemia Encefálica/imunologia , Encéfalo/imunologia , Imunidade Inata/imunologia , Células Matadoras Naturais/imunologia , Acidente Vascular Cerebral/imunologia , Animais , Encéfalo/citologia , Infarto Encefálico/etiologia , Isquemia Encefálica/complicações , Quimiocina CX3CL1/metabolismo , Proteínas de Ligação a DNA/genética , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/metabolismo , Acidente Vascular Cerebral/complicações
16.
J BUON ; 21(1): 208-20, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27061550

RESUMO

PURPOSE: The present study was designed to explore the significant biomarkers and pathway-related modules for predicting the effects of eribulin relative to paclitaxel in ovarian cancer. METHODS: The gene expression data E-GEOD-50831 were downloaded from the European Bioinformatics Institute (EBI) database. Differentially expressed genes (DEGs) were screened. Subsequently, differential coexpression network was constructed. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and pathway-related modules mining were conducted. Topological centralities (degree, betweenness, closeness and stress) analyses for coexpression network and pathway-related modules were performed to explore hub genes and the most significant pathways. Then, we verified our findings in an independent sample set via RT-PCR and Western blotting. RESULTS: Centralities results of ESCO1, CDC27and MCM4 ranked the top five. Moreover, among the top 10% hub genes, CDC27, MCM4 and SOS1 were pathway-enriched genes in two networks. A total of 5 and 6 pathway-related modules were obtained under two drugs treatment. Based analyses of degree, betweenness and other centralities, DNA replication pathway-related module was the most significant under paclitaxel treatment, while cell cycle pathway-related module was the most significant under eribulin treatment. RT-PCR and Western blotting results were consistent with the bioinformatics results. The expression level of MCM4 was remarkably decreased under eribulin treatment relative to paclitaxel. CONCLUSIONS: The inhibition of ovarian cancer growth by paclitaxel and eribulin might be connected with downregulation of cell cycle and DNA replication pathway. Moreover, MCM4 signature might be a potential biomarker to predict the effect of eribulin in ovarian cancer.


Assuntos
Neoplasias Ovarianas/tratamento farmacológico , Acetiltransferases/análise , Biomarcadores , Biologia Computacional , Replicação do DNA , Feminino , Furanos/uso terapêutico , Redes Reguladoras de Genes , Humanos , Cetonas/uso terapêutico , Componente 4 do Complexo de Manutenção de Minicromossomo/análise , Neoplasias Ovarianas/química , Paclitaxel/uso terapêutico , Transdução de Sinais
17.
J Immunol ; 190(5): 2415-23, 2013 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-23345334

RESUMO

IL-35 is a member of the IL-12 family of cytokines that is comprised of an IL-12 p35 subunit and an IL-12 p40-related protein subunit, EBV-induced gene 3 (EBI3). IL-35 functions through IL-35R and has a potent immune-suppressive activity. Although IL-35 was demonstrated to be produced by regulatory T cells, gene-expression analysis revealed that it is likely to have a wider distribution, including expression in cancer cells. In this study, we demonstrated that IL-35 is produced in human cancer tissues, such as large B cell lymphoma, nasopharyngeal carcinoma, and melanoma. To determine the roles of tumor-derived IL-35 in tumorigenesis and tumor immunity, we generated IL-35-producing plasmacytoma J558 and B16 melanoma cells and observed that the expression of IL-35 in cancer cells does not affect their growth and survival in vitro, but it stimulates tumorigenesis in both immune-competent and Rag1/2-deficient mice. Tumor-derived IL-35 increases CD11b(+)Gr1(+) myeloid cell accumulation in the tumor microenvironment and, thereby, promotes tumor angiogenesis. In immune-competent mice, spontaneous CTL responses to tumors are diminished. IL-35 does not directly inhibit tumor Ag-specific CD8(+) T cell activation, differentiation, and effector functions. However, IL-35-treated cancer cells had increased expression of gp130 and reduced sensitivity to CTL destruction. Thus, our study indicates novel functions for IL-35 in promoting tumor growth via the enhancement of myeloid cell accumulation, tumor angiogenesis, and suppression of tumor immunity.


Assuntos
Interleucinas/imunologia , Linfoma Difuso de Grandes Células B/imunologia , Melanoma Experimental/irrigação sanguínea , Melanoma/imunologia , Neoplasias Nasofaríngeas/imunologia , Plasmocitoma/irrigação sanguínea , Animais , Antígeno CD11b/genética , Antígeno CD11b/imunologia , Carcinoma , Receptor gp130 de Citocina/genética , Receptor gp130 de Citocina/imunologia , Citotoxicidade Imunológica , Humanos , Interleucinas/genética , Interleucinas/farmacologia , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Melanoma/genética , Melanoma/patologia , Melanoma Experimental/genética , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Células Mieloides/efeitos dos fármacos , Células Mieloides/imunologia , Células Mieloides/patologia , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patologia , Neovascularização Patológica , Plasmocitoma/genética , Plasmocitoma/imunologia , Plasmocitoma/patologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/genética , Molécula-1 de Adesão Celular Endotelial a Plaquetas/imunologia , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/imunologia , Células Tumorais Cultivadas , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
18.
Eur J Immunol ; 43(2): 468-79, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23225163

RESUMO

IL-27 is a member of the IL-12 family of cytokines that is comprised of an IL-12 p40-related protein subunit, EBV-induced gene 3, and a p35-related subunit, p28. IL-27 functions through IL-27R and has been shown to have potent antitumor activity via activation of a variety of cellular components, including antitumor CD8(+) T-cell responses. However, the exact mechanisms of how IL-27 enhances antitumor CD8(+) T-cell responses remain unclear. Here we show that IL-27 significantly enhances the survival of activated tumor antigen-specific CD8(+) T cells in vitro and in vivo, and programs tumor antigen-specific CD8(+) T cells into memory precursor-like effector cells, characterized by upregulation of Bcl-6, SOCS3, Sca-1, and IL-10. While STAT3 activation and the CTL survival-enhancing effects can be independent of CTL IL-10 production, we show here that IL-27-induced CTL IL-10 production contributes to memory precursor cell phenotype induction, CTL memory, and tumor rejection. Thus, IL-27 enhances antitumor CTL responses via programming tumor antigen-specific CD8(+) T cells into a unique memory precursor type of effector cells characterized by a greater survival advantage. Our results have important implications for designing immunotherapy against human cancer.


Assuntos
Antígenos de Neoplasias/imunologia , Linfócitos T CD8-Positivos/imunologia , Memória Imunológica/imunologia , Interleucina-10/imunologia , Interleucinas/imunologia , Animais , Antígenos Ly/imunologia , Antígenos Ly/metabolismo , Antígenos de Neoplasias/metabolismo , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/imunologia , Interleucina-10/metabolismo , Interleucinas/metabolismo , Proteínas de Membrana/imunologia , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Proto-Oncogênicas c-bcl-6/imunologia , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Fator de Transcrição STAT3/imunologia , Fator de Transcrição STAT3/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina/imunologia , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Regulação para Cima/imunologia
19.
J Immunol ; 188(7): 3099-106, 2012 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-22387555

RESUMO

EBV-induced gene 3 (EBI3)-encoded protein can form heterodimers with IL-27P28 and IL-12P35 to form IL-27 and IL-35. IL-27 and IL-35 may influence autoimmunity by inhibiting Th17 differentiation and facilitating the inhibitory roles of Foxp3(+) regulatory T (Treg) cells, respectively. In this study, we have evaluated the development of experimental autoimmune encephalomyelitis (EAE) in EBI3-deficient mice that lack both IL-27 and IL-35. We found that myelin oligodendrocyte glycoprotein peptide immunization resulted in marginally enhanced EAE development in EBI3-deficient C57BL6 and 2D2 TCR-transgenic mice. EBI3 deficiency resulted in significantly increased Th17 and Th1 responses in the CNS and increased T cell production of IL-2 and IL-17 in the peripheral lymphoid organs. EBI3-deficient and -sufficient 2D2 T cells had equal ability in inducing EAE in Rag1(-/-) mice; however, more severe disease was induced in EBI3(-/-)Rag1(-/-) mice than in Rag1(-/-) mice by 2D2 T cells. EBI3-deficient mice had increased numbers of CD4(+)Foxp3(+) Treg cells in peripheral lymphoid organs. More strikingly, EBI3-deficient Treg cells had more potent suppressive functions in vitro and in vivo. Thus, our data support an inhibitory role for EBI3 in Th17, Th1, IL-2, and Treg responses. Although these observations are consistent with the known functions of IL-27, the IL-35 contribution to the suppressive functions of Treg cells is not evident in this model. Increased Treg responses in EBI3(-/-) mice may explain why the EAE development is only modestly enhanced compared with wild-type mice.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Receptores de Citocinas/fisiologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Transferência Adotiva , Animais , Encefalomielite Autoimune Experimental/etiologia , Fatores de Transcrição Forkhead/análise , Regulação da Expressão Gênica/imunologia , Proteínas de Homeodomínio/imunologia , Terapia de Imunossupressão , Interleucina-2/imunologia , Interleucinas/deficiência , Interleucinas/imunologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Antígenos de Histocompatibilidade Menor , RNA Mensageiro/biossíntese , Receptores de Citocinas/deficiência , Receptores de Citocinas/genética , Especificidade do Receptor de Antígeno de Linfócitos T , Células Th1/imunologia
20.
Cancers (Basel) ; 16(3)2024 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-38339311

RESUMO

Gastric carcinoma, being one of the most prevalent types of solid tumors, has emerged as the third leading cause of death worldwide. The symptoms of gastric cancer (GC) are typically complex, which makes early detection challenging. Immune checkpoint inhibition has become the new standard targeted therapy for advanced or metastatic GC. It is currently being explored in various combinations, both with and without chemotherapy, across multiple therapies in clinical trials. Immunotherapy can stimulate immune responses in GC patients, leading to the destruction of cancer cells. Compared with traditional therapies, immunotherapy has shown strong effectiveness with tolerable toxicity levels. Hence, this innovative approach to the treatment of advanced GC has gained popularity. In this review, we have outlined the recent advancements in immunotherapy for advanced GC, including immune checkpoint inhibitors, cancer vaccines, vascular endothelial growth factor-A inhibitors, and chimeric antigen receptor T-cell therapy. Our current emphasis is on examining the immunotherapies presently employed in clinical settings, addressing the existing challenges associated with these therapeutic approaches, and exploring promising strategies to overcome their limitations.

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