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1.
Medicine (Baltimore) ; 99(16): e19607, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32311929

RESUMO

Studies of maternal oral contraceptive pill (OCP) exposure and the offspring's risk of atopic diseases are of current interest due to concerns about widespread use of OCP before or during pregnancy.We evaluated whether maternal OCP exposure is associated with an increased risk of atopic diseases by reviewing the literature and performing a meta-analysis. The PubMed and Embase databases were searched to identify potential studies for inclusion. Three common atopic outcomes were included: asthma, eczema, and rhinitis.We found 693 titles, abstracts, and citations, and 6 studies were included in this analysis. A meta-analysis revealed that maternal OCP exposure was associated with higher odds of asthma (odds ratio [OR] 1.1; 95% confidence interval [CI] 1.02-1.19; P = .014), rhinitis (OR 1.34; 95% CI 1.07-1.68; P = .011) during childhood, whereas there was no association with eczema (OR 1.17; 95% CI 0.81-1.68; P = .383). This analysis was limited by the small number of studies included and the limited adjustments for the possible confounders in the studies.Current evidence suggests that maternal OCP exposure increases the risk for respiratory allergic diseases (asthma and rhinitis) in the offspring, but not for eczema. Given the few studies included, future larger, prospective studies that control for important confounders are needed to verify our findings.


Assuntos
Asma/epidemiologia , Anticoncepcionais Orais , Dermatite Atópica/epidemiologia , Exposição Materna/estatística & dados numéricos , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Rinite Alérgica/epidemiologia , Criança , Feminino , Humanos , Razão de Chances , Gravidez , Fatores de Risco
2.
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
3.
Mol Cancer Ther ; 19(2): 384-396, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31582534

RESUMO

Hepatocellular carcinoma (HCC), the most prevalent primary liver cancer, is a leading cause of cancer-related death worldwide because of rising incidence and limited therapy. Although treatment with sorafenib or lenvatinib is the standard of care in patients with advanced-stage HCC, the survival benefit from sorafenib is limited due to low response rate and drug resistance. Ibrutinib, an irreversible tyrosine kinase inhibitor (TKI) of the TEC (e.g., BTK) and ErbB (e.g., EGFR) families, is an approved treatment for B-cell malignancies. Here, we demonstrate that ibrutinib inhibits proliferation, spheroid formation, and clonogenic survival of HCC cells, including sorafenib-resistant cells. Mechanistically, ibrutinib inactivated EGFR and its downstream Akt and ERK signaling in HCC cells, and downregulated a set of critical genes involved in cell proliferation, migration, survival, and stemness, and upregulated genes promoting differentiation. Moreover, ibrutinib showed synergy with sorafenib or regorafenib, a sorafenib congener, by inducing apoptosis of HCC cells. In vivo, this TKI combination significantly inhibited HCC growth and prolonged survival of immune-deficient mice bearing human HCCLM3 xenograft tumors and immune-competent mice bearing orthotopic mouse Hepa tumors at a dose that did not exhibit systemic toxicity. In immune-competent mice, the ibrutinib-sorafenib combination reduced the numbers of BTK+ immune cells in the tumor microenvironment. Importantly, we found that the BTK+ immune cells were also enriched in the tumor microenvironment in a subset of primary human HCCs. Collectively, our findings implicate BTK signaling in hepatocarcinogenesis and support clinical trials of the sorafenib-ibrutinib combination for this deadly disease.

4.
Adv Mater ; 31(43): e1904495, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31497903

RESUMO

Natural killer (NK) cells can not only recognize and eliminate abnormal cells but also recruit and re-educate immune cells to protect the host. However, the functions of NK cells are often limited in the immunosuppressive tumor microenvironment (TME). Here, artificial NK cells (designated as aNK) with minor limitations of TME for specific tumor killing and renegade macrophage re-education are created. The red blood cell membrane (RBCM) cloaks perfluorohexane (PFC) and glucose oxidase (GOX) to construct the aNK. The aNK can directly kill tumor cells by exhausting glucose and generating hydrogen peroxide (H2 O2 ). The generated H2 O2 is also similar to cytokines and chemokines for recruiting immune cells and re-educating survived macrophages to attack tumor cells. In addition, the oxygen-carried PFC can strengthen the catalytic reaction of GOX and normalize the hypoxic TME. In vitro and in vivo experiments display that aNK with slight TME limitations exhibit efficient tumor inhibition and immune activation. The aNK will provide a new sight to treat tumor as the supplement of aggressive NK cells.


Assuntos
Biomimética , Células Matadoras Naturais/imunologia , Macrófagos/imunologia , Animais , Linhagem Celular Tumoral , Citocinas/metabolismo , Glucose/metabolismo , Glucose Oxidase/metabolismo , Peróxido de Hidrogênio/metabolismo , Células Matadoras Naturais/metabolismo , Camundongos , Microambiente Tumoral/imunologia
5.
ACS Nano ; 13(8): 8618-8629, 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31246413

RESUMO

Natural nanoparticles have been extensively studied due to their diverse properties and easy accessibility. Here, the nanoparticles extracted from cuttlefish ink (CINPs) with significant antitumor efficacy are explored. These CINPs, with spherical morphology, good dispersibility, and biocompatibility, are rich in melanin and contain a variety of amino acids and monosaccharides. Through the activation of mitogen-activated protein kinase (MAPK) signaling pathway, CINPs can efficiently reprogram tumor-associated macrophages (TAMs) from immune-suppressive M2-like phenotype to antitumor M1-like phenotype. Besides, under near-infrared (NIR) irradiation, CINPs exhibit high photothermal effect and tumor cell killing ability, which make them a potential candidate in photothermal therapy (PTT) of tumor. In vivo, CINPs can increase the proportion of M1 macrophages and foster the recruitment of cytotoxic T lymphocytes (CTLs) to tumors, leading to reduced primary tumor growth and lung metastasis. In combination with their photothermal effect, which can induce tumor-specific antigens release, CINPs could almost completely inhibit tumor growth accompanied by more active immune responses. Collectively, these CINPs described here can provide both tumor immunotherapy and PTT, implying that CINPs are promising for tumor treatment.

6.
Nucleic Acids Res ; 47(W1): W248-W255, 2019 Jul 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.

7.
Biomaterials ; 199: 1-9, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30716690

RESUMO

Although photothermal therapy (PTT) and photodynamic therapy (PDT) are widely commended for tumor treatment recently, they still suffer severe challenges due to the non-specificity of photothermal agents (PTAs)/photosensitizers (PSs) and hypoxic tumor microenvironment. Here, an oxygen independent biomimetic nanoplatform based on carbon sphere dotted with cerium oxide and coated by cell membrane (MCSCe) was designed and synthesized with good biocompatibility, homologous targeting ability, and improved photophysical activity. Notably, MCSCe could realize accumulation of hydrogen peroxide (H2O2) in tumor cells and hyperthermia under single laser (808 nm) irradiation, which were simultaneously utilized by itself to produce more toxic hydroxyl radical (OH). Resultantly, the synergistic therapeutic effect against tumor cells was obtained under near infrared (NIR) laser irradiation.

8.
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
9.
Front Immunol ; 9: 873, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29740452

RESUMO

Interleukin-27 (IL-27) and its subunit P28 (also known as IL-30) have been shown to inhibit autoimmunity and have been suggested as potential immunotherapeutic for autoimmune diseases such as multiple sclerosis (MS). However, the potential of IL-27 and IL-30 as immunotherapeutic, and their mechanisms of action have not been fully understood. In this study, we evaluated the efficacy of adeno-associated viral vector (AAV)-delivered IL-27 (AAV-IL-27) and IL-30 (AAV-IL-30) in a murine model of MS. We found that one single administration of AAV-IL-27, but not AAV-IL-30 completely blocked the development of experimental autoimmune encephalomyelitis (EAE). AAV-IL-27 administration reduced the frequencies of Th17, Treg, and GM-CSF-producing CD4+ T cells and induced T cell expression of IFN-γ, IL-10, and PD-L1. However, experiments involving IL-10-deficient mice and PD-1 blockade revealed that AAV-IL-27-induced IL-10 and PD-L1 expression were not required for the prevention of EAE development. Surprisingly, neither AAV-IL-27 nor AAV-IL-30 treatment inhibited EAE development and Th17 responses when given at disease onset. We found that mice with established EAE had significant expansion of CD11b+Gr-1+ cells, and AAV-IL-27 treatment further expanded these cells and induced their expression of Th17-promoting cytokines such as IL-6. Adoptive transfer of AAV-IL-27-expanded CD11b+Gr-1+ cells enhanced EAE development. Thus, expansion of CD11b+Gr-1+ cells provides an explanation for the resistance to IL-27 therapy in mice with established disease.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Terapia Genética/métodos , Interleucina-27/imunologia , Esclerose Múltipla/imunologia , Células Mieloides/imunologia , Animais , Antígeno CD11b/imunologia , Antígeno CD11b/metabolismo , Dependovirus/genética , Encefalomielite Autoimune Experimental/terapia , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genética , Humanos , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-27/administração & dosagem , Interleucina-27/genética , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/terapia , Receptores de Quimiocinas/imunologia , Receptores de Quimiocinas/metabolismo , Receptores de Citocinas/genética , Receptores de Citocinas/imunologia , Resultado do Tratamento
10.
JCI Insight ; 3(7)2018 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-29618655

RESUMO

Tumor-induced expansion of Tregs is a significant obstacle to cancer immunotherapy. However, traditional approaches to deplete Tregs are often inefficient, provoking autoimmunity. We show here that administration of IL-27-expressing recombinant adeno-associated virus (AAV-IL-27) significantly inhibits tumor growth and enhances T cell responses in tumors. Strikingly, we found that AAV-IL-27 treatment causes rapid depletion of Tregs in peripheral blood, lymphoid organs, and - most pronouncedly - tumor microenvironment. AAV-IL-27-mediated Treg depletion is dependent on IL-27 receptor and Stat1 in Tregs and is a combined result of CD25 downregulation in Tregs and inhibition of IL-2 production by T cells. In combination with a GM-CSF vaccine, AAV-IL-27 treatment not only induced nearly complete tumor rejection, but also resulted in amplified neoantigen-specific T cell responses. AAV-IL-27 also dramatically increased the efficacy of anti-PD-1 therapy, presumably due to induction of PD-L1 in T cells and depletion of Tregs. Importantly, AAV-IL-27 therapy did not induce significant adverse events, partially due to its induction of IL-10. In a plasmacytoma mouse model, we found that IL-10 was required for AAV-IL-27-mediated tumor rejection. Thus, our study demonstrates the potential of AAV-IL-27 as an independent cancer therapeutic and as an efficient adjuvant for cancer immunotherapy.


Assuntos
Vacinas Anticâncer/administração & dosagem , Terapia Genética/métodos , Interleucinas/genética , Depleção Linfocítica/métodos , Neoplasias/terapia , Linfócitos T Reguladores/imunologia , Animais , Vacinas Anticâncer/imunologia , Linhagem Celular Tumoral/transplante , Dependovirus/genética , Modelos Animais de Doenças , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Humanos , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-10/metabolismo , Interleucinas/imunologia , Camundongos , Camundongos Knockout , Neoplasias/imunologia , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Linfócitos T Reguladores/metabolismo , Resultado do Tratamento , Microambiente Tumoral/imunologia
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.
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 , Transdução de Sinais/genética
13.
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
14.
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
15.
ACS Nano ; 10(6): 6189-200, 2016 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-27224853

RESUMO

Allogeneic transplantation of hematopoietic stem cells (HSC) in combination with T cells has a curative potential for hematopoietic malignancies through graft-versus-leukemia (GVL) effects, but is often compromised by the notorious side effect of graft-versus-host disease (GVHD) resulting from alloreactivity of the donor T cells. Here, we tested if temporary immunoisolation achieved by conformally encapsulating the donor T cells within a biocompatible and biodegradable porous film (∼450 nm in thickness) of chitosan and alginate could attenuate GVHD without compromising GVL. The nanoencapsulation was found not to affect the phenotype of T cells in vitro in terms of size, viability, proliferation, cytokine secretion, and cytotoxicity against tumor cells. Moreover, the porous nature of the nanoscale film allowed the encapsulated T cells to communicate with their environment, as evidenced by their intact capability of binding to antibodies. Lethally irradiated mice transplanted with bone marrow cells (BMCs) and the conformally encapsulated allogeneic T cells exhibited significantly improved survival and reduced GVHD together with minimal liver damage and enhanced engraftment of donor BMCs, compared to the transplantation of BMCs and non-encapsulated allogeneic T cells. Moreover, the conformal nanoencapsulation did not compromise the GVL effect of the donor T cells. These data show that conformal nanoencapsulation of T cells within biocompatible and biodegradable nanoscale porous materials is a potentially safe and effective approach to improve allogeneic HSC transplantation for treating hematological malignancies and possibly other diseases.


Assuntos
Doença Enxerto-Hospedeiro , Efeito Enxerto vs Leucemia , Nanocompostos , Linfócitos T , Animais , Leucemia , Camundongos , Transplante Homólogo
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 Leukoc Biol ; 100(2): 403-11, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27106672

RESUMO

IL-27 is a heterodimeric cytokine that is composed of two subunits, i.e., EBV-induced gene 3 and IL-27p28 (also known as IL-30). Although the role of endogenous IL-27 in the pathogenesis of autoimmune colitis, an experimental model of human inflammatory bowel disease, remains controversial, IL-27 local delivery has been shown to inhibit autoimmune colitis. IL-30 has been shown to inhibit Th1 and Th17 responses and is considered a potential therapeutic for certain autoimmune diseases. In this study, we have compared the therapeutic efficacy of adeno-associated viral vector-delivered IL-27 and IL-30 in a murine model of autoimmune colitis. We found that 1 single administration of adeno-associated viral vector-delivered IL-27, but not adeno-associated viral vector-delivered IL-30, nearly completely inhibited autoimmune colitis. Adeno-associated viral vector-delivered IL-27 administration inhibited Th17 responses and induced T cell expression of IL-10, programmed death ligand 1, and stem cell antigen 1. Intriguingly, adeno-associated viral vector-delivered IL-27 treatment enhanced Th1 responses and inhibited regulatory T cell responses. Experiments involving the adoptive transfer of IL-10-deficient T cells revealed that adeno-associated viral vector-delivered IL-27-induced IL-10 production was insufficient to mediate inhibition of autoimmune colitis, whereas anti-programmed death 1 antibody treatment resulted in the breaking of adeno-associated viral vector-delivered IL-27-induced T cell tolerance. Thus, systemic delivery of IL-27 inhibits Th17 responses and induces multiple inhibitory pathways, including programmed death ligand 1 in T cells, and adeno-associated viral vector-delivered IL-27, but not IL-30, may have a therapeutic potential for the treatment of human inflammatory bowel disease.


Assuntos
Doenças Autoimunes/terapia , Colite/terapia , Dependovirus/genética , Vetores Genéticos/administração & dosagem , Interleucina-27/genética , Linfócitos T Reguladores/imunologia , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Colite/imunologia , Colite/metabolismo , Citocinas/imunologia , Interleucina-10/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout
18.
Am J Cancer Res ; 5(7): 2277-84, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26328258

RESUMO

OBJECTIVE: To analyze the expressions of Bcl-2, B7-H1, EGFR and VEGF in colorectal cancer for the further investigation of their correlations with the clinical pathological features of colorectal cancer. METHOD: Fresh colorectal cancer tissues and the expressions of Bcl-2, B7-H1, VEGF and EGFR in paraneoplastic normal mucosal tissues of 57 cases were tested by immunohistochemisty method, and the results were analyzed by SPSS10.0. RESULTS: 1. Compared with paraneoplastic normal tissues, the expressions of Bcl-2 and B7-H1 in colorectal cancer tissues increased significantly with significant difference (P<0.05), while the expression of EGFR and VEGF in colorectal cancer tissues showed no significant difference with those in paraneoplastic normal tissue (P>0.05); 2. The correlation with clinical pathological features: there was significant difference of expression rates of EGFR between different genders (P<0.05); the expressions of BCL-2 and B7-H1 in colorectal cancer of the high- and medium- differentiated groups were significantly higher than those of the low-differentiated group, and the difference was significant (P<0.01); compared with the colorectal cancer patients without lymph node metastasis (Dukes stage A+B), the expression of B7-H1 in patients with lymph node metastasis (Dukes stage C+D) was significantly higher (P<0.05); 3. Within the high- and medium- differentiated colorectal cancer tissues, Bcl-2 expression rate in B7-H1 negative group was higher than the positive group with significant difference (P<0.01). CONCLUSIONS: In colorectal carcinoma, Bcl-2, B7-H1, EGFR and VEGF were all expressed, independent from age and depth of invasion. However, the expression level of Bcl-2 and B7-H1 correlated with tissue differentiation, and the latter also had correlation with tumor staging. Meanwhile, the short-term follow-up showed that high expression of Bcl-2/B7-H1 existed in death cases. Therefore, the expression detection of Bcl-2, B7-H1 might provide a clear understanding of the biological behavior of colorectal cancer, and was important for the diagnosis, treatment and prognosis judgment of colorectal cancer.

19.
Oncoimmunology ; 4(7): e1014232, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26140236

RESUMO

Interleukin-10 (IL-10) is a potent anti-inflammatory cytokine that regulates immune responses. IL-10 has also been shown to enhance antitumor CD8+ T-cell responses in tumor models although the underlying mechanisms are not fully understood. In this study, we used a series of genetic mouse models and the mouse plasmacytoma J558 model to investigate this issue. J558 tumors grew significantly faster in IL-10-/- mice than in wild type (WT) mice, but similarly in IL-10 -/- Rag2 -/- and Rag2 -/- mice. Tumors from IL-10 -/- mice contained fewer IFN-γ-producing CD8+ and CD4+ T cells than tumors from WT mice. Strikingly, depletion of total CD4+ T cells, but not CD25+ cells, resulted in tumor eradication in IL-10 -/- mice. Adoptive transfer studies revealed that CD4+ T cells from IL-10 -/- mice exhibited more potent suppression of cytotoxic T lymphocyte (CTL)-mediated tumor rejection than their WT counterparts, and IL-10-deficient tumor-infiltrating CD4+ T cells expressed higher levels of PD-L1 and CTLA-4 inhibitory molecules. Although IL-10-deficient CD8+ T cells are not defective in activation and initial rejection of tumors, adoptive transfer studies using IL-10-deficient P1CTL transgenic T cells that recognize the tumor rejection antigen P1A reveal that IL-10 is required for long-term persistence of CTLs and control of tumor growth. Thus, we have found that IL-10 enhances antitumor CTL responses by inhibiting highly suppressive CD4+ T cells and promoting CTL persistence. These data have important implications for the design of immunotherapy for human cancer.

20.
Oncoimmunology ; 4(7): e989137, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26140252

RESUMO

Epstein-Barr virus-induced gene 3 (EBI3) encoded protein can form heterodimers with IL-27P28, and IL-12P35 to form IL-27, and IL-35. However, IL-27 stimulates, whereas IL-35 inhibits antitumor T-cell responses. IL-27 also limits the Foxp3+ regulatory T cell (Treg) population, whereas IL-35 has been shown to expand Tregs and foster Treg suppressive functions. It remains unclear which group of forces are dominant during antitumor T-cell responses. In this study, we evaluated the tumor growth and antitumor T-cell responses in EBI3-deficient mice that lack both IL-27 and IL-35. We found that injecting B16 melanoma cells into EBI3-deficient C57BL/6 mice, or J558 plasmacytoma cells into EBI3-deficient BALB/c mice resulted in significantly increased tumor growth relative to those implanted in wild-type control mice. Tumors from EBI3-deficient mice contained significantly decreased proportions of CD8+ T cells and increased proportions of CD4+FoxP3+ Treg cells as compared to those from EBI3-intact mice. Tumor-infiltrating T cells from EBI3-deficient mice were impaired in their capacity to produce IFNγ. Phenotypically, Tregs from EBI3-deficient mice were highly suppressive and produced IL-10 in the tumor microenvironment. Depletion of Tregs or inactivation of the IL-10 pathway significantly abrogated tumor growth enhancement in Ebi3-/- mice. Finally, we showed that Ebi3-/- mice administered a melanoma vaccine failed to mount a CD8+ T-cell response and the vaccine failed to confer tumor rejection in EBI3-deficient mice. Taken together, these results suggest that Ebi3-/- mice show a phenotype of IL-27-deficiency rather than IL-35-deficiency during anti-tumor T-cell responses. Thus, our results suggest that endogenous IL-27 is critical for both spontaneous and vaccine-induced antitumor T-cell responses.

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