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1.
Nature ; 623(7985): 157-166, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37853118

RESUMO

Immunotherapy failures can result from the highly suppressive tumour microenvironment that characterizes aggressive forms of cancer such as recurrent glioblastoma (rGBM)1,2. Here we report the results of a first-in-human phase I trial in 41 patients with rGBM who were injected with CAN-3110-an oncolytic herpes virus (oHSV)3. In contrast to other clinical oHSVs, CAN-3110 retains the viral neurovirulence ICP34.5 gene transcribed by a nestin promoter; nestin is overexpressed in GBM and other invasive tumours, but not in the adult brain or healthy differentiated tissue4. These modifications confer CAN-3110 with preferential tumour replication. No dose-limiting toxicities were encountered. Positive HSV1 serology was significantly associated with both improved survival and clearance of CAN-3110 from injected tumours. Survival after treatment, particularly in individuals seropositive for HSV1, was significantly associated with (1) changes in tumour/PBMC T cell counts and clonal diversity, (2) peripheral expansion/contraction of specific T cell clonotypes; and (3) tumour transcriptomic signatures of immune activation. These results provide human validation that intralesional oHSV treatment enhances anticancer immune responses even in immunosuppressive tumour microenvironments, particularly in individuals with cognate serology to the injected virus. This provides a biological rationale for use of this oncolytic modality in cancers that are otherwise unresponsive to immunotherapy (ClinicalTrials.gov: NCT03152318 ).


Assuntos
Neoplasias Encefálicas , Glioblastoma , Herpesvirus Humano 1 , Terapia Viral Oncolítica , Vírus Oncolíticos , Humanos , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/patologia , Glioblastoma/imunologia , Glioblastoma/patologia , Nestina/genética , Terapia Viral Oncolítica/efeitos adversos , Vírus Oncolíticos/genética , Vírus Oncolíticos/imunologia , Vírus Oncolíticos/fisiologia , Reprodutibilidade dos Testes , Análise de Sobrevida , Linfócitos T/citologia , Linfócitos T/imunologia , Resultado do Tratamento , Microambiente Tumoral/imunologia , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/imunologia , Herpesvirus Humano 1/fisiologia
2.
Int J Mol Sci ; 19(12)2018 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-30544846

RESUMO

Interleukin 33 (IL-33) is a cytokine constitutively expressed by various cells of barrier tissues that contribute to the development of inflammatory immune responses. According to its function as an alarmin secreted by lung and airway epithelium, IL-33 plays a significant role in pathogenesis of allergic disorders. IL-33 is strongly involved in the pathogenesis of asthma, anaphylaxis, allergy and dermatitis, and genetic variations in IL33 locus are associated with increased susceptibility to asthma. Genome-wide association studies have identified risk "T" allele of the single-nucleotide polymorphism rs4742170 located in putative IL33 enhancer area as susceptible variant for development of specific wheezing phenotype in early childhood. Here, we demonstrate that risk "T" rs4742170 allele disrupts binding of glucocorticoid receptor (GR) transcription factor to IL33 putative enhancer. The IL33 promoter/enhancer constructs containing either 4742170 (T) allele or point mutations in the GR-binding site, were significantly more active and did not respond to cortisol in a pulmonary epithelial cell line. At the same time, the constructs containing rs4742170 (C) allele with a functional GR-binding site were less active and further inhibitable by cortisol. The latter effect was GR-dependent as it was completely abolished by GR-specific siRNA. This mechanism may explain the negative effect of the rs4742170 (T) risk allele on the development of wheezing phenotype that strongly correlates with allergic sensitization in childhood.


Assuntos
Alelos , Elementos Facilitadores Genéticos/genética , Interleucina-33/genética , Íntrons/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores de Glucocorticoides/metabolismo , Sons Respiratórios/genética , Sequência de Bases , Sítios de Ligação , Linhagem Celular Tumoral , Pré-Escolar , Humanos , Hidrocortisona/farmacologia , Fenótipo , Fosforilação/efeitos dos fármacos , Regiões Promotoras Genéticas
3.
Int J Mol Sci ; 19(10)2018 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-30257479

RESUMO

Cytokine interleukin 33 (IL-33) is constitutively expressed by epithelial barrier cells, and promotes the development of humoral immune responses. Along with other proinflammatory mediators released by the epithelium of airways and lungs, it plays an important role in a number of respiratory pathologies. In particular, IL-33 significantly contributes to pathogenesis of allergy and asthma; genetic variations in the IL33 locus are associated with increased susceptibility to asthma. Large-scale genome-wide association studies have identified minor "G" allele of the single-nucleotide polymorphism rs928413, located in the IL33 promoter area, as a susceptible variant for early childhood and atopic asthma development. Here, we demonstrate that the rs928413(G) allele creates a binding site for the cAMP response element-binding protein 1 (CREB1) transcription factor. In a pulmonary epithelial cell line, activation of CREB1, presumably via the p38 mitogen-activated protein kinases (MAPK) cascade, activates the IL33 promoter containing the rs928413(G) allele specifically and in a CREB1-dependent manner. This mechanism may explain the negative effect of the rs928413 minor "G" allele on asthma development.


Assuntos
Asma/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Interleucina-33/genética , Polimorfismo de Nucleotídeo Único , Alelos , Asma/metabolismo , Linhagem Celular Tumoral , Criança , Células Epiteliais/metabolismo , Predisposição Genética para Doença , Humanos , Pulmão/citologia , Pulmão/metabolismo , Sistema de Sinalização das MAP Quinases , Regiões Promotoras Genéticas , Ligação Proteica , Mucosa Respiratória/citologia , Mucosa Respiratória/metabolismo , Ativação Transcricional
4.
Sci Rep ; 11(1): 14120, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34239022

RESUMO

Transforming growth factor beta (TGF-ß) is the main cytokine responsible for the induction of the epithelial-mesenchymal transition of breast cancer cells, which is a hallmark of tumor transformation to the metastatic phenotype. Recently, research demonstrated that the chemokine CCL2 gene expression level directly correlates with the TGF-ß activity in breast cancer patients. CCL2 attracts tumor-associated macrophages and is, therefore, considered as an important inductor of breast cancer progression; however, the precise mechanisms underlying its regulation by TGF-ß are unknown. Here, we studied the behavior of the CCL2 gene in MDA-MB-231 and HCC1937 breast cancer cells representing mesenchymal-like phenotype activated by TGF-ß. Using bioinformatics, deletion screening and point mutagenesis, we identified binding sites in the CCL2 promoter and candidate transcription factors responsible for its regulation by TGF-ß. Among these factors, only the knock-down of EGR1 and RXRA made CCL2 promoter activity independent of TGF-ß. These factors also demonstrated binding to the CCL2 promoter in a TGF-ß-dependent manner in a chromatin immunoprecipitation assay, and point mutations in the EGR1 and RXRA binding sites totally abolished the effect of TGF-ß. Our results highlight the key role of EGR1 and RXRA transcription factors in the regulation of CCL2 gene in response to TGF-ß pathway.


Assuntos
Quimiocina CCL2/metabolismo , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Receptor X Retinoide alfa/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Sequência de Bases , Sítios de Ligação , Linhagem Celular Tumoral , Quimiocina CCL2/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Modelos Biológicos , Mutação Puntual/genética , Regiões Promotoras Genéticas/genética , Ligação Proteica , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
5.
Biochim Biophys Acta Mol Basis Dis ; 1866(3): 165626, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31785408

RESUMO

Toll-like receptor 4 (TLR4) is an innate immunity receptor predominantly expressed on myeloid cells and involved in the development of various diseases, many of them with complex genetics. Here we present data on functionality of single nucleotide polymorphism rs7873784 located in the 3'-untranslated region (3'-UTR) of TLR4 gene and associated with various pathologies involving chronic inflammation. We demonstrate that TLR4 3'-UTR strongly enhanced the activity of TLR4 promoter in U937 human monocytic cell line while minor rs7873784(C) allele created a binding site for transcription factor PU.1 (encoded by SPI1 gene), a known regulator of TLR4 expression. Increased binding of PU.1 further augmented the TLR4 transcription while PU.1 knockdown or complete disruption of the PU.1 binding site abrogated the effect. We hypothesize that additional functional PU.1 site may increase TLR4 expression in individuals carrying minor C variant of rs7873784 and modulate the development of certain pathologies, such as rheumatoid arthritis and type-2 diabetes mellitus.


Assuntos
Artrite Reumatoide/genética , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Proteínas Proto-Oncogênicas/genética , Receptor 4 Toll-Like/genética , Transativadores/genética , Regiões 3' não Traduzidas/genética , Alelos , Linhagem Celular , Linhagem Celular Tumoral , Células HEK293 , Humanos , Regiões Promotoras Genéticas/genética , Células U937
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