Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 13 de 13
Filtrar
Mais filtros










Base de dados
Tipo de estudo
Intervalo de ano de publicação
2.
Clin Cancer Res ; 26(22): 5778-5780, 2020 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-32958703

RESUMO

The use of checkpoint monotherapy in treating cancer has limited success. Post-translational modifications (PTM) of proteins such as glycosylation might have clinical implications due to distinct modifications found in diseases and its regulatory role in the immunometabolic gene expression. Such novel mechanistic targets hold great promise for combined immunotherapy.See related article by Shi et al., p. 5990.


Assuntos
Neoplasias , Processamento de Proteína Pós-Traducional , Glicosilação , Humanos , Imunidade , Imunoterapia , Neoplasias/terapia
3.
Sci Rep ; 10(1): 6550, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32300237

RESUMO

Human γδ T cells are potent cytotoxic effector cells, produce a variety of cytokines, and can acquire regulatory activity. Induction of FOXP3, the key transcription factor of regulatory T cells (Treg), by TGF-ß in human Vγ9 Vδ2 T cells has been previously reported. Vitamin C is an antioxidant and acts as multiplier of DNA hydroxymethylation. Here we have investigated the effect of the more stable phospho-modified Vitamin C (pVC) on TGF-ß-induced FOXP3 expression and the resulting regulatory activity of highly purified human Vγ9 Vδ2 T cells. pVC significantly increased the TGF-ß-induced FOXP3 expression and stability and also increased the suppressive activity of Vγ9 Vδ2 T cells. Importantly, pVC induced hypomethylation of the Treg-specific demethylated region (TSDR) in the FOXP3 gene. Genome-wide methylation analysis by Reduced Representation Bisulfite Sequencing additionally revealed differentially methylated regions in several important genes upon pVC treatment of γδ T cells. While Vitamin C also enhances effector functions of Vγ9 Vδ2 T cells in the absence of TGF-ß, our results demonstrate that pVC potently increases the suppressive activity and FOXP3 expression in TGF-ß-treated Vγ9 Vδ2 T cells by epigenetic modification of the FOXP3 gene.


Assuntos
Ácido Ascórbico/farmacologia , Epigênese Genética/efeitos dos fármacos , Fatores de Transcrição Forkhead/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Linfócitos T Reguladores/metabolismo , Adulto , Proliferação de Células/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/genética , Desmetilação , Humanos , Fosforilação/efeitos dos fármacos , Estabilidade Proteica/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Fator de Crescimento Transformador beta/farmacologia
4.
Front Immunol ; 10: 569, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30972064

RESUMO

The functional plasticity and anti-tumor potential of human γδ T cells have been widely studied. However, the epigenetic regulation of γδ T-cell/tumor cell interactions has been poorly investigated. In the present study, we show that treatment with the histone deacetylase inhibitor Valproic acid (VPA) significantly enhanced the expression and/or release of the NKG2D ligands MICA, MICB and ULBP-2, but not ULBP-1 in the pancreatic carcinoma cell line Panc89 and the prostate carcinoma cell line PC-3. Under in vitro tumor co-culture conditions, the expression of full length and the truncated form of the NKG2D receptor in γδ T cells was significantly downregulated. Furthermore, using a newly established flow cytometry-based method to analyze histone acetylation (H3K9ac) in γδ T cells, we showed constitutive H3K9aclow and inducible H3K9achigh expression in Vδ2 T cells. The detailed analysis of H3K9aclow Vδ2 T cells revealed a significant reversion of TEMRA to TEM phenotype during in vitro co-culture with pancreatic ductal adenocarcinoma cells. Our study uncovers novel mechanisms of how epigenetic modifiers modulate γδ T-cell differentiation during interaction with tumor cells. This information is important when considering combination therapy of VPA with the γδ T-cell-based immunotherapy for the treatment of certain types of cancer.


Assuntos
Inibidores de Histona Desacetilases/farmacologia , Linfócitos Intraepiteliais/imunologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/biossíntese , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Ácido Valproico/farmacologia , Acetilação , Linhagem Celular Tumoral , Proteínas Ligadas por GPI/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Histonas/metabolismo , Humanos , Memória Imunológica/imunologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Ativação Linfocitária/imunologia , Masculino , Células PC-3 , Neoplasias Pancreáticas/imunologia , Neoplasias da Próstata/imunologia
8.
Oncoimmunology ; 6(11): e1358839, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29147621

RESUMO

Despite aggressive treatment regimens based on surgery and radiochemotherapy, the prognosis of patients with grade IV glioblastoma multiforme (GBM) remains extremely poor, calling for alternative options such as immunotherapy. Immunological mechanisms including the Natural Killer Group 2 member D (NKG2D) receptor-ligand system play an important role in tumor immune surveillance and targeting the NKG2D system might be beneficial. However, before considering any kind of immunotherapy, a precise characterization of the immune system is important, particularly in GBM patients where conventional therapies with impact on the immune system are frequently co-administered. Here we performed an in-depth immunophenotyping of GBM patients and age-matched healthy controls and analyzed NKG2D ligand expression on primary GBM cells ex vivo. We report that GBM patients have a compromised innate immune system irrespective of steroid (dexamethasone) medication. However, dexamethasone drastically reduced the number of immune cells in the blood of GBM patients. Moreover, higher counts of immune cells influenced by dexamethasone like CD45+ lymphocytes and non-Vδ2 γδ T cells were associated with better overall survival. Higher levels of NKG2D ligands on primary GBM tumor cells were observed in patients who received radiochemotherapy, pointing towards increased immunogenic potential of GBM cells following standard radiochemotherapy. This study sheds light on how steroids and radiochemotherapy affect immune cell parameters of GBM patients, a pre-requisite for the development of new therapeutic strategies targeting the immune system in these patients.

9.
Oncotarget ; 7(40): 64743-64756, 2016 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-27556516

RESUMO

Previously, the expression of a non-secreted IL-4 variant (IL-4δ13) has been described in association with apoptosis and age-dependent Th2 T-cell polarization. Signaling pathways involved in this process have so far not been studied. Here we report the induction of IL-4δ13 expression in human γδ T-cells upon treatment with a sublethal dose of histone deacetylase (HDACi) inhibitor valproic acid (VPA). Induction of IL-4δ13 was associated with increased cytoplasmic IL-4Rα and decreased IL-4 expression, while mRNA for mature IL-4 was concomitantly down-regulated. Importantly, only the simultaneous combination of apoptosis and necroptosis inhibitors prevented IL-4δ13 expression and completely abrogated VPA-induced global histone H3K9 acetylation mark. Further, our work reveals a novel involvement of transcription factor c-Jun in the signaling network of IL-4, HDAC1, caspase-3 and mixed lineage kinase domain-like protein (MLKL). This study provides novel insights into the effects of epigenetic modulator VPA on human γδ T-cell differentiation.


Assuntos
Envelhecimento/fisiologia , Interleucina-4/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Linfócitos T/fisiologia , Células Th2/fisiologia , Caspase 3/metabolismo , Morte Celular , Células Cultivadas , Histona Desacetilase 1/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Histonas/metabolismo , Humanos , Interleucina-4/genética , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Ativação Linfocitária , Mutação/genética , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Transdução de Sinais , Regulação para Cima , Ácido Valproico/metabolismo
10.
Leuk Res ; 45: 33-9, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27070758

RESUMO

Gene expression, copy number variations (CNV), mutations and survival were studied to delineate TCRγδ+T-cell acute lymphoblastic leukemia (T-ALL) as a distinct subgroup from TCRαß+T-ALL. Gene Ontology analysis showed that differential regulation of genes involved in pathways for leukemogenesis, apoptosis, cytokine-cytokine receptor interaction and antigen processing/presentation may offer a survival benefit to TCRγδ+T-ALL patients. Genes involved in disease biology and having equal expression in both the subgroups, were further analysed for mutations and CNV using droplet digital PCR. TCRγδ+T-ALL patients exhibited differential level of mutations for NOTCH1 and IKZF3; however BRAF mutations were detected at equal levels in both the subgroups. Although TCRγδ+T-ALL patients with these mutations demonstrated improved disease-free survival (DFS) as compared TCRαß+T-ALL patients, it was not statistically significant. Patients with homozygous deletion of CDKN2A/CDKN2B showed poor DFS in each subgroup. TCRγδ+T-ALL patients with wild type/heterozygous deletion of CDKN2A/CDKN2B possess significantly better DFS over TCRαß+T-ALL patients (p=0.017 and 0.045, respectively). Thus, the present study has for the first time demonstrated TCRγδ clonality and CDKN2A/CDKN2B CNV together as potential prognostic markers in management of T-ALL. Further understanding the functional significance of differentially regulated genes in T-ALL patients would aid in designing risk based treatment strategies in subset specific manner.


Assuntos
Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Medição de Risco , Adolescente , Adulto , Criança , Pré-Escolar , Inibidor de Quinase Dependente de Ciclina p15/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Variações do Número de Cópias de DNA , Feminino , Expressão Gênica , Humanos , Lactente , Masculino , Mutação , Leucemia-Linfoma Linfoblástico de Células T Precursoras/classificação , Prognóstico , Receptores de Antígenos de Linfócitos T gama-delta/análise , Adulto Jovem
11.
Oncoimmunology ; 4(6): e1006088, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26155411

RESUMO

γδ T cell-based immunotherapeutic strategies in cancer patients are as yet of limited success. Drugs targeting epigenetic mechanisms including histone acetylation and DNA methylation trigger cell death in tumor cells but in addition have immunomodulatory activity. Here, we discuss the potential benefit of combining both strategies in cancer immunotherapy.

12.
Cell Immunol ; 296(1): 50-6, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25708484

RESUMO

Histone deacetylase inhibitors have been shown to possess therapeutic potential in various pathophysiological conditions. Valproic acid (VPA), a known histone deacetylase class I inhibitor, has been studied for its influence on immune cell functions. However, the potential impact of VPA on human γδ T-cells remains unknown. Here we investigated the effects of VPA on the proliferation and the immunophenotype of human γδ T-cells. We observed dose-dependent inhibition of proliferation, associated with significant cell death as revealed by flow cytometry. The cellular response to VPA clearly showed differential modulation of cell surface markers on γδ T-cells when compared to αß T-cells. Furthermore, histone H3 acetylation was detected in γδ T-cells even at toxic concentrations of VPA. Our investigations focusing on the impact of VPA on human γδ T-cells will be helpful in understanding its safety profile in clinical application, particularly in the context of γδ T-cell-targeted immunotherapy.


Assuntos
Inibidores de Histona Desacetilases/farmacologia , Ativação Linfocitária/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Linfócitos T/efeitos dos fármacos , Ácido Valproico/farmacologia , Acetilação , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Histonas/metabolismo , Humanos , Imunoterapia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Linfócitos T/imunologia
13.
Int J Cancer ; 133(7): 1557-66, 2013 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-23526433

RESUMO

The interaction of the MHC class I-related chain molecules A and B (MICA and MICB) with the corresponding natural killer group 2, member D (NKG2D) receptor triggers cytotoxic effector activity of natural killer cells and certain T-cell subsets and provides a costimulatory signal for cytokine production. Thus, the presence of MICA/B on transformed cells contributes to tumor immunosurveillance. Consequently, the proteolytic cleavage of MICA/B is regarded as an important immune escape mechanism of various cancer cells. To investigate the molecular machinery responsible for the shedding of endogenous MICA/B, we analyzed different human tumor entities including mammary, pancreatic and prostate carcinomas. Flow cytometry and enzyme-linked immunosorbent assay (ELISA) revealed that all tested tumor cells constitutively expressed MICA and MICB on the cell surface and also released NKG2D ligands into the supernatant. We demonstrate that the "a disintegrin and metalloproteases" (ADAMs) 10 and 17 are largely responsible for the generation of soluble MICA/B. Pharmacological inhibition of metalloproteases reduced the level of released MICA/B and increased cell surface expression. Studies using RNA interference not only revealed a prominent role of ADAM10 and ADAM17 in NKG2D ligand shedding but also a tumor cell-specific role of ADAM10 and/or ADAM17 in shedding of MICA or MICB. Moreover, we report that in the prostate carcinoma cell line PC-3, MICA was not shed at all but rather was secreted in exosomes. These data indicate that the release of NKG2D ligands from individual tumor entities is by far more complex than suggested in previously reported MICA/B transfection systems.


Assuntos
Proteínas ADAM/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Proteínas de Membrana/metabolismo , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Neoplasias/imunologia , Proteínas ADAM/antagonistas & inibidores , Proteínas ADAM/genética , Proteína ADAM10 , Proteína ADAM17 , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/genética , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/metabolismo , Linhagem Celular Tumoral , Citocinas/biossíntese , Dipeptídeos/farmacologia , Exossomos , Feminino , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Vigilância Imunológica , Células Matadoras Naturais/imunologia , Masculino , Inibidores de Metaloproteinases de Matriz/farmacologia , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Neoplasias/metabolismo , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/metabolismo , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/metabolismo , Interferência de RNA , RNA Interferente Pequeno , Subpopulações de Linfócitos T/imunologia , Tetraspanina 29/metabolismo , Evasão Tumoral/imunologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...