Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 5.196
Filtrar
1.
Nature ; 602(7897): 503-509, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35110735

RESUMO

The adoptive transfer of T lymphocytes reprogrammed to target tumour cells has demonstrated potential for treatment of various cancers1-7. However, little is known about the long-term potential and clonal stability of the infused cells. Here we studied long-lasting CD19-redirected chimeric antigen receptor (CAR) T cells in two patients with chronic lymphocytic leukaemia1-4 who achieved a complete remission in 2010. CAR T cells remained detectable more than ten years after infusion, with sustained remission in both patients. Notably, a highly activated CD4+ population emerged in both patients, dominating the CAR T cell population at the later time points. This transition was reflected in the stabilization of the clonal make-up of CAR T cells with a repertoire dominated by a small number of clones. Single-cell profiling demonstrated that these long-persisting CD4+ CAR T cells exhibited cytotoxic characteristics along with ongoing functional activation and proliferation. In addition, longitudinal profiling revealed a population of gamma delta CAR T cells that prominently expanded in one patient concomitant with CD8+ CAR T cells during the initial response phase. Our identification and characterization of these unexpected CAR T cell populations provide novel insight into the CAR T cell characteristics associated with anti-cancer response and long-term remission in leukaemia.


Assuntos
Linfócitos T CD4-Positivos , Imunoterapia Adotiva , Leucemia , Receptores de Antígenos Quiméricos , Antígenos CD19/imunologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Separação Celular , Humanos , Leucemia/imunologia , Leucemia/terapia , Receptores de Antígenos Quiméricos/imunologia , Fatores de Tempo
2.
Sci Rep ; 12(1): 3234, 2022 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-35217717

RESUMO

Leukemic cells proliferate faster than non-transformed counterparts. This requires them to change their metabolism to adapt to their high growth. This change can stress cells and facilitate recognition by immune cells such as cytotoxic lymphocytes, which express the activating receptor Natural Killer G2-D (NKG2D). The tumor suppressor gene p53 regulates cell metabolism, but its role in the expression of metabolism-induced ligands, and subsequent recognition by cytotoxic lymphocytes, is unknown. We show here that dichloroacetate (DCA), which induces oxidative phosphorylation (OXPHOS) in tumor cells, induces the expression of such ligands, e.g. MICA/B, ULBP1 and ICAM-I, by a wtp53-dependent mechanism. Mutant or null p53 have the opposite effect. Conversely, DCA sensitizes only wtp53-expressing cells to cytotoxic lymphocytes, i.e. cytotoxic T lymphocytes and NK cells. In xenograft in vivo models, DCA slows down the growth of tumors with low proliferation. Treatment with DCA, monoclonal antibodies and NK cells also decreased tumors with high proliferation. Treatment of patients with DCA, or a biosimilar drug, could be a clinical option to increase the effectiveness of CAR T cell or allogeneic NK cell therapies.


Assuntos
Antineoplásicos , Leucemia , Proteína Supressora de Tumor p53 , Antineoplásicos/metabolismo , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Leucemia/imunologia , Leucemia/metabolismo , Ligantes , Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Proteína Supressora de Tumor p53/imunologia , Proteína Supressora de Tumor p53/metabolismo
3.
Int J Hematol ; 115(3): 371-381, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35037229

RESUMO

Genomic deletion of donor-patient-mismatched HLA alleles in leukemic cells is a major cause of relapse after allogeneic hematopoietic stem cell transplantation (HSCT). Mismatched HLA is frequently lost as an individual allele or a whole region in HLA-class I, however, it is downregulated in HLA-class II. We hypothesized that there might be a difference in T cell recognition capacity against epitopes associated with HLA-class I and HLA-class II and consequently such allogeneic immune pressure induced HLA alterations in leukemic cells. To investigate this, we conducted in vitro experiments with T cell receptor-transduced T (TCR-T) cells. The cytotoxic activity of NY-ESO-1-specific TCR-T cells exhibited similarly against K562 cells with low HLA-A*02:01 expression. However, we demonstrated that the cytokine production against low HLA-DPB1*05:01 expression line decreased gradually from the HLA expression level approximately 2-log lower than normal expressors. Using sort-purified leukemia cells before and after HSCT, we applied the next-generation sequencing, and revealed that there were several marked downregulations of HLA-class II alleles which demonstrated consistently low expression from pre-transplantation. The marked downregulation of HLA-class II may lead to decreased antigen recognition ability of antigen-specific T cells and may be one of immune evasion mechanism associated with HLA-class II downregulation.


Assuntos
Regulação para Baixo , Epitopos/imunologia , Transplante de Células-Tronco Hematopoéticas , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/metabolismo , Leucemia/genética , Leucemia/imunologia , Linfócitos T/imunologia , Transplante Homólogo , Alelos , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/imunologia , Efeito Enxerto vs Leucemia/imunologia , Humanos , Células K562 , Leucemia/terapia , Recidiva
4.
Cells ; 11(1)2022 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-35011737

RESUMO

David Mason started his research career at a time when lymphoma diagnosis was based primarily on cellular morphology, clinical symptoms and special cytochemical stains using formalin fixed tissue sections. There were occasions, however, where the morphology was unhelpful, such as in the case of anaplastic or poorly differentiated tumours, where a distinction between lymphoma and a non-haematopoietic tumour was often problematical. Accurate diagnosis became even more important with the developments in the clinical staging of lymphoma and the availability of more effective treatments. One way forward to improve diagnosis was to use immunohistochemistry to study the antigens expressed by the tumor cells.


Assuntos
Carcinoma/patologia , Comportamento Cooperativo , Linfoma/patologia , Carcinoma/diagnóstico , Carcinoma/imunologia , Humanos , Leucemia/diagnóstico , Leucemia/imunologia , Linfoma/diagnóstico , Linfoma/imunologia
5.
Br J Haematol ; 196(4): 892-901, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34761389

RESUMO

Patients with haematological malignancies have a high risk of severe infection and death from SARS-CoV-2. In this prospective observational study, we investigated the impact of cancer type, disease activity, and treatment in 877 unvaccinated UK patients with SARS-CoV-2 infection and active haematological cancer. The primary end-point was all-cause mortality. In a multivariate analysis adjusted for age, sex and comorbidities, the highest mortality was in patients with acute leukaemia [odds ratio (OR) = 1·73, 95% confidence interval (CI) 1·1-2·72, P = 0·017] and myeloma (OR 1·3, 95% CI 0·96-1·76, P = 0·08). Having uncontrolled cancer (newly diagnosed awaiting treatment as well as relapsed or progressive disease) was associated with increased mortality risk (OR = 2·45, 95% CI 1·09-5·5, P = 0·03), as was receiving second or beyond line of treatment (OR = 1·7, 95% CI 1·08-2·67, P = 0·023). We found no association between recent cytotoxic chemotherapy or anti-CD19/anti-CD20 treatment and increased risk of death within the limitations of the cohort size. Therefore, disease control is an important factor predicting mortality in the context of SARS-CoV-2 infection alongside the possible risks of therapies such as cytotoxic treatment or anti-CD19/anti-CD20 treatments.


Assuntos
Antígenos CD20/imunologia , Antineoplásicos Imunológicos/uso terapêutico , COVID-19/complicações , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/tratamento farmacológico , Adulto , Antineoplásicos Imunológicos/efeitos adversos , COVID-19/etiologia , COVID-19/imunologia , Feminino , Neoplasias Hematológicas/imunologia , Humanos , Leucemia/complicações , Leucemia/tratamento farmacológico , Leucemia/imunologia , Masculino , Mieloma Múltiplo/complicações , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/imunologia , Estudos Prospectivos , Fatores de Risco
6.
Leukemia ; 36(2): 525-531, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34545183

RESUMO

Chronic eosinophilic leukemia-not otherwise specified (CEL-NOS) is a rare, aggressive, fatal disease characterized by blood eosinophilia and dysfunction of organs infiltrated with eosinophils. Clinically, the disease manifests with weight loss, cough, weakness, diarrhea, and multi-organ dysfunction that is unresponsive to therapy. We developed a one-time gene therapy for CEL-NOS using an adeno-associated virus (AAV) expressing an anti-eosinophil monoclonal antibody (AAVrh.10mAnti-Eos) to provide sustained suppression of eosinophil numbers in blood, thus reducing eosinophil tissue invasion and organ dysfunction. A novel CEL-NOS model was developed in NOD-scid IL2rγnull (NSG) mice by administration of AAV expressing the cytokine IL5 (AAVrh.10mIL5), resulting in marked peripheral and tissue eosinophilia of the heart, lung, liver, and spleen, and eventually death. Mice were administered AAVrh.10mAnti-Eos (1011 genome copies) 4 wk after administration of AAVrh.10mIL5 and evaluated for anti-eosinophil antibody expression, blood eosinophil counts, organ eosinophil invasion, and survival. AAVrh.10mAnti-Eos expressed persistent levels of the anti-eosinophil antibody for >24 wk. Strikingly, CEL-NOS treated mice had markedly lower blood eosinophil levels and reduced mortality when compared with control treated mice. These results suggest that a single treatment with AAVrh.10mAnti-Eos has the potential to provide substantial therapeutic benefit to patients with CEL-NOS, a fatal malignant disorder.


Assuntos
Anticorpos Monoclonais/farmacologia , Dependovirus/genética , Modelos Animais de Doenças , Eosinófilos/imunologia , Terapia Genética , Síndrome Hipereosinofílica/terapia , Interleucina-5/genética , Leucemia/terapia , Animais , Eosinófilos/efeitos dos fármacos , Feminino , Síndrome Hipereosinofílica/genética , Síndrome Hipereosinofílica/imunologia , Leucemia/genética , Leucemia/imunologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID
8.
Bull Cancer ; 108(10S): S181-S194, 2021 Oct.
Artigo em Francês | MEDLINE | ID: mdl-34920802

RESUMO

Bispecific therapies targeting CD3, so-called T-cell engagers (TCE), belong to the new spectrum of anti-tumor immunotherapies stimulating T-lymphocytes. TCE are unique constructs targeting the MHC-independent CD3 epsilon subunit (CD3e) and a tumor antigen. To date, only blinatumomab have reached market agreements in lymphoid malignancies with constructs targeting CD3exCD19. Other TCE are in advances development, with promising results targeting CD20 and BSMA in lymphoma and myeloma. These successes have relaunched the development of TCE in solid tumors, bringing mixed results so far (notably in terms of tolerance). Still, TCE pave the way to new immunotherapy in tumors considered to be refractory to inhibitors of immune checkpoints such as prostate cancer or colorectal cancer.


Assuntos
Anticorpos Biespecíficos/imunologia , Antígenos de Neoplasias/imunologia , Complexo CD3/imunologia , Imunoterapia Adotiva/métodos , Neoplasias/terapia , Linfócitos T/imunologia , Anticorpos Biespecíficos/uso terapêutico , Antígenos CD19/imunologia , Antígenos CD20/imunologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/terapia , Neoplasias do Sistema Digestório/imunologia , Neoplasias do Sistema Digestório/terapia , Feminino , Humanos , Tolerância Imunológica , Leucemia/imunologia , Leucemia/terapia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/terapia , Linfoma/imunologia , Linfoma/terapia , Masculino , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/terapia , Neoplasias/imunologia , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/terapia , Carcinoma de Pequenas Células do Pulmão/imunologia , Carcinoma de Pequenas Células do Pulmão/terapia
10.
Cell Rep ; 37(6): 109992, 2021 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-34758319

RESUMO

To elucidate mechanisms by which T cells eliminate leukemia, we study donor lymphocyte infusion (DLI), an established immunotherapy for relapsed leukemia. We model T cell dynamics by integrating longitudinal, multimodal data from 94,517 bone marrow-derived single T cell transcriptomes in addition to chromatin accessibility and single T cell receptor sequencing from patients undergoing DLI. We find that responsive tumors are defined by enrichment of late-differentiated T cells before DLI and rapid, durable expansion of early differentiated T cells after treatment, highly similar to "terminal" and "precursor" exhausted subsets, respectively. Resistance, in contrast, is defined by heterogeneous T cell dysfunction. Surprisingly, early differentiated T cells in responders mainly originate from pre-existing and novel clonotypes recruited to the leukemic microenvironment, rather than the infusion. Our work provides a paradigm for analyzing longitudinal single-cell profiling of scenarios beyond adoptive cell therapy and introduces Symphony, a Bayesian approach to infer regulatory circuitry underlying T cell subsets, with broad relevance to exhaustion antagonists across cancers.


Assuntos
Imunoterapia Adotiva/métodos , Leucemia/imunologia , Ativação Linfocitária/imunologia , Transfusão de Linfócitos/métodos , Recidiva Local de Neoplasia/imunologia , Transplante de Células-Tronco/métodos , Linfócitos T/imunologia , Evolução Clonal , Humanos , Leucemia/patologia , Leucemia/terapia , Estudos Longitudinais , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Doadores de Tecidos , Transplante Homólogo
11.
J Hematol Oncol ; 14(1): 199, 2021 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-34809678

RESUMO

Although chimeric antigen receptor T cells demonstrated remarkable efficacy in patients with chemo-resistant hematologic malignancies, a significant portion still resist or relapse. This immune evasion may be due to CAR T cells dysfunction, a hostile tumor microenvironment, or resistant cancer cells. Here, we review the intrinsic resistance mechanisms of cancer cells to CAR T cell therapy and potential strategies to circumvent them.


Assuntos
Neoplasias Hematológicas/terapia , Imunoterapia Adotiva , Animais , Neoplasias Hematológicas/imunologia , Humanos , Imunoterapia Adotiva/métodos , Leucemia/imunologia , Leucemia/terapia , Linfoma/imunologia , Linfoma/terapia , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/terapia , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/terapia , Evasão Tumoral
12.
Nat Immunol ; 22(12): 1577-1589, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34811546

RESUMO

Single-cell genomics technology has transformed our understanding of complex cellular systems. However, excessive cost and a lack of strategies for the purification of newly identified cell types impede their functional characterization and large-scale profiling. Here, we have generated high-content single-cell proteo-genomic reference maps of human blood and bone marrow that quantitatively link the expression of up to 197 surface markers to cellular identities and biological processes across all main hematopoietic cell types in healthy aging and leukemia. These reference maps enable the automatic design of cost-effective high-throughput cytometry schemes that outperform state-of-the-art approaches, accurately reflect complex topologies of cellular systems and permit the purification of precisely defined cell states. The systematic integration of cytometry and proteo-genomic data enables the functional capacities of precisely mapped cell states to be measured at the single-cell level. Our study serves as an accessible resource and paves the way for a data-driven era in cytometry.


Assuntos
Células Sanguíneas/metabolismo , Células da Medula Óssea/metabolismo , Separação Celular , Citometria de Fluxo , Perfilação da Expressão Gênica , Proteoma , Proteômica , Análise de Célula Única , Transcriptoma , Fatores Etários , Células Sanguíneas/imunologia , Células Sanguíneas/patologia , Células da Medula Óssea/imunologia , Células da Medula Óssea/patologia , Células Cultivadas , Bases de Dados Genéticas , Envelhecimento Saudável/genética , Envelhecimento Saudável/imunologia , Envelhecimento Saudável/metabolismo , Humanos , Leucemia/genética , Leucemia/imunologia , Leucemia/metabolismo , Leucemia/patologia , RNA-Seq , Biologia de Sistemas
13.
Adv Sci (Weinh) ; 8(24): e2103023, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34716694

RESUMO

Short peptides reflecting major histocompatibility complex (MHC) class I (MHC-I) epitopes frequently lack sufficient immunogenicity to induce robust antigen (Ag)-specific CD8+ T cell responses. In the current work, it is demonstrated that position-scanning peptide libraries themselves can serve as improved immunogens, inducing Ag-specific CD8+ T cells with greater frequency and function than the wild-type epitope. The approach involves displaying the entire position-scanning library onto immunogenic nanoliposomes. Each library contains the MHC-I epitope with a single randomized position. When a recently identified MHC-I epitope in the glycoprotein gp70 envelope protein of murine leukemia virus (MuLV) is assessed, only one of the eight positional libraries tested, randomized at amino acid position 5 (Pos5), shows enhanced induction of Ag-specific CD8+ T cells. A second MHC-I epitope from gp70 is assessed in the same manner and shows, in contrast, multiple positional libraries (Pos1, Pos3, Pos5, and Pos8) as well as the library mixture give rise to enhanced CD8+ T cell responses. The library mixture Pos1-3-5-8 induces a more diverse epitope-specific T-cell repertoire with superior antitumor efficacy compared to an established single mutation mimotope (AH1-A5). These data show that positional peptide libraries can serve as immunogens for improving CD8+ T-cell responses against endogenously expressed MHC-I epitopes.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Leucemia/imunologia , Ativação Linfocitária/imunologia , Biblioteca de Peptídeos , Animais , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos BALB C
14.
Front Immunol ; 12: 730507, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34671352

RESUMO

To avoid graft rejection, the hematopoietic stem cells with matched classical human leukocyte antigen (HLA) alleles are the primary choice for clinical allogeneic transplantation. However, even if the fully HLA-matched hematopoietic stem cells are used for transplantation, some patients still have poor prognosis after hematopoietic stem cell transplantation (HSCT), suggesting that the HLA system was not the only determinant of the outcomes of HSCT. In this study, we investigated whether the single-nucleotide polymorphisms (SNPs) of the co-stimulatory genes within non-HLA regions were related to the outcomes of HSCT. The genomic DNAs of 163 patients who had acute leukemia and received HSCT and their respective donors were collected for analysis. Thirty-four SNPs located in the four co-stimulatory genes including cytotoxic T-lymphocyte associated protein 4 (CTLA4), CD28, tumor necrosis factor ligand superfamily 4 (TNFSF4), and programmed cell death protein 1 (PDCD1) were selected to explore their relationship with the adverse outcomes after transplantation, including mortality, cytomegalovirus infection, graft-versus-host disease, and relapse. Our results revealed that nine SNPs in the CTLA4 gene, five SNPs in the PDCD1 gene, two SNPs in the TNFSF4 gene, and four SNPs in the CD28 gene were significantly associated with the occurrence of adverse outcomes post-HSCT. These SNPs may play important roles in immune response to allografts post-HSCT and can be the targets for developing strategy to identify appropriate donors.


Assuntos
Antígenos CD28/genética , Antígeno CTLA-4/genética , Antígenos HLA/imunologia , Transplante de Células-Tronco Hematopoéticas , Leucemia/cirurgia , Ligante OX40/genética , Polimorfismo de Nucleotídeo Único , Receptor de Morte Celular Programada 1/genética , Adolescente , Adulto , Idoso , Antígenos CD28/imunologia , Antígeno CTLA-4/imunologia , Criança , Pré-Escolar , Infecções por Citomegalovirus/genética , Infecções por Citomegalovirus/imunologia , Seleção do Doador , Feminino , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Lactente , Leucemia/genética , Leucemia/imunologia , Leucemia/mortalidade , Masculino , Pessoa de Meia-Idade , Ligante OX40/imunologia , Receptor de Morte Celular Programada 1/imunologia , Recidiva , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
15.
Front Immunol ; 12: 729085, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34630403

RESUMO

Recently, many discoveries have elucidated the cellular and molecular diversity in the leukemic microenvironment and improved our knowledge regarding their complex nature. This has allowed the development of new therapeutic strategies against leukemia. Advances in biotechnology and the current understanding of T cell-engineering have led to new approaches in this fight, thus improving cell-mediated immune response against cancer. However, most of the investigations focus only on conventional cytotoxic cells, while ignoring the potential of unconventional T cells that until now have been little studied. γδ T cells are a unique lymphocyte subpopulation that has an extensive repertoire of tumor sensing and may have new immunotherapeutic applications in a wide range of tumors. The ability to respond regardless of human leukocyte antigen (HLA) expression, the secretion of antitumor mediators and high functional plasticity are hallmarks of γδ T cells, and are ones that make them a promising alternative in the field of cell therapy. Despite this situation, in particular cases, the leukemic microenvironment can adopt strategies to circumvent the antitumor response of these lymphocytes, causing their exhaustion or polarization to a tumor-promoting phenotype. Intervening in this crosstalk can improve their capabilities and clinical applications and can make them key components in new therapeutic antileukemic approaches. In this review, we highlight several characteristics of γδ T cells and their interactions in leukemia. Furthermore, we explore strategies for maximizing their antitumor functions, aiming to illustrate the findings destined for a better mobilization of γδ T cells against the tumor. Finally, we outline our perspectives on their therapeutic applicability and indicate outstanding issues for future basic and clinical leukemia research, in the hope of contributing to the advancement of studies on γδ T cells in cancer immunotherapy.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia Adotiva , Linfócitos Intraepiteliais/efeitos dos fármacos , Linfócitos Intraepiteliais/transplante , Leucemia/terapia , Animais , Antineoplásicos Imunológicos/efeitos adversos , Proliferação de Células/efeitos dos fármacos , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Imunoterapia Adotiva/efeitos adversos , Linfócitos Intraepiteliais/imunologia , Linfócitos Intraepiteliais/metabolismo , Leucemia/genética , Leucemia/imunologia , Leucemia/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Fenótipo , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Transdução de Sinais , Microambiente Tumoral
16.
Nat Commun ; 12(1): 5773, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34599159

RESUMO

Protein localisation and translocation between intracellular compartments underlie almost all physiological processes. The hyperLOPIT proteomics platform combines mass spectrometry with state-of-the-art machine learning to map the subcellular location of thousands of proteins simultaneously. We combine global proteome analysis with hyperLOPIT in a fully Bayesian framework to elucidate spatiotemporal proteomic changes during a lipopolysaccharide (LPS)-induced inflammatory response. We report a highly dynamic proteome in terms of both protein abundance and subcellular localisation, with alterations in the interferon response, endo-lysosomal system, plasma membrane reorganisation and cell migration. Proteins not previously associated with an LPS response were found to relocalise upon stimulation, the functional consequences of which are still unclear. By quantifying proteome-wide uncertainty through Bayesian modelling, a necessary role for protein relocalisation and the importance of taking a holistic overview of the LPS-driven immune response has been revealed. The data are showcased as an interactive application freely available for the scientific community.


Assuntos
Inflamação/metabolismo , Leucemia/metabolismo , Leucemia/patologia , Lipopolissacarídeos/farmacologia , Proteômica , Algoritmos , Anti-Infecciosos/metabolismo , Anti-Inflamatórios/metabolismo , Apresentação do Antígeno , Autofagossomos/metabolismo , Teorema de Bayes , Pontos de Checagem do Ciclo Celular , Membrana Celular/metabolismo , Núcleo Celular/metabolismo , Forma Celular , Humanos , Imunidade , Inflamação/patologia , Leucemia/imunologia , Ativação Linfocitária/imunologia , Lisossomos/metabolismo , Proteínas de Neoplasias/metabolismo , Transporte Proteico , Proteoma/metabolismo , Transdução de Sinais , Linfócitos T/imunologia , Células THP-1 , Fatores de Tempo , Vesículas Transportadoras/metabolismo , Regulação para Cima , Proteínas rho de Ligação ao GTP/metabolismo
17.
Int J Biol Macromol ; 190: 284-290, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34492245

RESUMO

Staphylococcal enterotoxin C2 (SEC2), a classical representative of superantigens, activates T cells that produce massive cytokines. This characteristic makes SEC2 a promising candidate drug for cancer immunotherapy. Previous study showed that ST-4, a SEC2 mutant, enhanced recognition of mouse T-cell receptor Vß regions, and activated the increased number of T cells that produced more cytokines. However, the underlying molecular mechanism for stimulation of human peripheral blood mononuclear cells (PBMCs) and antitumor effect on human tumor cells remains unknown. Herein, we showed that ST-4 significantly activated TCR Vß 12, 13A, 14, 15, 17, and 20 CD4+ and CD8+ T cells, which produced substantial amounts of granzyme B and perforin. These cytokines exhibited antitumor effect on K562 cells by promoting apoptosis and inducing S-phase cell cycle arrest. Conversely, the granzyme B inhibitor or perforin inhibitor significantly weakened antitumor effect of ST-4, accompanied by a decrease of cleaved proapoptotic BAX and cytochrome c, and an increase of antiapoptotic BCL2. Taken together, these data suggest that granzyme B and perforin produced by ST-4-activated CD4+ T cells and CD8+ T cells play a pivotal role in inducing K562 cell apoptosis by the mitochondrial apoptotic pathway, and support ST-4 as a potential candidate for cancer immunotherapy.


Assuntos
Apoptose , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Enterotoxinas/genética , Granzimas/metabolismo , Leucemia/patologia , Mitocôndrias/metabolismo , Perforina/metabolismo , Proliferação de Células , Humanos , Células K562 , Leucemia/imunologia , Ativação Linfocitária , Mutação/genética , Receptores de Antígenos de Linfócitos T/metabolismo
18.
J Immunol Res ; 2021: 5562630, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34337077

RESUMO

Natural killer (NK) cells are part of the first line of defense that rapidly respond to malignant transformed cells. Chimeric antigen receptor- (CAR-) engineered NK cells, although are still at the preliminary stage, have been shown to be alternative to CAR-T cells, mainly due to the absence of graft-versus-host disease and safer clinical profile. Allogeneic human NK cell line NK-92 cells, equipped by CAR, are being developed for clinical applications. Herein, we designed third-generation CARs, optimized the production protocol, and generated CAR-NK-92 cells, targeting CD19 and/or CD138 antigens that employ CD28, 4-1BB, and CD3ζ signaling, with >80% CAR expression, designated as CD19-NK-92, CD138-NK-92, and dual-NK-92 cells. The generated CAR-NK-92 cells displayed high and selective cytotoxicity toward various corresponding leukemia, lymphoma, and multiple myeloma cell lines in vitro. Multitargeting approach using a mixture of CD19-NK-92 and CD138-NK-92 cells was also evaluated at various ratios to test the idea of personalized formulation to match the patients' antigen expression profile. Our data indicate that increasing the ratio of CD19-NK-92 to CD138-NK-92 could improve NK cytotoxicity in leukemia cells with a relatively higher expression of CD19 over CD138, supporting the personalized proof of concept. This information represents the basis for further in vivo studies and future progress to clinical trials.


Assuntos
Imunoterapia Adotiva/métodos , Células Matadoras Naturais/transplante , Leucemia/terapia , Receptores de Antígenos Quiméricos/metabolismo , Antígenos CD19/metabolismo , Linhagem Celular Tumoral , Células HEK293 , Humanos , Células Matadoras Naturais/metabolismo , Leucemia/imunologia , Leucemia/patologia , Estudo de Prova de Conceito , Receptores de Antígenos Quiméricos/genética , Sindecana-1/antagonistas & inibidores , Sindecana-1/metabolismo
19.
Biomolecules ; 11(8)2021 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-34439817

RESUMO

Epstein-Barr virus (EBV) and cytomegalovirus (CMV) are viruses globally distributed that have been associated with the development and prognosis of many pathologies, including hematological diseases. This study aimed to characterize the epidemiological profile of EBV infection and the infection-correlated hepatic manifestations in patients with hematological diseases of the northern Brazilian state of Amazonas. A total of 228 patients were serologically tested for the presence of anti-EBV and anti-CMV IgG antibodies through an enzyme-linked immunosorbent assay. The coinfection with CMV, sociodemographic and laboratory records of all patients were also assessed. The overall prevalence observed among the study population for EBV infection and EBV/CMV coinfection was 85.09% (95% CI: 0.80-0.90) and 78.51% (95% CI: 0.73-0.84), respectively. The age group 31-40 years old were more susceptible to EBV/CMV coinfection (95% CI: 1.59-93.41, p = 0.011), while young people aged 1-10 years old were less affected for both EBV infection (CI 95%; 0.66-0.91, p = 0.001) and EBV/CMV coinfection (95% CI: 0.52-0.81, p < 0.0001). High serum levels of the liver biomarker ferritin were associated with EBV infection (95% CI: 1.03-1.54, p = 0.031) and EBV/CMV coinfection (95% CI: 1.02-1.70, p = 0.038). Our findings indicated that the elevated prevalence of EBV infection is not associated with the hematological diseases or transfusion rates, but with the socioeconomic status of the study population. Also, this study suggests that the EBV infection and its coinfection with CMV are related to the increase of serum ferritin levels.


Assuntos
Anemia/epidemiologia , Anticorpos Antivirais/sangue , Infecções por Citomegalovirus/epidemiologia , Infecções por Vírus Epstein-Barr/epidemiologia , Ferritinas/sangue , Leucemia/epidemiologia , Linfoma/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia/imunologia , Anemia/patologia , Anemia/virologia , Biomarcadores/sangue , Transfusão de Sangue/estatística & dados numéricos , Brasil/epidemiologia , Criança , Pré-Escolar , Coinfecção , Citomegalovirus/crescimento & desenvolvimento , Citomegalovirus/patogenicidade , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/patologia , Infecções por Citomegalovirus/virologia , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/patologia , Infecções por Vírus Epstein-Barr/virologia , Feminino , Herpesvirus Humano 4/crescimento & desenvolvimento , Herpesvirus Humano 4/patogenicidade , Humanos , Imunoglobulina G/sangue , Lactente , Recém-Nascido , Leucemia/imunologia , Leucemia/patologia , Leucemia/virologia , Fígado/imunologia , Fígado/patologia , Fígado/virologia , Linfoma/imunologia , Linfoma/patologia , Linfoma/virologia , Masculino , Pessoa de Meia-Idade , Prevalência , Classe Social
20.
Int J Mol Sci ; 22(16)2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34445701

RESUMO

Chimeric antigen receptor (CAR) T-cells (CAR T-cells) are a promising therapeutic approach in treating hematological malignancies. CAR T-cells represent engineered autologous T-cells, expressing a synthetic CAR, targeting tumor-associated antigens (TAAs) independent of major histocompatibility complex (MHC) presentation. The most common target is CD19 on B-cells, predominantly used for the treatment of lymphoma and acute lymphocytic leukemia (ALL), leading to approval of five different CAR T-cell therapies for clinical application. Despite encouraging clinical results, treatment of other hematological malignancies such as acute myeloid leukemia (AML) remains difficult. In this review, we focus especially on CAR T-cell application in different hematological malignancies as well as strategies for overcoming CAR T-cell dysfunction and increasing their efficacy.


Assuntos
Neoplasias Hematológicas/terapia , Imunoterapia Adotiva/métodos , Imunoterapia Adotiva/tendências , Antígenos de Neoplasias/imunologia , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/patologia , Humanos , Imunoterapia/métodos , Leucemia/imunologia , Leucemia/terapia , Linfoma/imunologia , Linfoma/terapia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...