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1.
Hematol Oncol ; 37 Suppl 1: 95-100, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31187533

RESUMO

Chimeric antigen receptor (CAR) T-cell therapy has dramatically shifted the landscape of treatment for lymphoid malignancies, especially diffuse large B-cell lymphoma (DLBCL) and acute lymphoblastic leukemia (ALL). However, there continue to be significant limitations of this therapy, such as incomplete or nonsustained responses and severe toxicities in a subset of patients. Furthermore, expanding the role of CAR T-cell therapy to new disease types is an important next step. In this review, we will highlight landmark trials for anti-CD19 CAR T cells and first-in-human trials of novel CARs, as well as discuss promising innovative CAR designs that are still undergoing preclinical development. Lastly, we will discuss toxicity and mechanisms of CAR T-cell resistance and failure, as well as potential future treatment approaches to these common issues.


Assuntos
Imunoterapia Adotiva , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Antígenos CD19 , Antígenos de Neoplasias/imunologia , Ensaios Clínicos como Assunto , Engenharia Genética , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Neoplasias/diagnóstico , Neoplasias/imunologia , Neoplasias/terapia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos Quiméricos/genética , Pesquisa , Resultado do Tratamento
2.
Hematol Oncol ; 37 Suppl 1: 48-52, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31187535

RESUMO

Chimeric antigen receptor (CAR) T-cell therapy has the potential to revolutionize the management of B-cell lymphomas and possibly other cancers. Two anti-CD19 CAR T-cell products, axicabtagene ciloleucel and tisagenlecleucel, have been approved for the management of relapsed/refractory large B-cell lymphoma after two lines of systemic therapy. Additional trials are ongoing to evaluate these and other CAR T products at earlier stages of the disease course as well as in other lymphomas. While the potential to induce durable remissions with a single CAR T-cell infusion even in patients who are chemorefractory has generated much enthusiasm in the field, practitioners need to familiarize themselves with the unique toxicities associated with these therapies. This review will discuss the grading and management of the two most common toxicities, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), observed acutely after this therapy. In addition, late toxicities including prolonged cytopenias and on-target off-tumor effects will be reviewed.


Assuntos
Imunoterapia Adotiva/efeitos adversos , Neoplasias/imunologia , Neoplasias/terapia , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Antígenos CD19/imunologia , Antígenos de Neoplasias/imunologia , Biomarcadores , Ensaios Clínicos como Assunto , Citocinas/metabolismo , Gerenciamento Clínico , Humanos , Imunoterapia Adotiva/métodos , Linfoma/imunologia , Linfoma/patologia , Linfoma/terapia , Neoplasias/mortalidade , Neoplasias/patologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos Quiméricos/genética , Resultado do Tratamento
3.
Eur J Med Chem ; 178: 195-213, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31185411

RESUMO

iNKT cells recognize CD1d/α-galactosylceramide (α-GalCer) complexes via their invariant TCR receptor and stimulate the immune response. Many α-GalCer analogues have been investigated to interrogate this interaction. Following our previous work related to the modification of the hydrogen bond network between α-GalCer and CD1d, we have now focused our attention on the synthesis of 3-deoxy-3,3-difluoro- and 3,4-dideoxy-3,3,4,4-tetrafluoro-α-GalCer analogues, and studied their ability to stimulate human iNKT cells. In each case, deoxygenation at the indicated positions was accompanied by difluoro introduction in order to evaluate the resulting electronic effect on the stability of the ternary CD1d/Galcer/TCR complex which has been rationalized by modeling study. With deoxy-difluorination at the 3-position, the two epimeric 4-OH analogues were investigated to establish their capacity to compensate for the lack of the hydrogen bond donating group at the 3-position. The 3,4-dideoxytetrafluoro analogue was of interest to highlight the amide NH-bond hydrogen bond properties.


Assuntos
Antígenos CD1d/metabolismo , Galactosilceramidas/farmacologia , Células T Matadoras Naturais/efeitos dos fármacos , Receptores de Antígenos de Linfócitos T/metabolismo , Antígenos CD1d/química , Galactosilceramidas/síntese química , Galactosilceramidas/química , Galactosilceramidas/metabolismo , Células HeLa , Humanos , Ligações de Hidrogênio , Interferon gama/metabolismo , Interleucina-13/metabolismo , Modelos Moleculares , Conformação Molecular , Ligação Proteica , Receptores de Antígenos de Linfócitos T/química , Estereoisomerismo
4.
Nat Commun ; 10(1): 2603, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-31197149

RESUMO

During thymic negative selection, autoreactive thymocytes carrying T cell receptor (TCR) with overtly strong affinity to self-MHC/self-peptide are removed by Bim-dependent apoptosis, but how Bim is specifically regulated to link TCR activation and apoptosis induction is unclear. Here we identify a murine T cell-specific genomic enhancer EBAB (Bub1-Acoxl-Bim), whose deletion leads to accumulation of thymocytes expressing high affinity TCRs. Consistently, EBAB knockout mice have defective negative selection and fail to delete autoreactive thymocytes in various settings, with this defect accompanied by reduced Bim expression and apoptosis induction. By contrast, EBAB is dispensable for maintaining peripheral T cell homeostasis via Bim-dependent pathways. Our data thus implicate EBAB as an important, developmental stage-specific regulator of Bim expression and apoptosis induction to enforce thymic negative selection and suppress autoimmunity. Our study unravels a part of genomic enhancer codes that underlie complex and context-dependent gene regulation in TCR signaling.


Assuntos
Autoimunidade/genética , Proteína 11 Semelhante a Bcl-2/genética , Elementos Facilitadores Genéticos/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Timócitos/fisiologia , Animais , Apoptose/genética , Apoptose/imunologia , Autoimunidade/imunologia , Proteína 11 Semelhante a Bcl-2/metabolismo , Sistemas CRISPR-Cas/genética , Elementos Facilitadores Genéticos/genética , Feminino , Regulação da Expressão Gênica/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Animais , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Timo/citologia , Timo/imunologia
5.
Immunogenetics ; 71(7): 465-478, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31123763

RESUMO

Invariant NKT (iNKT) cells in both humans and non-human primates are activated by the glycolipid antigen, α-galactosylceramide (α-GalCer). However, the extent to which the molecular mechanisms of antigen recognition and in vivo phenotypes of iNKT cells are conserved among primate species has not been determined. Using an evolutionary genetic approach, we found a lack of diversifying selection in CD1 genes over 45 million years of evolution, which stands in stark contrast to the history of the MHC system for presenting peptide antigens to T cells. The invariant T cell receptor (TCR)-α chain was strictly conserved across all seven primate clades. Invariant NKT cells from rhesus macaques (Macaca mulatta) bind human CD1D-α-GalCer tetramer and are activated by α-GalCer-loaded human CD1D transfectants. The dominant TCR-ß chain cloned from a rhesus-derived iNKT cell line is nearly identical to that found in the human iNKT TCR, and transduction of the rhesus iNKT TCR into human Jurkat cells show that it is sufficient for binding human CD1D-α-GalCer tetramer. Finally, we used a 20-color flow cytometry panel to probe tissue phenotypes of iNKT cells in a cohort of rhesus macaques. We discovered several tissue-resident iNKT populations that have not been previously described in non-human primates but are known in humans, such as TCR-γδ iNKTs. These data reveal a diversity of iNKT cell phenotypes despite convergent evolution of the genes required for lipid antigen presentation and recognition in humans and non-human primates.


Assuntos
Antígenos CD1/genética , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Primatas/genética , Sequência de Aminoácidos , Animais , Antígenos CD1/metabolismo , Sequência Conservada , Evolução Molecular , Feminino , Humanos , Células Jurkat , Macaca mulatta/imunologia , Masculino , Fenótipo , Primatas/imunologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo
6.
Ann Lab Med ; 39(5): 438-446, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31037862

RESUMO

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired pluripotent hematopoietic stem cell disorder associated with an increase in the number of glycosyl-phosphatidyl inositol (GPI)-deficient blood cells. We investigated PNH clonal proliferation in the three cell lineages-granulocytes, T lymphocytes, and red blood cells (RBCs)-by analyzing PIGA gene mutations and T-cell receptor (TCR) clonality. METHODS: Flow cytometry was used on peripheral blood samples from 24 PNH patients to measure the GPI-anchored protein (GPI-AP) deficient fraction in each blood cell lineage. PIGA gene mutations were analyzed in granulocytes and T lymphocytes by Sanger sequencing. A TCR clonality assay was performed in isolated GPI-AP deficient T lymphocytes. RESULTS: The GPI-AP deficient fraction among the three lineages was the highest in granulocytes, followed by RBCs and T lymphocytes. PIGA mutations were detected in both granulocytes and T lymphocytes of 19 patients (79.2%), with a higher mutation burden in granulocytes. The GPI-AP deficient fractions of granulocytes and T lymphocytes correlated moderately (rs=0.519, P=0.049) and strongly (rs=0.696, P=0.006) with PIGA mutation burden, respectively. PIGA mutations were more frequently observed in patients with clonal rearrangements in TCR genes (P=0.015). The PIGA mutation burden of T lymphocytes was higher in patients with clonal TCRB rearrangement. CONCLUSIONS: PIGA mutations were present in approximately 80% of PNH patients. PNH clone size varies according to blood cell lineage, and clonal cells may obtain proliferation potential or gain a survival advantage over normal cells.


Assuntos
Proliferação de Células , Granulócitos/citologia , Hemoglobinúria Paroxística/diagnóstico , Proteínas de Membrana/genética , Linfócitos T/citologia , Adolescente , Adulto , Idoso , Linhagem da Célula , Criança , Feminino , Proteínas Ligadas por GPI/deficiência , Proteínas Ligadas por GPI/genética , Rearranjo Gênico , Granulócitos/metabolismo , Hemoglobinúria Paroxística/genética , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/metabolismo , Adulto Jovem
7.
Nat Commun ; 10(1): 2352, 2019 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-31138793

RESUMO

Regulatory T cells (Tregs) have crucial functions in the inhibition of immune responses. Their development and suppressive functions are controlled by the T cell receptor (TCR), but the TCR signaling mechanisms that mediate these effects remain ill-defined. Here we show that CARD11-BCL10-MALT1 (CBM) signaling mediates TCR-induced NF-κB activation in Tregs and controls the conversion of resting Tregs to effector Tregs under homeostatic conditions. However, in inflammatory milieus, cytokines can bypass the CBM requirement for this differentiation step. By contrast, CBM signaling, in a MALT1 protease-dependent manner, is essential for mediating the suppressive function of Tregs. In malignant melanoma models, acute genetic blockade of BCL10 signaling selectively in Tregs or pharmacological MALT1 inhibition enhances anti-tumor immune responses. Together, our data uncover a segregation of Treg differentiation and suppressive function at the CBM complex level, and provide a rationale to explore MALT1 inhibitors for cancer immunotherapy.


Assuntos
Proteína 10 de Linfoma CCL de Células B/imunologia , Proteínas Adaptadoras de Sinalização CARD/imunologia , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Animais , Proteína 10 de Linfoma CCL de Células B/metabolismo , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Diferenciação Celular , Citocinas/imunologia , Melanoma Experimental , Camundongos , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/metabolismo , NF-kappa B/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/metabolismo
8.
Am Soc Clin Oncol Educ Book ; 39: e70-e78, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31099621

RESUMO

Adoptive T-cell therapy using tumor-infiltrating lymphocytes (TILs) has demonstrated long-lasting antitumor activity in select patients with advanced melanoma. Cancer vaccines have been used for many decades and have shown some promise but overall relatively modest clinical activity across cancers. Technological advances in genome sequencing capabilities and T-cell engineering have had substantial impact on both adoptive cell therapy and the cancer vaccine field. The ability to identify neoantigens-a class of tumor antigens that is truly tumor specific and encoded by tumor mutations through rapid and relatively inexpensive next-generation sequencing-has already demonstrated the critical importance of these antigens as targets of antitumor-specific T-cell responses in the context of immune checkpoint blockade and other immunotherapies. Therapeutically targeting these antigens with either adoptive T-cell therapy or vaccine approaches has demonstrated early promise in the clinic in patients with advanced solid tumors. Chimeric antigen receptor (CAR) T cells, which are engineered by fusing an antigen-specific, single-chain antibody (scFv) with signaling molecules of the T-cell receptor (TCR)/CD3 complex creating an antibody-like structure on T cells that recognizes antigens independently of major histocompatibility complex (MHC) molecules, have demonstrated remarkable clinical activity in patients with advanced B-cell malignancies, leading to several approvals by the U.S. Food and Drug Administration (FDA).


Assuntos
Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/uso terapêutico , Imunoterapia Adotiva , Neoplasias/imunologia , Neoplasias/terapia , Animais , Biomarcadores Tumorais , Ensaios Clínicos como Assunto , Engenharia Genética , Terapia Genética , Humanos , Imunoterapia Adotiva/métodos , Medicina de Precisão/métodos , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Resultado do Tratamento
9.
Am Soc Clin Oncol Educ Book ; 39: 446-453, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31099671

RESUMO

Aggressive B-cell lymphomas that are primary refractory to, or relapse after, frontline chemoimmunotherapy have a low cure rate with conventional therapies. Although high-dose chemotherapy remains the standard of care at first relapse for sufficiently young and fit patients, fewer than one-quarter of patients with relapsed/refractory disease are cured with this approach. Anti-CD19 chimeric antigen receptor (CAR) T cells have emerged as an effective therapy in patients with multiple relapsed/refractory disease, capable of inducing durable remissions in patients with chemotherapy-refractory disease. Three anti-CD19 CAR T cells for aggressive B-cell lymphoma (axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene ciloleucel) are either U.S. Food and Drug Administration approved or in late-stage development. All three CAR T cells produce durable remissions in 33%-40% of treated patients. Differences among these products include the specific CAR constructs, costimulatory domains, manufacturing process, dose, and eligibility criteria for their pivotal trials. Notable toxicities include cytokine release syndrome and neurologic toxicities, which are usually treatable and reversible, as well as cytopenias and hypogammaglobulinemia. Incidences of cytokine release syndrome and neurotoxicity differ across CAR T-cell products, related in part to the type of costimulatory domain. Potential mechanisms of resistance include CAR T-cell exhaustion and immune evasion, CD19 antigen loss, and a lack of persistence. Rational combination strategies with CAR T cells are under evaluation, including immune checkpoint inhibitors, immunomodulators, and tyrosine kinase inhibitors. Novel cell products are also being developed and include CAR T cells that target multiple tumor antigens, cytokine-secreting CAR T cells, and gene-edited CAR T cells, among others.


Assuntos
Imunoterapia Adotiva , Linfoma de Células B/imunologia , Linfoma de Células B/terapia , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Antígenos CD19 , Antígenos de Neoplasias , Terapia Combinada , Progressão da Doença , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Linfoma de Células B/diagnóstico , Gradação de Tumores , Estadiamento de Neoplasias , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos Quiméricos/genética , Resultado do Tratamento
10.
Am Soc Clin Oncol Educ Book ; 39: 433-444, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31099694

RESUMO

Immune effector cells, including T cells and natural killer cells, which are genetically engineered to express a chimeric antigen receptor (CAR), constitute a powerful new class of therapeutic agents to treat patients with hematologic malignancies. Several CAR T-cell trials have shown impressive remission rates in patients with relapsed/refractory hematologic cancers. Although the clinical responses of these agents in hematologic malignancies have been very encouraging, they have also produced substantial morbidity and occasionally mortality resulting from toxicity. With more experience and collaboration, hopefully the toxicities and the costs will come down, increasing the availability of CAR T cells to patients in need.


Assuntos
Efeitos Psicossociais da Doença , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/epidemiologia , Imunoterapia Adotiva/efeitos adversos , Doenças do Sistema Nervoso/etiologia , Gerenciamento Clínico , Engenharia Genética , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/terapia , Humanos , Imunoterapia Adotiva/métodos , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/epidemiologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/genética , Índice de Gravidade de Doença , Linfócitos T/imunologia , Linfócitos T/metabolismo , Resultado do Tratamento
11.
Int J Mol Sci ; 20(10)2019 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-31109083

RESUMO

Chimeric antigen receptor T cell (CART) therapy is currently one of the most promising treatment approaches in cancer immunotherapy. However, the immunosuppressive nature of the tumor microenvironment, in particular increased reactive oxygen species (ROS) levels, provides considerable limitations. In this study, we aimed to exploit increased ROS levels in the tumor microenvironment with prodrugs of ROS accelerators, which are specifically activated in cancer cells. Upon activation, ROS accelerators induce further generation of ROS. This leads to an accumulation of ROS in tumor cells. We hypothesized that the latter cells will be more susceptible to CARTs. CD19-specific CARTs were generated with a CD19.CAR.CD28.CD137zeta third-generation retroviral vector. Cytotoxicity was determined by chromium-51 release assay. Influence of the ROS accelerators on viability and phenotype of CARTs was determined by flow cytometry. The combination of CARTs with the ROS accelerator PipFcB significantly increased their cytotoxicity in the Burkitt lymphoma cell lines Raji and Daudi, as well as primary chronic lymphocytic leukemia cells. Exposure of CARTs to PipFcB for 48 h did not influence T cell exhaustion, viability, or T cell subpopulations. In summary, the combination of CARTs with ROS accelerators may improve adoptive immunotherapy and help to overcome tumor microenvironment-mediated treatment resistance.


Assuntos
Leucemia de Células B/imunologia , Leucemia de Células B/metabolismo , Linfoma de Células B/imunologia , Linfoma de Células B/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Antígenos CD19/imunologia , Antígenos de Neoplasias/imunologia , Degranulação Celular , Linhagem Celular Tumoral , Citocinas/biossíntese , Citotoxicidade Imunológica , Humanos , Leucemia de Células B/patologia , Leucemia de Células B/terapia , Linfoma de Células B/patologia , Linfoma de Células B/terapia , Estresse Oxidativo , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos Quiméricos/genética
12.
Nat Commun ; 10(1): 2042, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053703

RESUMO

Metabolic pathways that regulate T-cell function show promise as therapeutic targets in diverse diseases. Here, we show that at rest cultured human effector memory and central memory CD4+ T-cells have elevated levels of glycolysis and oxidative phosphorylation (OXPHOS), in comparison to naïve T-cells. Despite having low resting metabolic rates, naive T-cells respond to TCR stimulation with robust and rapid increases in glycolysis and OXPHOS. This early metabolic switch requires Akt activity to support increased rates of glycolysis and STAT5 activity for amino acid biosynthesis and TCA cycle anaplerosis. Importantly, both STAT5 inhibition and disruption of TCA cycle anaplerosis are associated with reduced IL-2 production, demonstrating the functional importance of this early metabolic program. Our results define STAT5 as a key node in modulating the early metabolic program following activation in naive CD4+ T-cells and in turn provide greater understanding of how cellular metabolism shapes T-cell responses.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Fator de Transcrição STAT5/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Células Cultivadas , Ciclo do Ácido Cítrico/imunologia , Glicólise/imunologia , Voluntários Saudáveis , Humanos , Memória Imunológica , Ativação Linfocitária , Fosforilação Oxidativa , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-akt/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Fator de Transcrição STAT5/imunologia
13.
Nat Immunol ; 20(6): 747-755, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31061531

RESUMO

Despite gathering evidence that ubiquitylation can direct non-degradative outcomes, most investigations of ubiquitylation in T cells have focused on degradation. Here, we integrated proteomic and transcriptomic datasets from primary mouse CD4+ T cells to establish a framework for predicting degradative or non-degradative outcomes of ubiquitylation. Di-glycine remnant profiling was used to reveal ubiquitylated proteins, which in combination with whole-cell proteomic and transcriptomic data allowed prediction of protein degradation. Analysis of ubiquitylated proteins identified by di-glycine remnant profiling indicated that activation of CD4+ T cells led to an increase in non-degradative ubiquitylation. This correlated with an increase in non-proteasome-targeted K29, K33 and K63 polyubiquitin chains. This study revealed over 1,200 proteins that were ubiquitylated in primary mouse CD4+ T cells and highlighted the relevance of non-proteasomally targeted ubiquitin chains in T cell signaling.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Ativação Linfocitária/imunologia , Proteoma , Proteômica , Animais , Perfilação da Expressão Gênica , Ativação Linfocitária/genética , Espectrometria de Massas , Camundongos , Poliubiquitina/metabolismo , Proteômica/métodos , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Transcriptoma , Ubiquitinação
15.
Int J Mol Sci ; 20(8)2019 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-31013813

RESUMO

The generation of immune cells from human pluripotent stem cells (embryonic stem cells and induced pluripotent stem cells) has been of keen interest to regenerative medicine. Pluripotent stem cell-derived immune cells such as natural killer cells, macrophages, and lymphoid cells, especially T cells, can be used in immune cell therapy to treat incurable cancers. Moreover, since the advent of chimeric antigen receptor (CAR) technology, the success of CAR-T cells in the clinic has galvanized new efforts to harness the power of CAR technology to generate CAR-engineered immune cells from pluripotent stem cells. This review provides a summary of pluripotent stem cell-derived immune cells and CAR technology, together with perspectives on combining pluripotent stem-cell derived immune cells and CAR engineering to pave a new way for developing next generation immune cell therapy.


Assuntos
Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Células-Tronco/citologia , Células-Tronco/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Diferenciação Celular/imunologia , Humanos , Imunoterapia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/metabolismo , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos Quiméricos/genética , Transplante de Células-Tronco
16.
EBioMedicine ; 42: 97-108, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30824386

RESUMO

BACKGROUND: The latent HIV-1 reservoir in treated patients primarily consists of resting memory CD4+ T cells. Stimulating the T-cell receptor (TCR), which facilitates transition of resting into effector T cells, is the most effective strategy to purge these latently infected cells. Here we supply evidence that TCR-stimulated effector T cells still frequently harbor latent HIV-1. METHODS: Primary HIV-1 infected cells were used in a latency assay with or without dendritic cells (DCs) and reversion of HIV-1 latency was determined, in the presence or absence of specific pathway inhibitors. FINDINGS: Renewed TCR-stimulation or subsequent activation with latency reversing agents (LRAs) did not overcome latency. However, interaction of infected effector cells with DCs triggered further activation of latent HIV-1. When compared to TCR-stimulation only, CD4+ T cells from aviremic patients receiving TCR + DC-stimulation reversed latency more frequently. Such a "one-two punch" strategy seems ideal for purging the reservoir. We determined that DC contact activates the PI3K-Akt-mTOR pathway in CD4+ T cells. INTERPRETATION: This insight could facilitate the development of a novel class of potent LRAs that purge latent HIV beyond levels reached by T-cell activation.


Assuntos
Infecções por HIV/metabolismo , Infecções por HIV/virologia , HIV-1/fisiologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Latência Viral , Adulto , Idoso , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/virologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , HIV-1/efeitos dos fármacos , Humanos , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , NF-kappa B/metabolismo , Fosforilação , Ligação Proteica , Proteínas Proto-Oncogênicas c-fos/química , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Proto-Oncogênicas c-jun/química , Proteínas Proto-Oncogênicas c-jun/metabolismo , Transdução de Sinais , Latência Viral/imunologia
17.
BMC Cancer ; 19(1): 203, 2019 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-30841880

RESUMO

Chimeric antigen receptor T (CAR-T) cells are a promising new treatment for patients with relapsed or refractory hematologic malignancies, including lymphoma. Given the success of CAR-T cells directed against CD19, new targets are being developed and tested, since not all lymphomas express CD19. CD30 is promising target as it is universally expressed in virtually all classical Hodgkin lymphomas, anaplastic large cell lymphomas, and in a proportion of other lymphoma types, including cutaneous T cell lymphomas and diffuse large B cell lymphomas. Preclinical studies with CD30-directed CAR-T cells support the feasibility of this approach. Recently, two clinical trials of CD30-directed CAR-T cells in relapsed/refractory CD30+ lymphomas, including Hodgkin lymphoma, have been reported with minimal toxicities noted and preliminary efficacy seen in a proportion of patients. However, improving the persistence and expansion of CAR-T cells is key to further enhancing the efficacy of this treatment approach. Future directions include optimizing the lymphodepletion regimen, enhancing migration to the tumor site, and combination with other immune regulators. Several ongoing and upcoming clinical trials of CD30-directed CAR-T cells are expected to further enhance this approach to treat patients with relapsed and refractory CD30+ lymphomas.


Assuntos
Imunoterapia Adotiva , Antígeno Ki-1/antagonistas & inibidores , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Antígenos CD19 , Antígenos de Neoplasias/imunologia , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Doença de Hodgkin/imunologia , Doença de Hodgkin/terapia , Humanos , Linfoma Anaplásico de Células Grandes/imunologia , Linfoma Anaplásico de Células Grandes/terapia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos Quiméricos/genética , Resultado do Tratamento
18.
Proc Natl Acad Sci U S A ; 116(13): 5908-5913, 2019 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-30850545

RESUMO

Mechanosensing by T cells through the T cell receptor (TCR) is at the heart of immune recognition. While the mechanobiology of the TCR at the molecular level is increasingly well documented, its link to cell-scale response is poorly understood. Here we explore T cell spreading response as a function of substrate rigidity and show that remarkably, depending on the surface receptors stimulated, the cellular response may be either biphasic or monotonous. When adhering solely via the TCR complex, T cells respond to environmental stiffness in an unusual fashion, attaining maximal spreading on an optimal substrate stiffness comparable to that of professional antigen-presenting cells. However, in the presence of additional ligands for the integrin LFA-1, this biphasic response is abrogated and the cell spreading increases monotonously with stiffness up to a saturation value. This ligand-specific mechanosensing is effected through an actin-polymerization-dependent mechanism. We construct a mesoscale semianalytical model based on force-dependent bond rupture and show that cell-scale biphasic or monotonous behavior emerges from molecular parameters. As the substrate stiffness is increased, there is a competition between increasing effective stiffness of the bonds, which leads to increased cell spreading and increasing bond breakage, which leads to decreased spreading. We hypothesize that the link between actin and the receptors (TCR or LFA-1), rather than the ligand/receptor linkage, is the site of this mechanosensing.


Assuntos
Mecanotransdução Celular , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/metabolismo , Linhagem Celular , Humanos , Imunidade Celular , Cinética , Ligantes , Miosinas/metabolismo , Especificidade por Substrato , Linfócitos T/imunologia
19.
Virology ; 531: 192-202, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30927712

RESUMO

Functional characterisation of different HIV-1 subtypes may improve understanding of viral pathogenesis and spread. Here, we evaluated the ability of 345 unique HIV-1 Nef clones representing subtypes A, B, C and D to inhibit NFAT signalling following TCR stimulation. The contribution of this Nef function to disease progression was also assessed in 211 additional Nef clones isolated from unique subtype C infected individuals in early or chronic infection. On average, subtype A and C Nef clones exhibited significantly lower ability to inhibit TCR-mediated NFAT signalling compared to subtype B and D Nef clones. While this observation corroborates accumulating evidence supporting relative attenuation of subtypes A and C that may paradoxically contribute to their increased global prevalence and spread, no significant correlations between Nef-mediated NFAT inhibition activity and clinical markers of HIV-1 infection were observed, indicating that the relationship between Nef function and pathogenesis is complex.


Assuntos
Infecções por HIV/metabolismo , HIV-1/isolamento & purificação , HIV-1/metabolismo , Fatores de Transcrição NFATC/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Produtos do Gene nef do Vírus da Imunodeficiência Humana/metabolismo , Feminino , Infecções por HIV/genética , Infecções por HIV/virologia , HIV-1/classificação , HIV-1/genética , Humanos , Masculino , Fatores de Transcrição NFATC/genética , Filogenia , Receptores de Antígenos de Linfócitos T/genética , Transdução de Sinais , Produtos do Gene nef do Vírus da Imunodeficiência Humana/genética
20.
Nat Immunol ; 20(4): 447-457, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30833791

RESUMO

Invariant natural killer T cells (iNKT cells) develop through an incompletely understood process that requires positive selection by CD4+CD8+ double-positive thymocytes and SLAM family receptors (SFRs). Here we found that SFRs promoted the development of iNKT cells by reducing the strength of the T cell antigen receptor (TCR) signal after positive selection. This effect improved the survival of iNKT cells and their responses to antigen. Loss of SFRs upregulated the expression of inhibitory receptors, including PD-1, on iNKT cells to mitigate the deleterious effect of SFR deficiency. The role of SFRs could be mimicked by expression of SLAMF6 alone in SFR-deficient mice, and this involved the adaptor SAP-kinase Fyn complex and the phosphatase SHP-1. Thus, SFRs foster iNKT cell development by attenuating TCR signal strength after positive selection.


Assuntos
Células T Matadoras Naturais/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Família de Moléculas de Sinalização da Ativação Linfocitária/fisiologia , Animais , Proliferação de Células , Sobrevivência Celular , Receptores Coestimuladores e Inibidores de Linfócitos T/metabolismo , Humanos , Camundongos , Camundongos Knockout , Células T Matadoras Naturais/enzimologia , Proteína Tirosina Fosfatase não Receptora Tipo 6/genética , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-fyn/metabolismo , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais , Proteína Associada à Molécula de Sinalização da Ativação Linfocitária/genética , Família de Moléculas de Sinalização da Ativação Linfocitária/genética , Família de Moléculas de Sinalização da Ativação Linfocitária/metabolismo
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