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1.
Int J Mol Sci ; 22(3)2021 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-33498945

RESUMO

Thrombosis is a major cause of morbimortality in patients with chronic Philadelphia chromosome-negative myeloproliferative neoplasms (MPN). In the last decade, multiple lines of evidence support the role of leukocytes in thrombosis of MPN patients. Besides the increase in the number of cells, neutrophils and monocytes of MPN patients show a pro-coagulant activated phenotype. Once activated, neutrophils release structures composed of DNA, histones, and granular proteins, called extracellular neutrophil traps (NETs), which in addition to killing pathogens, provide an ideal matrix for platelet activation and coagulation mechanisms. Herein, we review the published literature related to the involvement of NETs in the pathogenesis of thrombosis in the setting of MPN; the effect that cytoreductive therapies and JAK inhibitors can have on markers of NETosis, and, finally, the novel therapeutic strategies targeting NETs to reduce the thrombotic complications in these patients.


Assuntos
Leucemia/complicações , Transtornos Mieloproliferativos/complicações , Neutrófilos , Trombose/etiologia , Animais , Humanos , Leucemia/imunologia , Transtornos Mieloproliferativos/imunologia , Trombose/imunologia
2.
Int J Mol Sci ; 22(2)2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33467555

RESUMO

Acute leukemias, the most common cancers in children, are characterized by excessive proliferation of malignant progenitor cells. As a consequence of impaired blood cell production, leukemia patients are susceptible to infectious complications-a major cause of non-relapse mortality. Neutrophil extracellular traps (NETs) are involved in various pathologies, from autoimmunity to cancer. Although aberrant NETs formation may be partially responsible for immune defects observed in acute leukemia, still little is known on the NET release in the course of leukemia. Here, we present the first comprehensive evaluation of NETs formation by neutrophils isolated from children with acute leukemia in different stages of the disease and treatment stimulated in vitro with phorbol 12-myristate 13-acetate (PMA), N-formyl-methionyl-leucyl-phenylalanine (fMLP), and calcium ionophore (CI). NETs release was measured using quantitative fluorescent method and visualized microscopically. In this setting, NETs release was significantly impaired in leukemic children both at the diagnosis and during the treatment, and full restoration of neutrophil function was achieved only after successful completion of the leukemia treatment. We suggest that neutrophil function impairment may result from both disease- and treatment-related factors. In this context, deficient innate immune response observed in acute leukemia patients may be present regardless of neutrophil count and contribute to secondary immunodeficiency observed in this population.


Assuntos
Armadilhas Extracelulares/imunologia , Imunidade Inata/imunologia , Leucemia/imunologia , Neutrófilos/imunologia , Doença Aguda , Adolescente , Ionóforos de Cálcio/farmacologia , Células Cultivadas , Criança , Pré-Escolar , Humanos , Imunidade Inata/efeitos dos fármacos , Lactente , Leucemia/sangue , Leucemia/tratamento farmacológico , N-Formilmetionina Leucil-Fenilalanina/farmacologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Acetato de Tetradecanoilforbol/farmacologia
3.
Virol J ; 18(1): 1, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33397387

RESUMO

BACKGROUND: Virus neutralization by antibodies is an important prognostic factor in many viral diseases. To easily and rapidly measure titers of neutralizing antibodies in serum or plasma, we developed pseudovirion particles composed of the spike glycoprotein of SARS-CoV-2 incorporated onto murine leukemia virus capsids and a modified minimal murine leukemia virus genome encoding firefly luciferase. This assay design is intended for use in laboratories with biocontainment level 2 and therefore circumvents the need for the biocontainment level 3 that would be required for replication-competent SARS-CoV-2 virus. To validate the pseudovirion assay, we set up comparisons with other available antibody tests including those from Abbott, Euroimmun and Siemens, using archived, known samples. RESULTS: 11 out of 12 SARS-CoV-2-infected patient serum samples showed neutralizing activity against SARS-CoV-2-spike pseudotyped MLV viruses, with neutralizing titers-50 (NT50) that ranged from 1:25 to 1:1,417. Five historical samples from patients hospitalized for severe influenza infection in 2016 tested negative in the neutralization assay (NT50 < 25). Three serum samples with high neutralizing activity against SARS-CoV-2/MLV pseudoviruses showed no detectable neutralizing activity (NT50 < 25) against SARS-CoV-1/MLV pseudovirions. We also compared the semiquantitative Siemens SARS-CoV-2 IgG test, which measures binding of IgG to recombinantly expressed receptor binding domain of SARS-CoV-2 spike glycoprotein with the neutralization titers obtained in the pseudovirion assay and the results show high concordance between the two tests (R2 = 0.9344). CONCLUSIONS: SARS-CoV-2 spike/MLV pseudovirions provide a practical means of assessing neutralizing activity of antibodies in serum or plasma from infected patients under laboratory conditions consistent with biocontainment level 2. This assay offers promise also in evaluating immunogenicity of spike glycoprotein-based candidate vaccines in the near future.


Assuntos
/imunologia , Leucemia/imunologia , Testes de Neutralização/métodos , Glicoproteína da Espícula de Coronavírus/imunologia , Vírion/imunologia , /imunologia , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Células HEK293 , Humanos , Imunoglobulina G/sangue , Camundongos
4.
Methods Mol Biol ; 2185: 3-23, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33165839

RESUMO

Classifying the hematological malignancies by assigning cells to their normal counterpart and describing the nature of disease progression are entirely reliant on an accurate picture for the development of the multifarious types of blood and immune cells. In recent years, our understanding of the complex relationships between the various hematopoietic stem cell-derived cell lineages has undergone substantial revision. There has been similar progress in how we describe the nature of the "target" cells that genetic insults transform to give rise to the hematological malignancies. Here I describe how both longstanding and new information has influenced classifying, for diagnosis, the hematological malignancies.


Assuntos
Leucemia/sangue , Leucemia/classificação , Leucemia/imunologia , Leucemia/patologia , Animais , Humanos
5.
PLoS Pathog ; 16(9): e1008811, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32903274

RESUMO

Damage-associated molecular patterns (DAMPs) are endogenous molecules activating the immune system upon release from injured cells. Here we show that the IFI16 protein, once freely released in the extracellular milieu of chronically inflamed tissues, can function as a DAMP either alone or upon binding to lipopolysaccharide (LPS). Specifically, using pull-down and saturation binding experiments, we show that IFI16 binds with high affinity to the lipid A moiety of LPS. Remarkably, IFI16 DAMP activity is potentiated upon binding to subtoxic concentrations of strong TLR4-activating LPS variants, as judged by TLR4-MD2/TIRAP/MyD88-dependent IL-6, IL-8 and TNF-α transcriptional activation and release in stimulated monocytes and renal cells. Consistently, using co-immunoprecipitation (co-IP) and surface plasmon resonance (SPR) approaches, we show that IFI16 is a specific TLR4-ligand and that IFI16/LPS complexes display a faster stimulation turnover on TLR4 than LPS alone. Altogether, our findings point to a novel pathomechanism of inflammation involving the formation of multiple complexes between extracellular IFI16 and subtoxic doses of LPS variants, which then signal through TLR4.


Assuntos
Inflamação/imunologia , Neoplasias Renais/imunologia , Leucemia/imunologia , Lipopolissacarídeos/metabolismo , Proteínas Nucleares/metabolismo , Fosfoproteínas/metabolismo , Receptor 4 Toll-Like/metabolismo , Humanos , Inflamação/metabolismo , Inflamação/patologia , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Leucemia/metabolismo , Leucemia/patologia , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais , Células Tumorais Cultivadas
6.
Nat Commun ; 11(1): 4227, 2020 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-32839441

RESUMO

In hematopoietic cell transplants, alloreactive T cells mediate the graft-versus-leukemia (GVL) effect. However, leukemia relapse accounts for nearly half of deaths. Understanding GVL failure requires a system in which GVL-inducing T cells can be tracked. We used such a model wherein GVL is exclusively mediated by T cells that recognize the minor histocompatibility antigen H60. Here we report that GVL fails due to insufficient H60 presentation and T cell exhaustion. Leukemia-derived H60 is inefficiently cross-presented whereas direct T cell recognition of leukemia cells intensifies exhaustion. The anti-H60 response is augmented by H60-vaccination, an agonist αCD40 antibody (FGK45), and leukemia apoptosis. T cell exhaustion is marked by inhibitory molecule upregulation and the development of TOX+ and CD39-TCF-1+ cells. PD-1 blockade diminishes exhaustion and improves GVL, while blockade of Tim-3, TIGIT or LAG3 is ineffective. Of all interventions, FGK45 administration at the time of transplant is the most effective at improving memory and naïve T cell anti-H60 responses and GVL. Our studies define important causes of GVL failure and suggest strategies to overcome them.


Assuntos
Apresentação do Antígeno/imunologia , Efeito Enxerto vs Leucemia/imunologia , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia/terapia , Linfócitos T/imunologia , Animais , Células Cultivadas , Humanos , Leucemia/imunologia , Leucemia/patologia , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Antígenos de Histocompatibilidade Menor/genética , Antígenos de Histocompatibilidade Menor/imunologia , Antígenos de Histocompatibilidade Menor/metabolismo , Recidiva , Transplante Homólogo
8.
PLoS One ; 15(6): e0234778, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32569289

RESUMO

Acute graft-versus-host-disease (GVHD), limits the use of hematopoietic cell transplant (HCT) to treat a variety of malignancies. Any new therapeutic approach must satisfy three requirements: 1) Prevent GVHD, 2) Maintain anti-pathogen immunity, and 3) Maintain anti-tumor immunity. In prior studies we have shown that the selective photosensitizer 2-Se-Cl eliminates highly alloreactive lymphocytes from the graft prior to HCT preventing GVHD and that antiviral immune responses were preserved following incubation with 2-Se-Cl. In this report, we investigated whether 2-Se-Cl treatment preserves antitumor immunity, and then used high dimensional flow cytometry to identify the determinants of successful immune reconstitution. Donor C57BL/6 splenocytes were cocultured for 4 days with irradiated BALB/c splenocytes and then exposed to 2-Se-Cl. Photodepletion (PD)-treated splenocytes were then infused into lethally irradiated BALB/c mice inoculated with A20 leukemia/lymphoma cells. Recipient mice that received PD-treated splenocytes survived > 100 days without evidence of GVHD or leukemia. In contrast, mice that did not receive PD-treated cells at time of HCT died of leukemia progression. Multiparameter flow cytometry of cytokines and surface markers on peripheral blood samples 15 days after HCT demonstrated unique patterns of immune reconstitution. We found that before clinical disease onset GVHD was marked by functionally exhausted T cells, while tumor clearance and long-term survival were associated with an expansion of polyfunctional T cells, monocytes, and DCs early after transplantation. Taken together these results demonstrate that 2-Se-Cl photodepletion is a new treatment that can facilitate HCT by preventing GVHD while preserving antiviral and anti-tumor immunity.


Assuntos
Doença Enxerto-Hospedeiro/prevenção & controle , Fármacos Fotossensibilizantes/farmacologia , Compostos de Selênio/farmacologia , Animais , Antígeno CTLA-4/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/efeitos da radiação , Feminino , Leucemia/imunologia , Leucemia/terapia , Camundongos , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/efeitos da radiação , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/imunologia
9.
Ann Hematol ; 99(9): 1979-1988, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32594216

RESUMO

The FLAMSA reduced intensity (RIC) concept, also known as "sequential therapy", is a conceptual platform for the treatment of leukemia separated in several parts: induction therapy, a sequence of antileukemic and immunosuppressive conditioning for allogeneic stem cell transplantation, and immune restitution supported by donor lymphocyte transfusions. The antileukemic part consists of fludarabine, cytosine arabinoside, and amsacrine (FLAMSA); non-cross reactive agents like fludarabine and amsacrine have been successfully used in cases of refractoriness and relapse. Immunosuppressive conditioning and transplantation follow after only 3 days of rest. This way, the toxicity of allogeneic transplantation could be reduced and the anti-leukemia effects by using allogeneic immune cells could be optimized. This review summarizes available data on efficacy and toxicity of this approach. Further, possible strategies for improvements are discussed in order to provide better chances for elderly and frail patients and patients with advanced and high-risk disease. Among others, several new agents are available that target molecular changes of leukemia for induction of remission and allow for bridging the time after transplantation until adoptive immunotherapy becomes safe and effective.


Assuntos
Amsacrina/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Citarabina/administração & dosagem , Leucemia/terapia , Condicionamento Pré-Transplante/tendências , Vidarabina/análogos & derivados , Antineoplásicos/administração & dosagem , Previsões , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/tendências , Humanos , Imunossupressores/administração & dosagem , Imunoterapia Adotiva/métodos , Imunoterapia Adotiva/tendências , Leucemia/imunologia , Condicionamento Pré-Transplante/métodos , Transplante Homólogo/métodos , Transplante Homólogo/tendências , Vidarabina/administração & dosagem
10.
Cancer Sci ; 111(7): 2223-2233, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32324315

RESUMO

Invariant natural killer T (iNKT) cells are innate-like CD1d-restricted T cells that express the invariant T cell receptor (TCR) composed of Vα24 and Vß11 in humans. iNKT cells specifically recognize glycolipid antigens such as α-galactosylceramide (αGalCer) presented by CD1d. iNKT cells show direct cytotoxicity toward CD1d-positive tumor cells, especially when CD1d presents glycolipid antigens. However, iNKT cell recognition of CD1d-negative tumor cells is unknown, and direct cytotoxicity of iNKT cells toward CD1d-negative tumor cells remains controversial. Here, we demonstrate that activated iNKT cells recognize leukemia cells in a CD1d-independent manner, however still in a TCR-mediated way. iNKT cells degranulated and released Th1 cytokines toward CD1d-negative leukemia cells (K562, HL-60, REH) as well as αGalCer-loaded CD1d-positive Jurkat cells. The CD1d-independent cytotoxicity was enhanced by natural killer cell-activating receptors such as NKG2D, 2B4, DNAM-1, LFA-1 and CD2, but iNKT cells did not depend on these receptors for the recognition of CD1d-negative leukemia cells. In contrast, TCR was essential for CD1d-independent recognition and cytotoxicity. iNKT cells degranulated toward patient-derived leukemia cells independently of CD1d expression. iNKT cells targeted myeloid malignancies more than acute lymphoblastic leukemia. These findings reveal a novel anti-tumor mechanism of iNKT cells in targeting CD1d-negative tumor cells and indicate the potential of iNKT cells for clinical application to treat leukemia independently of CD1d.


Assuntos
Antígenos CD1d/metabolismo , Leucemia/imunologia , Leucemia/metabolismo , Ativação Linfocitária/imunologia , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/metabolismo , Animais , Antígenos CD1d/genética , Biomarcadores , Degranulação Celular , Linhagem Celular Tumoral , Receptores Coestimuladores e Inibidores de Linfócitos T/metabolismo , Citocinas/metabolismo , Citotoxicidade Imunológica , Modelos Animais de Doenças , Feminino , Edição de Genes , Xenoenxertos , Humanos , Imunofenotipagem , Leucemia/genética , Leucemia/patologia , Ativação Linfocitária/genética , Camundongos , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores Desencadeadores da Citotoxicidade Natural/metabolismo
11.
Adv Exp Med Biol ; 1244: 215-233, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32301017

RESUMO

CAR-T (chimeric antigens receptor-T) cell therapy is a breakthrough therapy of the twenty-first century for the management of different malignancies including lymphomas and leukemias. Numeral trials are underway to understand the optimal CAR-T cell design and dose to maximize efficacy and mitigate toxicity. Currently two CAR-T cell therapy products, axicabtagene ciloleucel and tisagenlecleucel, are approved by the US Food and Drug Administration, which have shown excellent responses in otherwise poor prognostic lymphomas and leukemias. The favorable outcomes achieved of this therapy were noted to be durable during long-term follow-up. Understanding the challenges associated with manufacturing and the reasons for T cell failure including poor T cell expansion, persistence, and tumor resistance are critical for its wide-scale application in order to attain the full potential of this novel therapy. Here we review the salient features of the different CAR-T products and discuss the pivotal trials that led to its approval.


Assuntos
Imunoterapia Adotiva , Neoplasias/imunologia , Neoplasias/terapia , Receptores de Antígenos Quiméricos , Linfócitos T , Humanos , Leucemia/imunologia , Leucemia/terapia , Linfoma/imunologia , Linfoma/terapia
12.
Biol Blood Marrow Transplant ; 26(7): 1312-1317, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32283185

RESUMO

The COVID-19 pandemic has created significant barriers to timely donor evaluation, cell collection, and graft transport for allogeneic hematopoietic stem cell transplantation (allo-HCT). To ensure availability of donor cells on the scheduled date of infusion, many sites now collect cryopreserved grafts before the start of pretransplantation conditioning. Post-transplantation cyclophosphamide (ptCY) is an increasingly used approach for graft-versus-host disease (GVHD) prophylaxis, but the impact of graft cryopreservation on the outcomes of allo-HCT using ptCY is not known. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we compared the outcomes of HCT using cryopreserved versus fresh grafts in patients undergoing HCT for hematologic malignancy with ptCY. We analyzed 274 patients with hematologic malignancy undergoing allo-HCT between 2013 and 2018 with cryopreserved grafts and ptCY. Eighteen patients received bone marrow grafts and 256 received peripheral blood stem cell grafts. These patients were matched for age, graft type, disease risk index (DRI), and propensity score with 1080 patients who underwent allo-HCT with fresh grafts. The propensity score, which is an assessment of the likelihood of receiving a fresh graft versus a cryopreserved graft, was calculated using logistic regression to account for the following: disease histology, Karnofsky Performance Score (KPS), HCT Comorbidity Index, conditioning regimen intensity, donor type, and recipient race. The primary endpoint was overall survival (OS). Secondary endpoints included acute and chronic graft-versus-host disease (GVHD), non-relapse mortality (NRM), relapse/progression and disease-free survival (DFS). Because of multiple comparisons, only P values <.01 were considered statistically significant. The 2 cohorts (cryopreserved and fresh) were similar in terms of patient age, KPS, diagnosis, DRI, HCT-CI, donor/graft source, and conditioning intensity. One-year probabilities of OS were 71.1% (95% confidence interval [CI], 68.3% to 73.8%) with fresh grafts and 70.3% (95% CI, 64.6% to 75.7%) with cryopreserved grafts (P = .81). Corresponding probabilities of OS at 2 years were 60.6% (95% CI, 57.3% to 63.8%) and 58.7% (95% CI, 51.9% to 65.4%) (P = .62). In matched-pair regression analysis, graft cryopreservation was not associated with a significantly higher risk of mortality (hazard ratio [HR] for cryopreserved versus fresh, 1.05; 95% CI, .86 to 1.29; P = .60). Similarly, rates of neutrophil recovery (HR, .91; 95% CI, .80 to 1.02; P = .12), platelet recovery (HR, .88; 95% CI, .78 to 1.00; P = .05), grade III-IV acute GVHD (HR, .78; 95% CI, .50 to 1.22; P = .27), NRM (HR, 1.16; 95% CI, .86 to 1.55; P = .32) and relapse/progression (HR, 1.21; 95% CI, .97 to 1.50; P = .09) were similar with cryopreserved grafts versus fresh grafts. There were somewhat lower rates of chronic GVHD (HR, 78; 95% CI, .61 to .99; P = .04) and DFS (HR for treatment failure, 1.19; 95% CI, 1.01 to 1.29; P = .04) with graft cryopreservation that were of marginal statistical significance after adjusting for multiple comparisons. Overall, our data indicate that graft cryopreservation does not significantly delay hematopoietic recovery, increase the risk of acute GVHD or NRM, or decrease OS after allo-HCT using ptCY.


Assuntos
Transplante de Medula Óssea/métodos , Infecções por Coronavirus/epidemiologia , Criopreservação/métodos , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia/terapia , Linfoma/terapia , Síndromes Mielodisplásicas/terapia , Pneumonia Viral/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Ciclofosfamida/uso terapêutico , Feminino , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/patologia , Teste de Histocompatibilidade , Humanos , Leucemia/imunologia , Leucemia/mortalidade , Leucemia/patologia , Linfoma/imunologia , Linfoma/mortalidade , Linfoma/patologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/imunologia , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/patologia , Pandemias , Irmãos , Análise de Sobrevida , Condicionamento Pré-Transplante/métodos , Transplante Homólogo , Estados Unidos/epidemiologia , Doadores não Relacionados/provisão & distribução
13.
Leukemia ; 34(6): 1626-1636, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31908357

RESUMO

Immunotherapy targeting leukemia-associated antigens has shown promising results. Because of the heterogeneity of leukemia, vaccines with a single peptide have elicited only a limited immune response. Targeting several peptides together elicited peptide-specific cytotoxic T lymphocytes (CTLs) in leukemia patients, and this was associated with clinical responses. Thus, the discovery of novel antigens is essential. In the current study, we investigated cyclin E as a novel target for immunotherapy. Cyclin E1 and cyclin E2 were found to be highly expressed in hematologic malignancies, according to reverse transcription polymerase chain reaction and western blot analysis. We identified two HLA-A*0201 binding nonameric peptides, CCNE1M from cyclin E1 and CCNE2L from cyclin E2, which both elicited the peptide-specific CTLs. The peptide-specific CTLs specifically kill leukemia cells. Furthermore, CCNE1M and CCNE2L CTLs were increased in leukemia patients who underwent allogeneic hematopoietic stem cell transplantation, and this was associated with desired clinical outcomes. Our findings suggest that cyclin E1 and cyclin E2 are potential targets for immunotherapy in leukemia.


Assuntos
Antígenos de Neoplasias/metabolismo , Vacinas Anticâncer/imunologia , Ciclina E/imunologia , Ciclinas/imunologia , Antígeno HLA-A2/imunologia , Leucemia/imunologia , Proteínas Oncogênicas/imunologia , Adulto , Idoso , Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/farmacologia , Epitopos de Linfócito T/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linfócitos T Citotóxicos/imunologia , Adulto Jovem
14.
Leukemia ; 34(7): 1885-1897, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31974433

RESUMO

Acute graft-versus-host disease (aGVHD) and tumor relapse remain major complications after allogeneic hematopoietic stem cell transplantation. Alloreactive T cells and cancer cells share a similar metabolic phenotype to meet the bioenergetic demands necessary for cellular proliferation and effector functions. Nicotinamide adenine dinucleotide (NAD) is an essential co-factor in energy metabolism and is constantly replenished by nicotinamide phosphoribosyl-transferase (Nampt), the rate-limiting enzyme in the NAD salvage pathway. Here we show, that Nampt blockage strongly ameliorates aGVHD and limits leukemic expansion. Nampt was highly elevated in serum of patients with gastrointestinal GVHD and was particularly abundant in human and mouse intestinal T cells. Therapeutic application of the Nampt small-molecule inhibitor, Fk866, strongly attenuated experimental GVHD and caused NAD depletion in T-cell subsets, which displayed differential susceptibility to NAD shortage. Fk866 robustly inhibited expansion of alloreactive but not memory T cells and promoted FoxP3-mediated lineage stability in regulatory T cells. Furthermore, Fk866 strongly reduced the tumor burden in mouse leukemia and graft-versus-leukemia models. Ex vivo studies using lymphocytes from GVHD patients demonstrated potent antiproliferative properties of Fk866, suggesting potential clinical utility. Thus, targeting NAD immunometabolism represents a novel approach to selectively inhibit alloreactive T cells during aGVHD with additional antileukemic efficacy.


Assuntos
Acrilamidas/farmacologia , Antineoplásicos/farmacologia , Citocinas/antagonistas & inibidores , Doença Enxerto-Hospedeiro/prevenção & controle , Memória Imunológica/imunologia , Leucemia/tratamento farmacológico , NAD/metabolismo , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Piperidinas/farmacologia , Linfócitos T Reguladores/imunologia , Animais , Apoptose , Proliferação de Células , Metabolismo Energético , Feminino , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/metabolismo , Doença Enxerto-Hospedeiro/patologia , Humanos , Memória Imunológica/efeitos dos fármacos , Leucemia/imunologia , Leucemia/metabolismo , Leucemia/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Linfócitos T Reguladores/efeitos dos fármacos , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Cancer Res ; 80(3): 471-483, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31767627

RESUMO

Recent studies have shown that stem cell memory T (TSCM) cell-like properties are important for successful adoptive immunotherapy by the chimeric antigen receptor-engineered-T (CAR-T) cells. We previously reported that both human and murine-activated T cells are converted into stem cell memory-like T (iTSCM) cells by coculture with stromal OP9 cells expressing the NOTCH ligand. However, the mechanism of NOTCH-mediated iTSCM reprogramming remains to be elucidated. Here, we report that the NOTCH/OP9 system efficiently converted conventional human CAR-T cells into TSCM-like CAR-T, "CAR-iTSCM" cells, and that mitochondrial metabolic reprogramming played a key role in this conversion. NOTCH signaling promoted mitochondrial biogenesis and fatty acid synthesis during iTSCM formation, which are essential for the properties of iTSCM cells. Forkhead box M1 (FOXM1) was identified as a downstream target of NOTCH, which was responsible for these metabolic changes and the subsequent iTSCM differentiation. Like NOTCH-induced CAR-iTSCM cells, FOXM1-induced CAR-iTSCM cells possessed superior antitumor potential compared with conventional CAR-T cells. We propose that NOTCH- or FOXM1-driven CAR-iTSCM formation is an effective strategy for improving cancer immunotherapy. SIGNIFICANCE: Manipulation of signaling and metabolic pathways important for directing production of stem cell memory-like T cells may enable development of improved CAR-T cells.


Assuntos
Proteína Forkhead Box M1/metabolismo , Memória Imunológica/imunologia , Leucemia/imunologia , Biogênese de Organelas , Receptores de Antígenos Quiméricos/imunologia , Receptores Notch/metabolismo , Linfócitos T/imunologia , Animais , Diferenciação Celular , Técnicas de Cocultura , Humanos , Imunoterapia Adotiva , Leucemia/metabolismo , Leucemia/patologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Transdução de Sinais , Células-Tronco/imunologia , Células Estromais/imunologia , Células Estromais/metabolismo , Células Estromais/patologia
17.
Clin Transl Oncol ; 22(1): 1-10, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31127471

RESUMO

Immunomodulation is a mechanism that stimulates or inhibits immune responses under the influence of secretory mediators. This study will review the role of cytokines and chemotherapy in the modulation of immune responses in leukemia. We searched the PubMed database and Google scholar search engine of English-language papers (1995-2018) using the "Immunomodulation", "Leukemia", "Tregs", "Natural killer cells", "Mesenchymal stem cells", "Macrophages" and "chemotherapy" as keywords. In leukemias, T regulatory cells (Tregs), natural killer cells (NK), macrophages (MQs) and mesenchymal stem cells (MSCs) alter their functional and secretion patterns. Some of the changes in NK cells and classic MQ (M1) potentiate the immune responses against leukemia, but some Tregs changes will compromise the immune system. The effect of a cell on immunomodulation is in contrast to another cell, in which the cells are engaged in a competition so that a cell that having a higher effect on immunomodulation will be the contest winner. The outcome of immunomodulation in response to leukemia is determined by the ratio of stimulatory activity of NK cells and M1 to the inhibitory effect of Tregs, while the dual role of MSCs through immunomodulators and cytokines can be effective in weakening/enhancing the immune response.


Assuntos
Antineoplásicos/uso terapêutico , Citocinas/metabolismo , Imunomodulação/imunologia , Células Matadoras Naturais/imunologia , Leucemia/imunologia , Linfócitos T Reguladores/imunologia , Humanos , Imunomodulação/efeitos dos fármacos , Leucemia/tratamento farmacológico , Leucemia/metabolismo , Leucemia/patologia
18.
Acta Haematol ; 143(2): 112-117, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31288222

RESUMO

In addition to intrinsic factors, leukemia cell growth is influenced by the surrounding nonhematopoietic cells in the leukemic microenvironment, including fibroblasts, mesenchymal stem cells, vascular cells, and various immune cells. Despite the fact that macrophages are an important component of human innate immunity, tumor-associated macrophages (TAMs) have long been considered as an accomplice promoting tumor growth and metastasis. TAMs are activated by an abnormal malignant microenvironment, polarizing into a specific phenotype and participating in tumor progression. TAMs that exist in the microenvironment of different types of leukemia are called leukemia-associated macrophages (LAMs), which are reported to be associated with the progression of leukemia. This review describes the role of LAMs in different leukemia subtypes.


Assuntos
Leucemia/patologia , Macrófagos/metabolismo , Progressão da Doença , Humanos , Imunidade Inata , Leucemia/imunologia , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/patologia , Macrófagos/citologia , Macrófagos/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Microambiente Tumoral
19.
J Exp Med ; 217(2)2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-31873722

RESUMO

Numerous studies support a role of the microenvironment in maintenance of the leukemic clone, as well as in treatment resistance. It is clear that disruption of the normal bone marrow microenvironment is sufficient to promote leukemic transformation and survival in both a cell autonomous and non-cell autonomous manner. In this review, we provide a snapshot of the various cell types shown to contribute to the leukemic microenvironment as well as treatment resistance. Several of these studies suggest that leukemic blasts occupy specific cellular and biochemical "niches." Effective dissection of critical leukemic niche components using single-cell approaches has allowed a more precise and extensive characterization of complexity that underpins both the healthy and malignant bone marrow microenvironment. Knowledge gained from these observations can have an important impact in the development of microenvironment-directed targeted approaches aimed at mitigating disease relapse.


Assuntos
Medula Óssea/patologia , Leucemia/metabolismo , Leucemia/patologia , Microambiente Tumoral , Adipócitos/metabolismo , Animais , Linfócitos B/imunologia , Medula Óssea/metabolismo , Endotélio Vascular/metabolismo , Humanos , Imunoterapia Adotiva , Leucemia/tratamento farmacológico , Leucemia/imunologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Osteoblastos/metabolismo , Receptores de Antígenos Quiméricos , Transdução de Sinais/efeitos dos fármacos , Nicho de Células-Tronco , Linfócitos T/imunologia
20.
Sci Rep ; 9(1): 18729, 2019 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-31822751

RESUMO

Among hematological cancers, Acute Lymphoblastic Leukemia (ALL) and Chronic Lymphocytic Leukemia (CLL) are the most common leukemia in children and elderly people respectively. Some patients do not respond to chemotherapy treatments and it is necessary to complement it with immunotherapy-based treatments such as chimeric antigen receptor (CAR) therapy, which is one of the newest and more effective treatments against these cancers and B-cell lymphoma. Although complete remission results are promising, CAR T cell therapy presents still some risks for the patients, including cytokine release syndrome (CRS) and neurotoxicity. We proposed a different immune cell source for CAR therapy that might prevent these side effects while efficiently targeting malignant cells. NK cells from different sources are a promising vehicle for CAR therapy, as they do not cause graft versus host disease (GvHD) in allogenic therapies and they are prompt to attack cancer cells without prior sensitization. We studied the efficacy of NK cells from adult peripheral blood (AB) and umbilical cord blood (CB) against different target cells in order to determine the best source for CAR therapy. AB CAR-NK cells are slightly better at killing CD19 presenting target cells and CB NK cells are easier to stimulate and they have more stable number from donor to donor. We conclude that CAR-NK cells from both sources have their advantages to be an alternative and safer candidate for CAR therapy.


Assuntos
Imunoterapia Adotiva/métodos , Células Matadoras Naturais/transplante , Leucemia/terapia , Idoso , Idoso de 80 Anos ou mais , Antígenos CD19/imunologia , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Feminino , Sangue Fetal/imunologia , Doença Enxerto-Hospedeiro/etiologia , Humanos , Células Matadoras Naturais/imunologia , Leucemia/imunologia , Leucemia Linfocítica Crônica de Células B/imunologia , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos Quiméricos/imunologia , Indução de Remissão
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