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1.
Mo Med ; 118(1): 68-73, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33551489

RESUMO

Magnesium and vitamin D each have the possibility of affecting the immune system and consequently the cytokine storm and coagulation cascade in COVID-19 infections. Vitamin D is important for reducing the risk of upper respiratory tract infections and plays a role in pulmonary epithelial health. While the importance of vitamin D for a healthy immune system has been known for decades, the benefits of magnesium has only recently been elucidated. Indeed, magnesium is important for activating vitamin D and has a protective role against oxidative stress. Magnesium deficiency increases endothelial cell susceptibility to oxidative stress, promotes endothelial dysfunction, reduces fibrinolysis and increases coagulation. Furthermore, magnesium deficient animals and humans have depressed immune responses, which, when supplemented with magnesium, a partial or near full reversal of the immunodeficiency occurs. Moreover, intracellular free magnesium levels in natural killer cells and CD8 killer T cells regulates their cytotoxicity. Considering that magnesium and vitamin D are important for immune function and cellular resilience, a deficiency in either may contribute to cytokine storm in the novel coronavirus 2019 (COVID-19) infection.


Assuntos
/complicações , Síndrome da Liberação de Citocina/etiologia , Coagulação Intravascular Disseminada/etiologia , Doenças do Sistema Imunitário/etiologia , Deficiência de Magnésio/complicações , Deficiência de Vitamina D/complicações , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , /tratamento farmacológico , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Magnésio/administração & dosagem , Magnésio/farmacologia , Magnésio/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , /genética , Vitamina D/administração & dosagem , Vitamina D/farmacologia , Vitamina D/uso terapêutico , Vitaminas/administração & dosagem , Vitaminas/farmacologia , Vitaminas/uso terapêutico
2.
Urol Clin North Am ; 47(4): 433-442, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33008494

RESUMO

Natural killer (NK) cells are potently cytolytic innate lymphocytes involved in the immune surveillance of tumors and virally infected cells. Although much progress has been made in manipulating the ability of T cells to recognize and eliminate tumors, a comprehensive understanding of NK-cell infiltration into solid tumors, and their amenability to immunomodulation, remains incomplete. This article discusses recent studies showing that urologic tumors are infiltrated by NK cells and that these NK cells are often dysfunctional, but that strategies interfering with inhibitory axes have significant potential to alleviate this dysfunction.


Assuntos
Imunoterapia/métodos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Terapia de Alvo Molecular/métodos , Neoplasias Urogenitais/terapia , Terapia Biológica/métodos , Feminino , Humanos , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/imunologia , Neoplasias Renais/imunologia , Neoplasias Renais/terapia , Masculino , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/terapia , Medição de Risco , Resultado do Tratamento , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/terapia , Neoplasias Urogenitais/imunologia
3.
Anticancer Res ; 40(10): 5355-5359, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988854

RESUMO

BACKGROUND/AIM: Recent studies indicate that chimeric antigen receptor (CAR)-T-cells seem to be superior to CAR modified NK-92 cells. One, at least partial, explanation to this discrepancy has been addressed herein, by having NK-92 cells as target cells in cytotoxicity reactions using peripheral blood mononuclear cells. MATERIALS AND METHODS: A time-resolved fluorometric assay (TDA-labeled NK-92 or K562 as target cells) was used for measuring the cytotoxic activity of blood mononuclear cells (PBMC). RESULTS: The cytotoxic capacity of the NK-92 cells was initially demonstrated by their ability to efficiently kill K562 cells. Interestingly, having PBMC as effector cells rendered the very same NK-92 cells sensitive to NK-cell mediated cytolysis. A 1:100 target:effector ratio gave 34.1% lysis compared to 72.2% lysis for K562 cells. Incubating PBMC for longer times (24 up to 48 h) potentiated their NK-activity against NK-92 cells even more, reaching a level close to that obtained with K562 cells. CONCLUSION: This study pinpoints a severe problem that has to be considered in future immune-based cancer therapies with NK-92 as well as CAR-transduced NK-92 cells.


Assuntos
Imunoterapia Adotiva , Células Matadoras Naturais/efeitos dos fármacos , Leucócitos Mononucleares/efeitos dos fármacos , Neoplasias/terapia , Citotoxicidade Imunológica/efeitos dos fármacos , Humanos , Imunidade Celular/efeitos dos fármacos , Imunidade Celular/imunologia , Interleucina-2/genética , Interleucina-2/imunologia , Células K562 , Neoplasias/imunologia , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia
5.
Transplantation ; 104(8): 1574-1579, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32732834

RESUMO

BACKGROUND: Antibody-dependent cell-mediated cytotoxicity (ADCC) is an important pathway responsible for antibody-mediated rejection (AMR). Imlifidase (IdeS) cleaves human IgG into F(ab')2 and Fc fragments, potentially inhibiting ADCC. Here we examined the effect of IdeS on allo-antibody-mediated NK cell activation (Allo-CFC) and ADCC in vitro. METHODS: For Allo-CFC, normal whole blood was incubated with third-party peripheral blood mononuclear cells (PBMCs) pretreated with anti-HLA antibody positive (HS) or negative (NC) sera to measure IFNγ+ NK cell%. For ADCC, normal PBMCs were incubated with Farage B (FB) cells with HS or NC sera to measure 7-AAD+ lysed FB cell%. To assess the effect of IdeS on these assays, serum-treated PBMCs (Allo-CFC-1) and serum used for PBMC pretreatment (Allo-CFC-2) in Allo-CFC, and serum used for ADCC were preincubated with IdeS. Sera from IdeS-treated patients were also tested for Allo-CFC (Allo-CFC-3). RESULTS: IFNγ+ NK cell% were significantly elevated in HS versus NC sera in Allo-CFC-1 (10 ± 3% versus 2 ± 1%, P = 0.001), Allo-CFC-2 (20 ± 10% versus 4 ± 2%, P = 0.01) and 7AAD+ FB cell% (11 ± 3% versus 4 ± 2%, P = 0.02) in ADCC. These were significantly reduced by IdeS treatment. Patient sera with significantly reduced anti-HLA antibody levels at 1 day postimlifidase lost the capacity to activate NK cells in Allo-CFC-3, but those at 1-3 months postimlifidase regained the capacity. CONCLUSIONS: IdeS inhibited NK cell activation and ADCC in vitro and in treated patients. These results and reported inhibition of complement activating anti-HLA antibodies by IdeS suggest its possible role in treatment of AMR.


Assuntos
Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Proteínas de Bactérias/uso terapêutico , Imunossupressores/farmacologia , Células Matadoras Naturais/efeitos dos fármacos , Transplante de Órgãos/efeitos adversos , Adulto , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Proteínas de Bactérias/farmacologia , Bioensaio , Células Cultivadas , Ativação do Complemento/efeitos dos fármacos , Dessensibilização Imunológica/métodos , Antígenos HLA/imunologia , Humanos , Imunossupressores/uso terapêutico , Interferon gama/imunologia , Interferon gama/metabolismo , Isoanticorpos/imunologia , Isoanticorpos/metabolismo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Leucócitos Mononucleares , Cultura Primária de Células , Receptores de IgG/imunologia , Receptores de IgG/metabolismo , Transplante Homólogo/efeitos adversos
6.
Science ; 369(6506): 993-999, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32820126

RESUMO

Stimulator of interferon genes (STING) links innate immunity to biological processes ranging from antitumor immunity to microbiome homeostasis. Mechanistic understanding of the anticancer potential for STING receptor activation is currently limited by metabolic instability of the natural cyclic dinucleotide (CDN) ligands. From a pathway-targeted cell-based screen, we identified a non-nucleotide, small-molecule STING agonist, termed SR-717, that demonstrates broad interspecies and interallelic specificity. A 1.8-angstrom cocrystal structure revealed that SR-717 functions as a direct cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) mimetic that induces the same "closed" conformation of STING. SR-717 displayed antitumor activity; promoted the activation of CD8+ T, natural killer, and dendritic cells in relevant tissues; and facilitated antigen cross-priming. SR-717 also induced the expression of clinically relevant targets, including programmed cell death 1 ligand 1 (PD-L1), in a STING-dependent manner.


Assuntos
Antineoplásicos/farmacologia , Materiais Biomiméticos/farmacologia , Proteínas de Membrana/metabolismo , Nucleotídeos Cíclicos/farmacologia , Animais , Antígeno B7-H1/metabolismo , Materiais Biomiméticos/química , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Cristalografia por Raios X , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Camundongos , Nucleotídeos Cíclicos/química , Conformação Proteica/efeitos dos fármacos
7.
Front Immunol ; 11: 1512, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32655581

RESUMO

Natural Killer (NK) cells are innate immune responders critical for viral clearance and immunomodulation. Despite their vital role in viral infection, the contribution of NK cells in fighting SARS-CoV-2 has not yet been directly investigated. Insights into pathophysiology and therapeutic opportunities can therefore be inferred from studies assessing NK cell phenotype and function during SARS, MERS, and COVID-19. These studies suggest a reduction in circulating NK cell numbers and/or an exhausted phenotype following infection and hint toward the dampening of NK cell responses by coronaviruses. Reduced circulating NK cell levels and exhaustion may be directly responsible for the progression and severity of COVID-19. Conversely, in light of data linking inflammation with coronavirus disease severity, it is necessary to examine NK cell potential in mediating immunopathology. A common feature of coronavirus infections is that significant morbidity and mortality is associated with lung injury and acute respiratory distress syndrome resulting from an exaggerated immune response, of which NK cells are an important component. In this review, we summarize the current understanding of how NK cells respond in both early and late coronavirus infections, and the implication for ongoing COVID-19 clinical trials. Using this immunological lens, we outline recommendations for therapeutic strategies against COVID-19 in clearing the virus while preventing the harm of immunopathological responses.


Assuntos
Transferência Adotiva/métodos , Betacoronavirus/imunologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Células Matadoras Naturais/imunologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Corticosteroides/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Ácido Ascórbico/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/virologia , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Suscetibilidade a Doenças/imunologia , Humanos , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/imunologia , Memória Imunológica , Interferon Tipo I/metabolismo , Interferon Tipo I/uso terapêutico , Células Matadoras Naturais/efeitos dos fármacos , Camundongos , Pandemias , Pneumonia Viral/mortalidade , Pneumonia Viral/virologia
8.
Nat Commun ; 11(1): 3421, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32647184

RESUMO

The OX40-OX40L pathway provides crucial co-stimulatory signals for CD4 T cell responses, however the precise cellular interactions critical for OX40L provision in vivo and when these occur, remains unclear. Here, we demonstrate that provision of OX40L by dendritic cells (DCs), but not T cells, B cells nor group 3 innate lymphoid cells (ILC3s), is critical specifically for the effector Th1 response to an acute systemic infection with Listeria monocytogenes (Lm). OX40L expression by DCs is regulated by cross-talk with NK cells, with IFNγ signalling to the DC to enhance OX40L in a mechanism conserved in both mouse and human DCs. Strikingly, DC expression of OX40L is redundant in a chronic intestinal Th1 response and expression by ILC3s is necessary. Collectively these data reveal tissue specific compartmentalisation of the cellular provision of OX40L and define a mechanism controlling DC expression of OX40L in vivo.


Assuntos
Microambiente Celular , Ligante OX40/metabolismo , Células Th1/imunologia , Animais , Comunicação Celular , Sinais (Psicologia) , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Humanos , Interferon gama/biossíntese , Interleucina-12/farmacologia , Intestinos/citologia , Antígeno Ki-1/metabolismo , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/metabolismo , Listeria monocytogenes/fisiologia , Camundongos Endogâmicos C57BL , Receptores CXCR5/metabolismo , Receptores OX40/metabolismo , Baço/metabolismo , Regulação para Cima/efeitos dos fármacos
9.
Ecotoxicol Environ Saf ; 203: 111006, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32684520

RESUMO

Nickel (Ni) is a widely distributed metal in the environment and an important pollutant because of its many industrial applications. With increasing incidences of Ni contamination, Ni toxicity has become a global public health concern and recent evidence suggests that Ni adversely affects the immune system. Hence, this paper reviews the literature on immune-related effects of Ni exposure, the immunotoxicological effects of Ni, and the underlying mechanism of Ni immunotoxicity. The main focus was on the effect of Ni on the development of organs of immune system, lymphocyte subpopulations, cytokines, immunoglobulins, natural killer (NK) cells, and macrophages. Moreover, Ni toxicity also induces inflammation and several studies demonstrated that Ni could induce immunotoxicity. Excessive Ni exposure can inhibit the development of immune organs by excessively inducing apoptosis and inhibiting proliferation. Furthermore, Ni can decrease T and B lymphocytes, the specific mechanism of which requires further research. The effects of Ni on immunoglobulin A (IgA), IgG, and IgM remain unknown and while Ni inhibited IgA, IgG, and IgM levels in an animal experiment, the opposite result was found in research on humans. Ni inhibits the production of cytokines in non-inflammatory responses. Cytokine levels increased in Ni-induced inflammation responses, and Ni activates inflammation through toll like (TL)4-mediated nuclear factor-κB (NF-κB) and signal transduction cascades mitogen-activated protein kinase (MAPK) pathways. Ni has been indicated to inactivate NK cells and macrophages both in vitro and in vivo. Identifying the mechanisms underlying the Ni-induced immunotoxicity may help to explain the growing risk of infections and cancers in human populations that have been exposed to Ni for a long time. Such knowledge may also help to prevent and treat Ni-related carcinogenicity and toxicology.


Assuntos
Poluentes Ambientais/toxicidade , Sistema Imunitário/efeitos dos fármacos , Níquel/toxicidade , Animais , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Citocinas/metabolismo , Humanos , Sistema Imunitário/crescimento & desenvolvimento , Sistema Imunitário/patologia , Inflamação/induzido quimicamente , Inflamação/metabolismo , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia
10.
Cell Mol Immunol ; 17(9): 995-997, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32612152

Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/imunologia , Terapia de Alvo Molecular/métodos , Pneumonia Viral/imunologia , Pneumonia/imunologia , Síndrome Respiratória Aguda Grave/imunologia , Antivirais/uso terapêutico , Apirase/antagonistas & inibidores , Apirase/genética , Apirase/imunologia , Linfócitos B/imunologia , Linfócitos B/patologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Betacoronavirus/imunologia , Estudos de Casos e Controles , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/genética , Infecções por Coronavirus/virologia , Expressão Gênica/efeitos dos fármacos , Humanos , Fatores Imunológicos/uso terapêutico , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Subfamília C de Receptores Semelhantes a Lectina de Células NK/antagonistas & inibidores , Subfamília C de Receptores Semelhantes a Lectina de Células NK/genética , Subfamília C de Receptores Semelhantes a Lectina de Células NK/imunologia , Pandemias , Pneumonia/tratamento farmacológico , Pneumonia/genética , Pneumonia/virologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/genética , Pneumonia Viral/virologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Síndrome Respiratória Aguda Grave/genética , Síndrome Respiratória Aguda Grave/virologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/patologia
11.
Nat Genet ; 52(6): 582-593, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32483290

RESUMO

In metastatic cancer, the degree of heterogeneity of the tumor microenvironment (TME) and its molecular underpinnings remain largely unstudied. To characterize the tumor-immune interface at baseline and during neoadjuvant chemotherapy (NACT) in high-grade serous ovarian cancer (HGSOC), we performed immunogenomic analysis of treatment-naive and paired samples from before and after treatment with chemotherapy. In treatment-naive HGSOC, we found that immune-cell-excluded and inflammatory microenvironments coexist within the same individuals and within the same tumor sites, indicating ubiquitous variability in immune cell infiltration. Analysis of TME cell composition, DNA copy number, mutations and gene expression showed that immune cell exclusion was associated with amplification of Myc target genes and increased expression of canonical Wnt signaling in treatment-naive HGSOC. Following NACT, increased natural killer (NK) cell infiltration and oligoclonal expansion of T cells were detected. We demonstrate that the tumor-immune microenvironment of advanced HGSOC is intrinsically heterogeneous and that chemotherapy induces local immune activation, suggesting that chemotherapy can potentiate the immunogenicity of immune-excluded HGSOC tumors.


Assuntos
Cistadenocarcinoma Seroso/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica , Neoplasias Ovarianas/tratamento farmacológico , Microambiente Tumoral/imunologia , Animais , Cisplatino/imunologia , Cisplatino/farmacologia , Estudos de Coortes , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/imunologia , Variações do Número de Cópias de DNA , Feminino , Perfilação da Expressão Gênica/estatística & dados numéricos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genes myc , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Camundongos , Mutação , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/imunologia , Análise de Componente Principal , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Via de Sinalização Wnt
12.
Nat Rev Cancer ; 20(8): 437-454, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32581320

RESUMO

Immunotherapy with checkpoint blockade induces rapid and durable immune control of cancer in some patients and has driven a monumental shift in cancer treatment. Neoantigen-specific CD8+ T cells are at the forefront of current immunotherapy strategies, and the majority of drug discovery and clinical trials revolve around further harnessing these immune effectors. Yet the immune system contains a diverse range of antitumour effector cells, and these must function in a coordinated and synergistic manner to overcome the immune-evasion mechanisms used by tumours and achieve complete control with tumour eradication. A key antitumour effector is the natural killer (NK) cells, cytotoxic innate lymphocytes present at high frequency in the circulatory system and identified by their exquisite ability to spontaneously detect and lyse transformed or stressed cells. Emerging data show a role for intratumoural NK cells in driving immunotherapy response and, accordingly, there have been renewed efforts to further elucidate and target the pathways controlling NK cell antitumour function. In this Review, we discuss recent clinical evidence that NK cells are a key immune constituent in the protective antitumour immune response and highlight the major stages of the cancer-NK cell immunity cycle. We also perform a new analysis of publicly available transcriptomic data to provide an overview of the prognostic value of NK cell gene expression in 25 tumour types. Furthermore, we discuss how the role of NK cells evolves with tumour progression, presenting new opportunities to target NK cell function to enhance cancer immunotherapy response rates across a more diverse range of cancers.


Assuntos
Antineoplásicos/imunologia , Antineoplásicos/uso terapêutico , Células Matadoras Naturais/imunologia , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Comunicação Celular/genética , Comunicação Celular/imunologia , Comunicação Celular/fisiologia , Ciclo Celular/imunologia , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Genes cdc/efeitos dos fármacos , Genes cdc/genética , Genes cdc/imunologia , Genes cdc/fisiologia , Humanos , Vigilância Imunológica/imunologia , Imunoterapia/métodos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/fisiologia , Processos Neoplásicos , Prognóstico
13.
Nature ; 583(7817): 609-614, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32581358

RESUMO

Cytokines were the first modern immunotherapies to produce durable responses in patients with advanced cancer, but they have only modest efficacy and limited tolerability1,2. In an effort to identify alternative cytokine pathways for immunotherapy, we found that components of the interleukin-18 (IL-18) pathway are upregulated on tumour-infiltrating lymphocytes, suggesting that IL-18 therapy could enhance anti-tumour immunity. However, recombinant IL-18 previously did not demonstrate efficacy in clinical trials3. Here we show that IL-18BP, a high-affinity IL-18 decoy receptor, is frequently upregulated in diverse human and mouse tumours and limits the anti-tumour activity of IL-18 in mice. Using directed evolution, we engineered a 'decoy-resistant' IL-18 (DR-18) that maintains signalling potential but is impervious to inhibition by IL-18BP. Unlike wild-type IL-18, DR-18 exerted potent anti-tumour effects in mouse tumour models by promoting the development of poly-functional effector CD8+ T cells, decreasing the prevalence of exhausted CD8+ T cells that express the transcriptional regulator of exhaustion TOX, and expanding the pool of stem-like TCF1+ precursor CD8+ T cells. DR-18 also enhanced the activity and maturation of natural killer cells to effectively treat anti-PD-1 resistant tumours that have lost surface expression of major histocompatibility complex class I molecules. These results highlight the potential of the IL-18 pathway for immunotherapeutic intervention and implicate IL-18BP as a major therapeutic barrier.


Assuntos
Imunoterapia , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Interleucina-18/imunologia , Neoplasias/imunologia , Neoplasias/terapia , Animais , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Modelos Animais de Doenças , Feminino , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Estimativa de Kaplan-Meier , Células Matadoras Naturais/citologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Linfócitos do Interstício Tumoral/citologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Masculino , Camundongos , Receptores de Interleucina-18/metabolismo , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos , Células-Tronco/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
14.
Nat Commun ; 11(1): 2860, 2020 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-32503978

RESUMO

The MYC oncogene drives T- and B- lymphoid malignancies, including Burkitt's lymphoma (BL) and Acute Lymphoblastic Leukemia (ALL). Here, we demonstrate a systemic reduction in natural killer (NK) cell numbers in SRα-tTA/Tet-O-MYCON mice bearing MYC-driven T-lymphomas. Residual mNK cells in spleens of MYCON T-lymphoma-bearing mice exhibit perturbations in the terminal NK effector differentiation pathway. Lymphoma-intrinsic MYC arrests NK maturation by transcriptionally repressing STAT1/2 and secretion of Type I Interferons (IFNs). Treating T-lymphoma-bearing mice with Type I IFN improves survival by rescuing NK cell maturation. Adoptive transfer of mature NK cells is sufficient to delay both T-lymphoma growth and recurrence post MYC inactivation. In MYC-driven BL patients, low expression of both STAT1 and STAT2 correlates significantly with the absence of activated NK cells and predicts unfavorable clinical outcomes. Our studies thus provide a rationale for developing NK cell-based therapies to effectively treat MYC-driven lymphomas in the future.


Assuntos
Linfoma de Burkitt/imunologia , Células Matadoras Naturais/imunologia , Linfoma de Células T/imunologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , Transferência Adotiva , Animais , Linfoma de Burkitt/mortalidade , Linhagem Celular Tumoral/transplante , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Vigilância Imunológica/genética , Interferon Tipo I/farmacologia , Interferon Tipo I/uso terapêutico , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/transplante , Linfoma de Células T/tratamento farmacológico , Linfoma de Células T/genética , Linfoma de Células T/patologia , Masculino , Camundongos , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-myc/genética , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/imunologia
15.
Cancer Immunol Immunother ; 69(10): 2021-2031, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32405793

RESUMO

Following excision of colorectal tumors, metastatic disease is prevalent, primarily occurs in the liver, and is highly predictive of poor prognosis. The perioperative period is now recognized as critical in determining the incidence of postoperative metastases and long-term cancer outcomes. Thus, various perioperative prophylactic interventions are currently studied during this time frame. However, immune stimulation during the perioperative period has rarely been attempted due to specific contraindications to surgery and various adverse effects. Here, to prevent liver metastases, we perioperatively employed a TLR-9 agonist, CpG-C, which exhibits minimal pyrogenic and other adverse effects in patients. We found that marginating-hepatic (MH) cells in BALB/c mice contained high percentage of NK cells, but exhibited negligible NK cytotoxicity, as previously reported in humans. However, a single CpG-C administration (25-100 µg/mouse) doubled MH-NK cell numbers, increased NK cell activation and maturation markers (NKp46, CD11b), decreased the inhibitory NKG2A ligand, and dramatically increased MH-NK-cell cytotoxicity against the syngeneic CT26 colon cancer line. Moreover, in operated mice, this innocuous intervention also markedly improved resistance to CT26 and MC38 hepatic metastases in BALB/c and C57BL/6 mice, respectively. Beneficial effects of CpG-C were mediated through activation of MH-NK cells, as indicated by an in vivo NK depletion study. Last, CpG-C protected against surgery-induced suppression of MH-NK cytotoxicity and improved their activation indices. Thus, we suggest that systemic perioperative CpG-C treatment should be considered and studied as a novel therapeutic approach to improve long-term cancer outcomes in colorectal cancer patients.


Assuntos
Neoplasias do Colo/prevenção & controle , Células Matadoras Naturais/efeitos dos fármacos , Neoplasias Hepáticas/prevenção & controle , Oligodesoxirribonucleotídeos/administração & dosagem , Animais , Apoptose , Proliferação de Células , Neoplasias do Colo/imunologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Feminino , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Período Perioperatório , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Curr Pharm Biotechnol ; 21(12): 1176-1185, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32351178

RESUMO

BACKGROUND: In the last decade, there have been accumulating data that the use of medicinal plants could bring additional benefits to the supportive treatment of various diseases. Nigella sativa (N. sativa, family Ranunculaceae) is one of these plants that has attracted considerable interest. The extracts and seeds of N. sativa and its active component thymoquinone have been studied extensively and the results suggest that N. sativa might carry some therapeutic potential for many diseases, including cancer. METHODS: The selection criteria for references were applied through Pubmed with "N. sativa and cancer", "N. sativa and breast cancer", "N. sativa and metastasis", "N. sativa and cytotoxicity of natural killer cells". The pathway analysis was performed using the PANTHER tool by using five randomly selected N. sativa affected genes (Cyclin D1, P53, p21 protein (Cdc42/Rac) activated kinase 1 (PAK1), B-cell lymphoma 2 (Bcl-2) and vascular endothelial growth factor (VEGF)) in order to elucidate further potentially affected signaling pathways. RESULTS: The aim of this review was to summarize studies regarding the effects of N. sativa in cancer generally, with a focus on breast cancer, its anti-metastatic effects, and how N. sativa modulates the cytotoxicity of Natural Killer cells that play a crucial role in tumor surveillance. CONCLUSION: In summary, the data suggest that N. sativa might be used for its anti-cancer and antimetastatic properties and as an immune system activator against cancer.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Benzoquinonas/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Células Matadoras Naturais/efeitos dos fármacos , Nigella sativa/química , Extratos Vegetais/uso terapêutico , Antineoplásicos Fitogênicos/isolamento & purificação , Benzoquinonas/isolamento & purificação , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/imunologia , Feminino , Humanos , Células Matadoras Naturais/imunologia , Metástase Neoplásica , Extratos Vegetais/isolamento & purificação , Plantas Medicinais , Sementes/química , Transdução de Sinais
17.
Prostate ; 80(10): 742-752, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32449811

RESUMO

BACKGROUND: Docetaxel is an effective first-line chemotherapy agent used in the treatment of castration-resistant prostate cancer (CRPC) patients. However, most times chemotherapy with docetaxel eventually fails due to the development of docetaxel resistance. Natural killer (NK) cells are the first line of defense against cancer and infections. NK cell function is determined by a delicate balance between signals received via activating and inhibitory receptors. The aim of this study is to explore whether the potential docetaxel-resistant mechanism is associated with impaired NK cell cytotoxicity toward CRPC cells. METHODS: By performing MTT assay, we explored the role of docetaxel in regulating NK cells' cytotoxicity. Western blot and quantitative real-time polymerase chain reaction analysis were used to measure messenger RNA and protein levels separately. Luciferase reporter assay and chromatin immunoprecipitation assay were performed to analyze the mechanism. RESULTS: We found that docetaxel could suppress the immunotherapy efficacy of NK cells toward CRPC cells via the androgen receptor (AR)-lectin-like transcript 1 (LLT1) signals in vitro. Analysis of the mechanism revealed that docetaxel functioned through increasing AR to upregulate LLT1 expression in CRPC cells. AR transcriptionally activated LLT1 expression by binding to its promoter region. Furthermore, targeting AR with ASC-J9 or blocking LL1 by anti-human LLT1 monoclonal antibody could reverse the suppressive effect of docetaxel on the immunotherapy efficacy of NK cells toward CRPC cells. CONCLUSIONS: We concluded that chemotherapy agent docetaxel could increase AR that transcriptionally regulated the expression of NK inhibitory ligand LLT1 on CRPC cells. An increase of LL1 may further suppress the immunological efficacy of NK cells to kill CRPC cells. Additionally, targeting AR or blocking LL1 could enhance the immunotherapy efficacy of NK cells toward CRPC cells which might be considered as a new therapeutic option for the prevention or treatment of docetaxel resistance.


Assuntos
Docetaxel/efeitos adversos , Células Matadoras Naturais/efeitos dos fármacos , Lectinas Tipo C/imunologia , Neoplasias de Próstata Resistentes à Castração/imunologia , Neoplasias de Próstata Resistentes à Castração/terapia , Receptores Androgênicos/imunologia , Receptores de Superfície Celular/imunologia , Antagonistas de Receptores de Andrógenos/farmacologia , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Técnicas de Cocultura , Terapia Combinada , Curcumina/análogos & derivados , Curcumina/farmacologia , Docetaxel/uso terapêutico , Células HEK293 , Humanos , Imunoterapia Adotiva/métodos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/transplante , Lectinas Tipo C/antagonistas & inibidores , Lectinas Tipo C/biossíntese , Masculino , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Receptores Androgênicos/biossíntese , Receptores Androgênicos/genética , Receptores de Superfície Celular/antagonistas & inibidores , Receptores de Superfície Celular/biossíntese , Regulação para Cima/efeitos dos fármacos
18.
Cell Biol Int ; 44(9): 1792-1797, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32458561

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is uncontrollably spread all over the world. The host immune responses strongly try to confront it with all the potential cells and cytokines. With chronically condition of SARS-CoV-2, natural killer cells and T cells become exhausted and decreasing their count leads to lymphopenia. Inability to eradicate the infected organ makes hyperinitiation of the immune system, which releases the excessive inflammatory cytokines to compensate the exhausted one as well as the low lymphocytes counts; it consequently leads to the cytokine storm syndrome. These mechanisms and the potential therapeutic targeting are discussed in this paper.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/terapia , Linfopenia/imunologia , Linfopenia/terapia , Pneumonia Viral/imunologia , Pneumonia Viral/terapia , Infecções por Coronavirus/epidemiologia , Citocinas/antagonistas & inibidores , Citocinas/imunologia , Humanos , Imunossupressores/administração & dosagem , Imunoterapia/métodos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Linfopenia/epidemiologia , Pandemias , Pneumonia Viral/epidemiologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
19.
Cancer Immunol Immunother ; 69(10): 2009-2020, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32399587

RESUMO

OBJECTIVE: The subset distribution and immunophenotype of circulating immune cells ("peripheral blood immune cell profile") may reflect tumor development and response to cancer treatment. In order to use the peripheral blood immune cell profile as biomarker to monitor patients over time, it is crucial to know how immune cell subsets respond to therapeutic interventions. In this study, we investigated the effects of tumor resection and adjuvant therapy on the peripheral blood immune cell profile in patients with colon carcinoma (CC). METHODS: The subset distribution and immunophenotype of T cells (CD3+CD56-), CD56dim NK cells (CD3-CD56dim), CD56bright NK cells (CD3-CD56bright) and NKT-like cells (CD3+CD56+) were studied in preoperative and postoperative peripheral blood mononuclear cell (PBMC) samples of 24 patients with CC by multiparameter flow cytometry. Changes in immunophenotype of circulating immune cells after tumor resection were studied in patients treated with and without (capecitabine-based) adjuvant therapy. RESULTS: The NKT-like cell (% of total PBMCs) and CD8+ T cell (% of total T cells) populations expanded in the peripheral blood of non-adjuvant-treated CC patients after surgery. NK- and NKT-like cells showed upregulation of activating receptors and downregulation of inhibitory receptors in non-adjuvant-treated CC patients after surgery. These changes were not observed in the peripheral blood of adjuvant-treated CC patients. CONCLUSIONS: Our results suggest tumor-induced suppression of NK- and NKT-like cells in CC patients, an effect that could not be detected after tumor resection. In contrast, adjuvant therapy maintained tumor-induced immunosuppression of NK- and NKT-like cells in CC patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores/sangue , Neoplasias do Colo/imunologia , Células Matadoras Naturais/imunologia , Leucócitos Mononucleares/imunologia , Linfócitos T/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Complexo CD3 , Estudos de Casos e Controles , Quimioterapia Adjuvante , Neoplasias do Colo/sangue , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Feminino , Seguimentos , Humanos , Imunofenotipagem , Células Matadoras Naturais/efeitos dos fármacos , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Prognóstico , Linfócitos T/efeitos dos fármacos
20.
Nature ; 583(7815): 290-295, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32422645

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly emerged coronavirus that is responsible for the current pandemic of coronavirus disease 2019 (COVID-19), which has resulted in more than 3.7 million infections and 260,000 deaths as of 6 May 20201,2. Vaccine and therapeutic discovery efforts are paramount to curb the pandemic spread of this zoonotic virus. The SARS-CoV-2 spike (S) glycoprotein promotes entry into host cells and is the main target of neutralizing antibodies. Here we describe several monoclonal antibodies that target the S glycoprotein of SARS-CoV-2, which we identified from memory B cells of an individual who was infected with severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003. One antibody (named S309) potently neutralizes SARS-CoV-2 and SARS-CoV pseudoviruses as well as authentic SARS-CoV-2, by engaging the receptor-binding domain of the S glycoprotein. Using cryo-electron microscopy and binding assays, we show that S309 recognizes an epitope containing a glycan that is conserved within the Sarbecovirus subgenus, without competing with receptor attachment. Antibody cocktails that include S309 in combination with other antibodies that we identified further enhanced SARS-CoV-2 neutralization, and may limit the emergence of neutralization-escape mutants. These results pave the way for using S309 and antibody cocktails containing S309 for prophylaxis in individuals at a high risk of exposure or as a post-exposure therapy to limit or treat severe disease.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Betacoronavirus/imunologia , Reações Cruzadas/imunologia , Vírus da SARS/imunologia , Síndrome Respiratória Aguda Grave/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/farmacologia , Anticorpos Neutralizantes/química , Anticorpos Neutralizantes/farmacologia , Anticorpos Antivirais/química , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/farmacologia , Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Linfócitos B/imunologia , Betacoronavirus/química , Betacoronavirus/efeitos dos fármacos , Chlorocebus aethiops , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/terapia , Infecções por Coronavirus/virologia , Reações Cruzadas/efeitos dos fármacos , Microscopia Crioeletrônica , Epitopos de Linfócito B/química , Epitopos de Linfócito B/imunologia , Células HEK293 , Humanos , Evasão da Resposta Imune/imunologia , Fragmentos Fab das Imunoglobulinas/química , Fragmentos Fab das Imunoglobulinas/imunologia , Fragmentos Fab das Imunoglobulinas/farmacologia , Memória Imunológica/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Modelos Moleculares , Testes de Neutralização , Pandemias/prevenção & controle , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/imunologia , Pneumonia Viral/prevenção & controle , Pneumonia Viral/terapia , Pneumonia Viral/virologia , Vírus da SARS/química , Vírus da SARS/efeitos dos fármacos , Síndrome Respiratória Aguda Grave/virologia , Glicoproteína da Espícula de Coronavírus/química , Células Vero
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