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1.
Adv Exp Med Biol ; 1244: 1-36, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32301008

RESUMO

Tumor exists as a complex network of structures with an ability to evolve and evade the host immune surveillance mechanism. The immune milieu which includes macrophages, dendritic cells, natural killer cells, neutrophils, mast cells, B cells, and T cells are found in the core, the invasive margin, or the adjacent stromal or lymphoid component of the tumor. The immune infiltrate is heterogeneous and varies within a patient and between patients of the same tumor histology. The location, density, functionality, and cross-talk between the immune cells in the tumor microenvironment influence the nature of immune response, prognosis, and treatment outcomes in cancer patients. Therefore, an understanding of the characteristics of the immune cells and their role in tumor immune surveillance is of paramount importance to identify immune targets and to develop novel immune therapeutics in the war against cancer. In this chapter, we provide an overview of the individual components of the human immune system and the translational relevance of predictive biomarkers.


Assuntos
Imunoterapia , Neoplasias/imunologia , Neoplasias/terapia , Humanos , Vigilância Imunológica , Microambiente Tumoral/imunologia
2.
Am J Trop Med Hyg ; 102(6): 1189-1190, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32329432

RESUMO

Public health measures are needed to resolve the novel coronavirus disease (COVID-19) pandemic, although a looming economic fallout merits close attention. Early safe reintroduction of immune individuals into the workforce may be essential to protecting the economic welfare of communities. Reverse transcriptase-polymerase chain reaction testing, our primary diagnostic tool to date, has sensitivity and timing concerns, owing to sampling/handling errors, as well as a complex virus-host interaction. Reverse transcriptase-polymerase chain reaction assays do not establish immune status once the virus has been cleared. Targeted serosurveillance for the determination of individuals' potential for transmissibility, particularly if paired with direct pathogen testing, may aid in "cleared for business" decision-making.


Assuntos
Anticorpos Antivirais/sangue , Betacoronavirus/patogenicidade , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/epidemiologia , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/epidemiologia , RNA Viral/genética , Betacoronavirus/genética , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Humoral , Imunoensaio/normas , Vigilância Imunológica , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Quarentena/métodos , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Reação em Cadeia da Polimerase Via Transcriptase Reversa/normas , Estados Unidos/epidemiologia
3.
Mol Immunol ; 120: 101-112, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32113130

RESUMO

Histocompatibility Leukocyte Antigens, or HLAs, are one of the most polymorphic molecules in humans. This high degree of polymorphism endows HLA molecules with the ability to present a vast array of peptides, an essential trait for responding to ever-evolving pathogens. Unlike classical HLA molecules (HLA-Ia), some non-classical HLA-Ib molecules, including HLA-E, are almost monomorphic. Several studies show HLA-E can present self-peptides originating from the leader sequence of other HLA molecules, which signals to our immune system that the cell is healthy. Therefore, it was traditionally thought that the chief role of HLA-E in the body was in immune surveillance. However, there is emerging evidence that HLA-E is also able to present pathogen-derived peptides to the adaptive immune system, namely T cells, in a manner that is similar to classical HLA-Ia molecules. Here we describe the early findings of this less conventional role of HLA-E in the adaptive immune system and its importance for immunity.


Assuntos
Antígenos de Histocompatibilidade Classe I/imunologia , Imunidade Adaptativa , Sequência de Aminoácidos , Apresentação do Antígeno/imunologia , Sítios de Ligação , Infecções por Citomegalovirus/imunologia , Infecções por Vírus Epstein-Barr/imunologia , Infecções por HIV/imunologia , Antígeno HLA-A2/química , Antígeno HLA-A2/genética , Antígeno HLA-A2/imunologia , Antígenos de Histocompatibilidade Classe I/química , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Vigilância Imunológica , Células Matadoras Naturais/imunologia , Modelos Moleculares , Polimorfismo Genético , Conformação Proteica , Infecções por Salmonella/imunologia , Homologia de Sequência de Aminoácidos , Linfócitos T/imunologia , Tuberculose/imunologia
4.
Washington, D.C.; OPS; 2020-02-26.
em Espanhol | PAHO-IRIS | ID: phr-51883

RESUMO

El manual de Vigilancia de las neumonías y meningitis bacterianas en menores de 5 años: guía práctica se ha convertido en una referencia destacada para los profesionales de salud de la Región de las Américas que se ocupan de las actividades de vigilancia epidemiológica. En él se tratan las enfermedades, los principales agentes etiológicos, las vacunas disponibles, los procedimientos de laboratorio y de vigilancia para la captación y el seguimiento de los casos, así como el análisis de los datos para la producción de información pertinente. En esta segunda edición se presentan nuevos conceptos y se actualizan los procedimientos con el propósito de reflejar la introducción de pruebas de biología molecular en el diagnóstico por laboratorio y la disponibilidad de nuevas vacunas.


Assuntos
Meningites Bacterianas , Pneumonia Bacteriana , Imunização , Vacinação , Líquido Cefalorraquidiano , Vigilância Imunológica , Vigilância em Saúde Pública , Saúde da Criança
5.
Nature ; 577(7792): 689-694, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31942068

RESUMO

Immune surveillance against pathogens and tumours in the central nervous system is thought to be limited owing to the lack of lymphatic drainage. However, the characterization of the meningeal lymphatic network has shed light on previously unappreciated ways that an immune response can be elicited to antigens that are expressed in the brain1-3. Despite progress in our understanding of the development and structure of the meningeal lymphatic system, the contribution of this network in evoking a protective antigen-specific immune response in the brain remains unclear. Here, using a mouse model of glioblastoma, we show that the meningeal lymphatic vasculature can be manipulated to mount better immune responses against brain tumours. The immunity that is mediated by CD8 T cells to the glioblastoma antigen is very limited when the tumour is confined to the central nervous system, resulting in uncontrolled tumour growth. However, ectopic expression of vascular endothelial growth factor C (VEGF-C) promotes enhanced priming of CD8 T cells in the draining deep cervical lymph nodes, migration of CD8 T cells into the tumour, rapid clearance of the glioblastoma and a long-lasting antitumour memory response. Furthermore, transfection of an mRNA construct that expresses VEGF-C works synergistically with checkpoint blockade therapy to eradicate existing glioblastoma. These results reveal the capacity of VEGF-C to promote immune surveillance of tumours, and suggest a new therapeutic approach to treat brain tumours.


Assuntos
Neoplasias Encefálicas/imunologia , Glioblastoma/imunologia , Vigilância Imunológica/imunologia , Linfonodos/imunologia , Vasos Linfáticos/imunologia , Fator C de Crescimento do Endotélio Vascular/metabolismo , Animais , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/imunologia , Linhagem Celular Tumoral , Movimento Celular , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/patologia , Apresentação Cruzada , Feminino , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Células HEK293 , Humanos , Memória Imunológica/imunologia , Linfangiogênese , Masculino , Melanoma/tratamento farmacológico , Melanoma/imunologia , Meninges/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Fator C de Crescimento do Endotélio Vascular/administração & dosagem , Fator C de Crescimento do Endotélio Vascular/genética , Fator C de Crescimento do Endotélio Vascular/uso terapêutico
6.
PLoS One ; 15(1): e0220484, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31990938

RESUMO

The growing occurrence of multidrug-resistant (MDR) Salmonella enterica in poultry has been reported with public health concern worldwide. We reported, recently, the occurrence of Escherichia coli and Salmonella enterica serovars carrying clinically relevant resistance genes in dairy cattle farms in the Wakiso District, Uganda, highlighting an urgent need to monitor food-producing animal environments. Here, we present the prevalence, antimicrobial resistance, and sequence type of 51 Salmonella isolates recovered from 379 environmental samples from chicken farms in Uganda. Among the Salmonella isolates, 32/51 (62.7%) were resistant to at least one antimicrobial, and 10/51 (19.6%) displayed multiple drug resistance. Through PCR, five replicon plasmids were identified among chicken Salmonella isolates including IncFIIS 17/51 (33.3%), IncI1α 12/51 (23.5%), IncP 8/51 (15.7%), IncX1 8/51 (15.7%), and IncX2 1/51 (2.0%). In addition, we identified two additional replicons through WGS (Whole Genome Sequencing; ColpVC and IncFIB). A significant seasonal difference between chicken sampling periods was observed (p = 0.0017). We conclude that MDR Salmonella highlights the risks posed to animals and humans. Implementing a robust, integrated surveillance system will aid in monitoring MDR zoonotic threats.


Assuntos
Farmacorresistência Bacteriana Múltipla/genética , Genes Bacterianos , Plasmídeos/metabolismo , Doenças das Aves Domésticas/epidemiologia , Infecções por Salmonella/epidemiologia , Salmonella enterica/genética , Animais , Antibacterianos/classificação , Antibacterianos/farmacologia , Galinhas/microbiologia , Fazendas , Humanos , Vigilância Imunológica , Plasmídeos/química , Doenças das Aves Domésticas/microbiologia , Doenças das Aves Domésticas/transmissão , Prevalência , Replicon , Infecções por Salmonella/microbiologia , Infecções por Salmonella/transmissão , Salmonella enterica/efeitos dos fármacos , Salmonella enterica/isolamento & purificação , Estações do Ano , Uganda/epidemiologia , Sequenciamento Completo do Genoma
7.
Scand J Immunol ; 91(3): e12850, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31733115

RESUMO

Cervical cancer incidence worldwide exceeds half a million new cases per year. The human papillomavirus (HPV) being the major causative agent of CC uses a variety of strategies to evade immune surveillance, where the immune status varies amongst individuals. This immune evasion altered by HPV is reflected in persistent infections, causing the evolution of cervical neoplasia. The role of the immune system in viral recognition and elimination is of extreme relevance in the development of CC. The interactions of the HLA-E ligand in the target cell along with CD94/NKG2 receptors, which are expressed predominantly, but not exclusively, on NK cells' surface, are responsible for activating or inhibiting cytotoxic activity according to their function. The engagement between HLA-E and CD94/NKG2 molecules is one of the fundamental surveillance mechanisms in patients with CIN I, II and III, where HLA-E expression increases significantly, especially in HPV 16 and 18 infections. Higher HLA-E expression was observed in most histopathological types of CC, and at the same time was correlated to best survival of the patient. This review aims to summarize and discuss the immunological role of HLA-E in the context of HPV infection and immune system evasion, and the oncogenic process of cervical cancer.


Assuntos
Antígenos de Histocompatibilidade Classe I/imunologia , Evasão da Resposta Imune , Papillomaviridae/imunologia , Infecções por Papillomavirus/imunologia , Suscetibilidade a Doenças , Feminino , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Vigilância Imunológica , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/virologia , Neoplasias do Colo do Útero/etiologia , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia
9.
Cancer Immunol Immunother ; 68(12): 2015-2027, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31705171

RESUMO

The transformation and progression of myelodysplastic syndromes (MDS) to secondary acute myeloid leukemia (sAML) involve genetic, epigenetic, and microenvironmental factors. Driver mutations have emerged as valuable markers for defining risk groups and as candidates for targeted treatment approaches in MDS. It is also evident that the risk of transformation to sAML is increased by evasion of adaptive immune surveillance. This study was designed to explore the immune microenvironment, immunogenic tumor-intrinsic mechanisms (HLA and PD-L1 expression), and tumor genetic features (somatic mutations and altered karyotypes) in MDS patients and to determine their influence on the progression of the disease. We detected major alterations of the immune microenvironment in MDS patients, with a reduced count of CD4+ T cells, a more frequent presence of markers related to T cell exhaustion, a more frequent presence of myeloid-derived suppressor cells (MDSCs), and changes in the functional phenotype of NK cells. HLA Class I (HLA-I) expression was normally expressed in CD34+ blasts and during myeloid differentiation. Only two out of thirty-six patients with homozygosity for HLA-C groups acquired complete copy-neutral loss of heterozygosity in the HLA region. PD-L1 expression on the leukemic clone was also increased in MDS patients. Finally, no interplay was observed between the anti-tumor immune microenvironment and mutational genomic features. In summary, extrinsic and intrinsic immunological factors might severely impair immune surveillance and contribute to clonal immune escape. Genomic alterations appear to make an independent contribution to the clonal evolution and progression of MDS.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Células Matadoras Naturais/imunologia , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicas/genética , Células Supressoras Mieloides/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/metabolismo , Carcinogênese , Senescência Celular , Progressão da Doença , Feminino , Antígenos HLA-C/genética , Humanos , Vigilância Imunológica , Masculino , Pessoa de Meia-Idade , Mutação/genética , Evasão Tumoral , Microambiente Tumoral/imunologia , Adulto Jovem
10.
Semin Immunol ; 43: 101299, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31771762

RESUMO

The interferons (IFNs) are cytokines with important antineoplastic and immune modulatory effects. These cytokines have been conserved through evolution as important elements of the immune surveillance against cancer. Despite this, defining their precise and specific roles in the generation of antitumor responses remains challenging. Emerging evidence suggests the existence of previously unknown roles for IFNs in the control of the immune response against cancer that may redefine our understanding on how these cytokines function. Beyond the engagement of classical JAK-STAT signaling pathways that promote transcription and expression of gene products, the IFNs engage multiple other signaling cascades to generate products that mediate biological responses and outcomes. There is recent emerging evidence indicating that IFNs control the expression of both traditional immune checkpoints like the PD-L1/PD1 axis, but also less well understood "intracellular" immune checkpoints whose targeting may define new approaches for the treatment of malignancies.


Assuntos
Imunoterapia/tendências , Interferons/metabolismo , Neoplasias/imunologia , Animais , Antígeno B7-H1/metabolismo , Humanos , Imunidade , Vigilância Imunológica , Receptor de Morte Celular Programada 1/metabolismo , Transdução de Sinais
11.
Cancer Immunol Immunother ; 68(12): 1935-1947, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31641795

RESUMO

BACKGROUND: Due to the strong tumoricidal activities of activated natural killer T (NKT) cells, invariant NKT cell-based immunotherapy has shown promising clinical efficacy. However, suppressive factors, such as regulatory T cells (Tregs), may be obstacles in the use of NKT cell-based cancer immunotherapy for advanced cancer patients. Here, we investigated the suppressive effects of Tregs on NKT cells and the underlying mechanisms with the aim to improve the antitumor activities of NKT cells. METHODS: Peripheral blood samples were obtained from healthy donors, patients with benign tumors, and patients with head and neck squamous cell carcinoma (HNSCC). NKT cells, induced with α-galactosylceramide (α-GalCer), and monocyte-derived dendritic cells (DCs) were co-cultured with naïve CD4+ T cell-derived Tregs to investigate the mechanism of the Treg suppressive effect on NKT cell cytotoxic function. The functions and phenotypes of NKT cells were evaluated with flow cytometry and cytometric bead array. RESULTS: Treg suppression on NKT cell function required cell-to-cell contact and was mediated via impaired DC maturation. NKT cells cultured under Treg-enriched conditions showed a decrease in CD4- NKT cell frequency, which exert strong tumoricidal responsiveness upon α-GalCer stimulation. The same results were observed in HNSCC patients with significantly increased effector Tregs. CONCLUSION: Tregs exert suppressive effects on NKT cell tumoricidal function by inducing more CD4- NKT cell anergy and less CD4+ NKT cell anergy. Both Treg depletion and NKT cell recovery from the anergy state may be important for improving the clinical efficacy of NKT cell-based immunotherapy in patients with advanced cancers.


Assuntos
Neoplasias de Cabeça e Pescoço/imunologia , Células T Matadoras Naturais/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Linfócitos T Reguladores/imunologia , Idoso , Idoso de 80 Anos ou mais , Células Cultivadas , Anergia Clonal , Citotoxicidade Imunológica , Feminino , Humanos , Vigilância Imunológica , Imunossupressão , Masculino , Pessoa de Meia-Idade
12.
Nat Immunol ; 20(12): 1656-1667, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31636463

RESUMO

Natural killer (NK) cells have crucial roles in tumor surveillance. We found that tumor-infiltrating NK cells in human liver cancers had small, fragmented mitochondria in their cytoplasm, whereas liver NK cells outside tumors, as well as peripheral NK cells, had normal large, tubular mitochondria. This fragmentation was correlated with reduced cytotoxicity and NK cell loss, resulting in tumor evasion of NK cell-mediated surveillance, which predicted poor survival in patients with liver cancer. The hypoxic tumor microenvironment drove the sustained activation of mechanistic target of rapamycin-GTPase dynamin-related protein 1 (mTOR-Drp1) in NK cells, resulting in excessive mitochondrial fission into fragments. Inhibition of mitochondrial fragmentation improved mitochondrial metabolism, survival and the antitumor capacity of NK cells. These data reveal a mechanism of immune escape that might be targetable and could invigorate NK cell-based cancer treatments.


Assuntos
Imunoterapia Adotiva/métodos , Células Matadoras Naturais/imunologia , Neoplasias Hepáticas/imunologia , Linfócitos do Interstício Tumoral/imunologia , Mitocôndrias/metabolismo , Idoso , Animais , Citotoxicidade Imunológica , Proteínas Quinases Associadas com Morte Celular/metabolismo , Feminino , Humanos , Vigilância Imunológica , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/terapia , Masculino , Camundongos , Microscopia Confocal , Pessoa de Meia-Idade , Mitocôndrias/ultraestrutura , Dinâmica Mitocondrial , Análise de Sobrevida , Serina-Treonina Quinases TOR/metabolismo , Evasão Tumoral
13.
Chaos ; 29(8): 083127, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31472488

RESUMO

In this paper, we present a new fractional-order mathematical model for a tumor-immune surveillance mechanism. We analyze the interactions between various tumor cell populations and immune system via a system of fractional differential equations (FDEs). An efficient numerical procedure is suggested to solve these FDEs by considering singular and nonsingular derivative operators. An optimal control strategy for investigating the effect of chemotherapy treatment on the proposed fractional model is also provided. Simulation results show that the new presented model based on the fractional operator with Mittag-Leffler kernel represents various asymptomatic behaviors that tracks the real data more accurately than the other fractional- and integer-order models. Numerical simulations also verify the efficiency of the proposed optimal control strategy and show that the growth of the naive tumor cell population is successfully declined.


Assuntos
Vigilância Imunológica , Modelos Imunológicos , Neoplasias/imunologia , Animais , Humanos
14.
Nihon Yakurigaku Zasshi ; 154(3): 108-113, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31527359

RESUMO

Similar to calcium (Ca2+) and chloride (Cl-) ion channels/transporters, potassium (K+) channels have been recognized as a crucial cancer treatment target. Recent studies have provided convincing evidences of positive correlation between elevated expression levels of Ca2+-activated K+ (KCa) channels and cancer proliferation, metastasis, and poor patient prognosis. In cancer cells, KCa1.1 and KCa3.1 KCa channels are co-localized with Ca2+-permeable Orai/TRP channels to provide a positive-feedback loop for Ca2+ entry. They are responsible for the promotion of cell growth and metastasis in the different types of cancer, and are therefore potential therapeutic targets and biomarkers for cancer. We determined the epigenetic and post-transcriptional dysregulation of KCa3.1 by class I histone deacetylase inhibitors in breast and prostate cancer cells. We further determined the transcriptional repression and protein degradation of KCa1.1 by vitamin D receptor agonists and androgen receptor antagonists, which are expected as potential therapeutic drugs for triple-negative breast cancer. The anti-inflammatory cytokine, interleukin-10 (IL-10) is an immunosuppressive factor involved in tumorigenesis, and plays a crucial role in escape from tumor immune surveillance. We determined KCa3.1 activators are a possible therapeutic option to suppress the tumor-promoting activities of IL-10. These results may provide new insights into cancer treatment focused on Ca2+-activated K+ channels.


Assuntos
Neoplasias da Mama/patologia , Inibidores de Histona Desacetilases/farmacologia , Canais de Potássio Cálcio-Ativados/metabolismo , Neoplasias da Próstata/patologia , Antagonistas de Receptores de Andrógenos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Epigênese Genética , Feminino , Humanos , Vigilância Imunológica , Interleucina-10/metabolismo , Masculino , Proteólise , Processamento Pós-Transcricional do RNA , Receptores de Calcitriol/agonistas
15.
Int J Mol Sci ; 20(18)2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31533245

RESUMO

Extracellular heat shock proteins (ex-HSPs) have been found in exosomes, oncosomes, membrane surfaces, as well as free HSP in cancer and various pathological conditions, also known as alarmins. Such ex-HSPs include HSP90 (α, ß, Gp96, Trap1), HSP70, and large and small HSPs. Production of HSPs is coordinately induced by heat shock factor 1 (HSF1) and hypoxia-inducible factor 1 (HIF-1), while matrix metalloproteinase 3 (MMP-3) and heterochromatin protein 1 are novel inducers of HSPs. Oncosomes released by tumor cells are a major aspect of the resistance-associated secretory phenotype (RASP) by which immune evasion can be established. The concepts of RASP are: (i) releases of ex-HSP and HSP-rich oncosomes are essential in RASP, by which molecular co-transfer of HSPs with oncogenic factors to recipient cells can promote cancer progression and resistance against stresses such as hypoxia, radiation, drugs, and immune systems; (ii) RASP of tumor cells can eject anticancer drugs, targeted therapeutics, and immune checkpoint inhibitors with oncosomes; (iii) cytotoxic lipids can be also released from tumor cells as RASP. ex-HSP and membrane-surface HSP (mHSP) play immunostimulatory roles recognized by CD91+ scavenger receptor expressed by endothelial cells-1 (SREC-1)+ Toll-like receptors (TLRs)+ antigen-presenting cells, leading to antigen cross-presentation and T cell cross-priming, as well as by CD94+ natural killer cells, leading to tumor cytolysis. On the other hand, ex-HSP/CD91 signaling in cancer cells promotes cancer progression. HSPs in body fluids are potential biomarkers detectable by liquid biopsies in cancers and tissue-damaged diseases. HSP-based vaccines, inhibitors, and RNAi therapeutics are also reviewed.


Assuntos
Espaço Extracelular/metabolismo , Proteínas de Choque Térmico/metabolismo , Evasão da Resposta Imune , Vigilância Imunológica , Animais , Biomarcadores , Vesículas Extracelulares/metabolismo , Proteínas de Choque Térmico/antagonistas & inibidores , Proteínas de Choque Térmico/genética , Humanos , Evasão da Resposta Imune/genética , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Vigilância Imunológica/genética , Imunomodulação , Biópsia Líquida , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/etiologia , Neoplasias/metabolismo , Neoplasias/patologia , Receptores de Superfície Celular/metabolismo
16.
Future Oncol ; 15(26): 3053-3069, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31411057

RESUMO

Natural killer (NK) cells lead immune surveillance against cancer and early elimination of small tumors. Owing to their ability to engage tumor targets without the need of specific antigen, the therapeutic potential of NK cells has been extensively explored in hematological malignancies. In solid tumors, however, their role in the clinical arena remains poorly exploited despite a broad accumulation of preclinical data. In this article, we review our current knowledge of NK cells' biology, and highlight the challenges facing NK cell antitumor strategies in solid tumors. We further summarize the abundant preclinical attempts at overcoming these challenges, present past and ongoing clinical trial data and finally discuss the potential impact of novel insights on the development of NK cell-based therapies.


Assuntos
Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Animais , Humanos , Vigilância Imunológica , Imunoterapia Adotiva , Neoplasias/etiologia , Neoplasias/metabolismo , Neoplasias/terapia , Células-Tronco Neoplásicas/metabolismo , Receptores KIR/metabolismo , Transdução de Sinais , Evasão Tumoral/genética , Evasão Tumoral/imunologia
17.
Immunobiology ; 224(5): 649-658, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31421859

RESUMO

Transforming growth factor-ß (TGF-ß) is known to function as a dual role regulatory cytokine for being either a suppresser or promoter during tumor initiation and progression. In solid tumors, TGF-ß secreted from tumor microenvironment acts as a suppresser against host immunity, like natural killer (NK) cells, to favor tumor evasion. However, besides solid tumors, the underlying mechanism of how TGF-ß regulates leukemogenesis, tumor progression, immunoediting, and NK function is still not clear in detail. In this study, we found that TGF-ß induced leukemia MEG-01 and U937 cells to become less sensitive to NK-92MI targeting by down-regulating CD48, a ligand for NK activating receptor 2B4, but not down-regulating other tumor-associated carbohydrate antigens (TACAs). In CD48-knockdown cells, cells responding to NK-92MI targeting displayed a phenotype of less NK susceptibility and cell conjugation. On the other hand, when NK cells were treated with TGF-ß, TGF-ß suppressed NK recognition, degranulation, and killing activity in time-dependent manner by regulating ICAM-1 binding capacity instead of affecting expressions of activating and inhibitory receptors. Taken together, both leukemia cells and immune NK cells could be regulated by TGF-ß through suppressing leukemia cell surface CD48 to escape from host surveillance and down-regulating NK cell surface ICAM-1 binding activity to impair NK functions, respectively. Our results suggested that TGF-ß had effect in leukemia similar to that observed in solid tumors but through different regulatory mechanism.


Assuntos
Antígeno CD48/metabolismo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Leucemia/etiologia , Leucemia/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Antígeno CD48/genética , Degranulação Celular , Linhagem Celular Tumoral , Citotoxicidade Imunológica/efeitos dos fármacos , Suscetibilidade a Doenças , Humanos , Vigilância Imunológica , Molécula 1 de Adesão Intercelular/imunologia , Molécula 1 de Adesão Intercelular/metabolismo , Leucemia/patologia , Proteína 1 de Membrana Associada ao Lisossomo/metabolismo , Receptores de Células Matadoras Naturais/metabolismo , Fator de Crescimento Transformador beta/farmacologia
18.
Neoplasia ; 21(10): 945-962, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31422285

RESUMO

Down-regulation or loss of MHC class I expression is a major mechanism used by cancer cells to evade immunosurveillance and increase their oncogenic potential. MHC I mediated antigen presentation is a complex regulatory process, controlled by antigen processing machinery (APM) dictating immune response. Transcriptional regulation of the APM that can modulate gene expression profile and their correlation to MHC I mediated antigen presentation in cancer cells remain enigmatic. Here, we reveal that Scaffold/Matrix-Associated Region 1- binding protein (SMAR1), positively regulates MHC I surface expression by down-regulating calnexin, an important component of antigen processing machinery (APM) in cancer cells. SMAR1, a bonafide MAR binding protein acts as a transcriptional repressor of several oncogenes. It is down-regulated in higher grades of cancers either through proteasomal degradation or through loss of heterozygosity (LOH) at the Chr.16q24.3 locus where the human homolog of SMAR1 (BANP) has been mapped. It binds to a short MAR region of the calnexin promoter forming a repressor complex in association with GATA2 and HDAC1. A reverse correlation between SMAR1 and calnexin was thus observed in SMAR1-LOH cells and also in tissues from breast cancer patients. To further extrapolate our findings, influenza A (H1N1) virus infection assay was performed. Upon viral infection, the levels of SMAR1 significantly increased resulting in reduced calnexin expression and increased MHC I presentation. Taken together, our observations establish that increased expression of SMAR1 in cancers can positively regulate MHC I surface expression thereby leading to higher chances of tumor regression and elimination of cancer cells.


Assuntos
Calnexina/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/genética , Regulação Neoplásica da Expressão Gênica , Antígenos de Histocompatibilidade Classe I/genética , Vigilância Imunológica/genética , Proteínas Nucleares/genética , Calnexina/química , Calnexina/metabolismo , Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/metabolismo , Citometria de Fluxo , Genes Reporter , Antígenos de Histocompatibilidade Classe I/química , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Vírus da Influenza A , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Proteoma , Proteômica/métodos , Relação Estrutura-Atividade
19.
Int J Mol Sci ; 20(15)2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31366013

RESUMO

Natural Killer (NK) cells play a critical role in host defense against viral infections. The mechanisms of recognition and killing of virus-infected cells mediated by NK cells are still only partially defined. Several viruses induce, on the surface of target cells, the expression of molecules that are specifically recognized by NK cell-activating receptors. The main NK cell-activating receptors involved in the recognition and killing of virus-infected cells are NKG2D and DNAM-1. In particular, ligands for DNAM-1 are nectin/nectin-like molecules involved also in mechanisms allowing viral infection. Viruses adopt several immune evasion strategies, including those affecting NK cell-mediated immune surveillance, causing persistent viral infection and the development of virus-associated diseases. The virus's immune evasion efficacy depends on molecules differently expressed during the various phases of infection. In this review, we overview the molecular strategies adopted by viruses, specifically cytomegalovirus (CMV), human immunodeficiency virus (HIV-1), herpes virus (HSV), Epstein-Barr virus (EBV) and hepatitis C virus (HCV), aiming to evade NK cell-mediated surveillance, with a special focus on the modulation of DNAM-1 activating receptor and its ligands in various phases of the viral life cycle. The increasing understanding of mechanisms involved in the modulation of activating ligands, together with those mediating the viral immune evasion strategies, would provide critical tools leading to design novel NK cell-based immunotherapies aiming at viral infection control, thus improving cure strategies of virus-associated diseases.


Assuntos
Antígenos de Diferenciação de Linfócitos T/metabolismo , Vigilância Imunológica , Células Matadoras Naturais/imunologia , Viroses/imunologia , Animais , Humanos , Células Matadoras Naturais/virologia , Nectinas/metabolismo , Viroses/virologia , Replicação Viral
20.
J Immunol ; 203(2): 311-320, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31285310

RESUMO

As interest in γδ T cells grows rapidly, what key points are emerging, and where is caution warranted? γδ T cells fulfill critical functions, as reflected in associations with vaccine responsiveness and cancer survival in humans and ever more phenotypes of γδ T cell-deficient mice, including basic physiological deficiencies. Such phenotypes reflect activities of distinct γδ T cell subsets, whose origins offer interesting insights into lymphocyte development but whose variable evolutionary conservation can obfuscate translation of knowledge from mice to humans. By contrast, an emerging and conserved feature of γδ T cells is their "adaptate" biology: an integration of adaptive clonally-restricted specificities, innate tissue-sensing, and unconventional recall responses that collectively strengthen host resistance to myriad challenges. Central to adaptate biology are butyrophilins and other γδ cell regulators, the study of which should greatly enhance our understanding of tissue immunogenicity and immunosurveillance and guide intensifying clinical interest in γδ cells and other unconventional lymphocytes.


Assuntos
Vigilância Imunológica/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Animais , Butirofilinas/imunologia , Humanos , Monitorização Imunológica/métodos , Subpopulações de Linfócitos T/imunologia
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