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1.
Semin Immunol ; 42: 101295, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31604533

RESUMO

The past few years have witnessed exciting progress in the application of immune check-point blockade (ICB) for the treatment of various human cancers. ICB was first used against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) to demonstrate durable anti-tumor responses followed by ICB against programmed cell death-1 (PD-1) or its ligand, PD-L1. Present approaches involve the use of combinations of blocking antibodies against CTLA-4, PD-1 and other inhibitory receptors (IRs) such as TIM3, TIGIT and LAG3. Despite this success, most patients are not cured by ICB therapy and there are limitations to the use of antibodies including cost, tumor penetration, the accessibility of receptors, and clearance from the cell surface as well as inflammatory and autoimmune complications. Recently, we demonstrated that the down-regulation or inhibition of glycogen synthase kinase 3 (GSK-3) down-regulates PD-1 expression in infectious diseases and cancer (Taylor et al., 2016 Immunity 44, 274-86; 2018 Cancer Research 78, 706-717; Krueger and Rudd 2018 Immunity 46, 529-531). In this Review, we outline the use of small molecule inhibitors (SMIs) that target intracellular pathways for co-receptor blockade in cancer immunotherapy.


Assuntos
Quinase 3 da Glicogênio Sintase/imunologia , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/imunologia , Animais , Antineoplásicos Imunológicos/uso terapêutico , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Humanos , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores
2.
Mol Cancer Ther ; 17(4): 869-882, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29483207

RESUMO

A recurring historic finding in cancer drug development is encouraging antitumor effects observed in tumor-bearing mice that fail to translate into the clinic. An intriguing exception to this pattern is immune checkpoint therapy, as the sustained tumor regressions observed in subsets of cancer patients are rare in mice. Reasoning that this may be due in part to relatively low mutational loads of mouse tumors, we mutagenized transplantable mouse tumor cell lines EMT-6/P, B16F1, RENCA, CT26, and MC38 in vitro with methylnitro-nitrosoguanidine (MNNG) or ethylmethane sulfonate (EMS) and tested their responsiveness to PD-L1 blockade. Exome sequencing confirmed an increase in somatic mutations by mutagen treatment, an effect mimicked in EMT-6 variants chronically exposed in vivo to cisplatin or cyclophosphamide. Certain mutagenized variants of B16F1, EMT-6/P, CT26, and MC38 (but not RENCA) were more immunogenic than their parents, yet anti-PD-L1 sensitization developed only in some EMT-6/P and B16F1 variants. Treatment response patterns corresponded with changes in immune cell infiltration and especially increases in CD8+ T cells. Chronically cisplatin-exposed EMT-6 variants were also more responsive to anti-PD-L1 therapy. Although tumor PD-L1 expression was upregulated in in vivo chemotherapy-exposed variants, PD-L1 expression levels were not consistently associated with anti-PD-L1 treatment activity across mutagenized or chemotherapy-exposed variants. In summary, mutagenized and more immunogenic mouse tumors were not universally sensitized to PD-L1 blockade. Chemically mutagenized variants may be useful to evaluate the impact of immunologically "hot" or "cold" tumors with a high mutational load, to which certain chemotherapy agents may contribute, on immunotherapy outcomes. Mol Cancer Ther; 17(4); 869-82. ©2018 AACR.


Assuntos
Anticorpos Monoclonais/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/genética , Metanossulfonato de Etila/toxicidade , Neoplasias Mamárias Experimentais/genética , Melanoma Experimental/genética , Metilnitronitrosoguanidina/toxicidade , Mutação , Animais , Apoptose , Proliferação de Células , Feminino , Neoplasias Mamárias Experimentais/induzido quimicamente , Neoplasias Mamárias Experimentais/tratamento farmacológico , Melanoma Experimental/induzido quimicamente , Melanoma Experimental/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Células Tumorais Cultivadas
3.
Immunity ; 46(4): 529-531, 2017 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-28423334

RESUMO

The identity of PD-1 dependency on other receptors and signaling has been unclear. In a recent issue of Science, Hui et al. (2017) and Kamphorst et al. (2017) now show that CD28 expression is a target of PD-1-associated phosphatases and is needed for T cell expansion in anti-PD-1 immunotherapy.


Assuntos
Antígenos CD28 , Linfócitos T , Ciclo Celular , Humanos , Imunoterapia , Transdução de Sinais
4.
Nat Commun ; 8: 13991, 2017 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-28071661

RESUMO

Formation of organ-specific vasculatures requires cross-talk between developing tissue and specialized endothelial cells. Here we show how developing zebrafish spinal cord neurons coordinate vessel growth through balancing of neuron-derived Vegfaa, with neuronal sFlt1 restricting Vegfaa-Kdrl mediated angiogenesis at the neurovascular interface. Neuron-specific loss of flt1 or increased neuronal vegfaa expression promotes angiogenesis and peri-neural tube vascular network formation. Combining loss of neuronal flt1 with gain of vegfaa promotes sprout invasion into the neural tube. On loss of neuronal flt1, ectopic sprouts emanate from veins involving special angiogenic cell behaviours including nuclear positioning and a molecular signature distinct from primary arterial or secondary venous sprouting. Manipulation of arteriovenous identity or Notch signalling established that ectopic sprouting in flt1 mutants requires venous endothelium. Conceptually, our data suggest that spinal cord vascularization proceeds from veins involving two-tiered regulation of neuronal sFlt1 and Vegfaa via a novel sprouting mode.


Assuntos
Neurônios/fisiologia , Medula Espinal/embriologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Veias/embriologia , Proteínas de Peixe-Zebra/metabolismo , Animais , Animais Geneticamente Modificados , Biomarcadores/metabolismo , Embrião não Mamífero/citologia , Células Endoteliais/metabolismo , Células Endoteliais/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Mutação , Neovascularização Fisiológica , Receptores Notch/genética , Receptores Notch/metabolismo , Medula Espinal/irrigação sanguínea , Fator A de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Veias/metabolismo , Proteínas de Peixe-Zebra/genética
5.
Artigo em Inglês | MEDLINE | ID: mdl-31544130

RESUMO

T-cell activation is mediated by a combination of signals from the antigen receptor (TCR) and co-receptors such as CD28, cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed cell death antigen 1 (PD-1), CD28H and others. Each is a member of the CD28 receptor gene family. CD28 sends positive signals that promote T-cell responses, while CTLA-4 and PD-1 limit responses. It is the balance between these positive and negative signals that determines the amplitude and level of T-cell responses. The regulatory role of other family members is also becoming the focus of increasing interest. The function of certain CD28 family members such as CTLA-4 and PD-1 is dependent the expression of CD28. Together, these findings have important implications in generation of immune responses and the application of anti-receptor blocking reagents in immunotherapy.

6.
Nature ; 495(7441): 333-8, 2013 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-23446348

RESUMO

Circular RNAs (circRNAs) in animals are an enigmatic class of RNA with unknown function. To explore circRNAs systematically, we sequenced and computationally analysed human, mouse and nematode RNA. We detected thousands of well-expressed, stable circRNAs, often showing tissue/developmental-stage-specific expression. Sequence analysis indicated important regulatory functions for circRNAs. We found that a human circRNA, antisense to the cerebellar degeneration-related protein 1 transcript (CDR1as), is densely bound by microRNA (miRNA) effector complexes and harbours 63 conserved binding sites for the ancient miRNA miR-7. Further analyses indicated that CDR1as functions to bind miR-7 in neuronal tissues. Human CDR1as expression in zebrafish impaired midbrain development, similar to knocking down miR-7, suggesting that CDR1as is a miRNA antagonist with a miRNA-binding capacity ten times higher than any other known transcript. Together, our data provide evidence that circRNAs form a large class of post-transcriptional regulators. Numerous circRNAs form by head-to-tail splicing of exons, suggesting previously unrecognized regulatory potential of coding sequences.


Assuntos
Regulação da Expressão Gênica , RNA/metabolismo , Animais , Autoantígenos/genética , Autoantígenos/metabolismo , Sítios de Ligação , Encéfalo/metabolismo , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Linhagem Celular , Sequência Conservada , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , RNA/genética , RNA Circular , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Peixe-Zebra/metabolismo
7.
Int J Dev Biol ; 55(4-5): 419-29, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21858767

RESUMO

The circulatory system is the first organ system that develops during embryogenesis, and is essential for embryo viability and survival. Crucial for developing a functional vasculature are the specification of arterial-venous identity in vessels and the formation of a hierarchical branched vascular network. Sprouting angiogenesis, intussusception, and flow driven remodeling events collectively contribute to establishing the vascular architecture. At the molecular level, arterial-venous identity and branching are regulated by genetically hardwired mechanisms involving Notch, vascular endothelial growth factor and neural guidance molecule signaling pathways, modulated by hemodynamic factors. MicroRNAs are small, non-coding RNAs that act as silencers to fine-tune the gene expression profile. MicroRNAs are known to influence cell fate decisions, and microRNA expression can be controlled by blood flow, thus placing microRNAs potentially at the center of the genetic cascades regulating vascular differentiation. In the present review, we summarize current progress regarding microRNA functions in blood vessel development with an emphasis on studies performed in zebrafish and mouse models.


Assuntos
Vasos Sanguíneos/crescimento & desenvolvimento , MicroRNAs/fisiologia , Neovascularização Fisiológica , Fluxo Sanguíneo Regional/fisiologia , Animais , Células Endoteliais/fisiologia , Perfilação da Expressão Gênica , Camundongos , MicroRNAs/genética , Miócitos de Músculo Liso/fisiologia , Neovascularização Patológica/genética , Neovascularização Fisiológica/genética , Peixe-Zebra
8.
Development ; 138(10): 2111-20, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21521739

RESUMO

Endothelial tip cells guide angiogenic sprouts by exploring the local environment for guidance cues such as vascular endothelial growth factor (VegfA). Here we present Flt1 (Vegf receptor 1) loss- and gain-of-function data in zebrafish showing that Flt1 regulates tip cell formation and arterial branching morphogenesis. Zebrafish embryos expressed soluble Flt1 (sFlt1) and membrane-bound Flt1 (mFlt1). In Tg(flt1(BAC):yfp) × Tg(kdrl:ras-cherry)(s916) embryos, flt1:yfp was expressed in tip, stalk and base cells of segmental artery sprouts and overlapped with kdrl:cherry expression in these domains. flt1 morphants showed increased tip cell numbers, enhanced angiogenic behavior and hyperbranching of segmental artery sprouts. The additional arterial branches developed into functional vessels carrying blood flow. In support of a functional role for the extracellular VEGF-binding domain of Flt1, overexpression of sflt1 or mflt1 rescued aberrant branching in flt1 morphants, and overexpression of sflt1 or mflt1 in controls resulted in short arterial sprouts with reduced numbers of filopodia. flt1 morphants showed reduced expression of Notch receptors and of the Notch downstream target efnb2a, and ectopic expression of flt4 in arteries, consistent with loss of Notch signaling. Conditional overexpression of the notch1a intracellular cleaved domain in flt1 morphants restored segmental artery patterning. The developing nervous system of the trunk contributed to the distribution of Flt1, and the loss of flt1 affected neurons. Thus, Flt1 acts in a Notch-dependent manner as a negative regulator of tip cell differentiation and branching. Flt1 distribution may be fine-tuned, involving interactions with the developing nervous system.


Assuntos
Neovascularização Fisiológica , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/embriologia , Peixe-Zebra/metabolismo , Animais , Animais Geneticamente Modificados , Sequência de Bases , Vasos Sanguíneos/embriologia , Vasos Sanguíneos/metabolismo , Diferenciação Celular , Regulação da Expressão Gênica no Desenvolvimento , Macrófagos/metabolismo , Sistema Nervoso/embriologia , Sistema Nervoso/metabolismo , Oligodesoxirribonucleotídeos Antissenso/genética , Receptores Notch/metabolismo , Transdução de Sinais , Solubilidade , Distribuição Tecidual , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/antagonistas & inibidores , Proteínas de Peixe-Zebra/genética
9.
Development ; 138(10): 1935-45, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21471154

RESUMO

Endodermal organogenesis requires a precise orchestration of cell fate specification and cell movements, collectively coordinating organ size and shape. In Caenorhabditis elegans, uncoordinated-53 (unc-53) encodes a neural guidance molecule that directs axonal growth. One of the vertebrate homologs of unc-53 is neuron navigator 3 (Nav3). Here, we identified a novel vertebrate neuron navigator 3 isoform in zebrafish, nav3a, and we provide genetic evidence in loss- and gain-of-function experiments showing its functional role in endodermal organogenesis during zebrafish embryogenesis. In zebrafish embryos, nav3a expression was initiated at 22 hpf in the gut endoderm and at 40 hpf expanded to the newly formed liver bud. Endodermal nav3a expression was controlled by Wnt2bb signaling and was independent of FGF and BMP signaling. Morpholino-mediated knockdown of nav3a resulted in a significantly reduced liver size, and impaired development of pancreas and swim bladder. In vivo time-lapse imaging of liver development in nav3a morphants revealed a failure of hepatoblast movement out from the gut endoderm during the liver budding stage, with hepatoblasts being retained in the intestinal endoderm. In hepatocytes in vitro, nav3a acts as a positive modulator of actin assembly in lamellipodia and filipodia extensions, allowing cellular movement. Knockdown of nav3a in vitro impeded hepatocyte movement. Endodermal-specific overexpression of nav3a in vivo resulted in additional ectopic endodermal budding beyond the normal liver and pancreatic budding sites. We conclude that nav3a is required for directing endodermal organogenesis involving coordination of endodermal cell behavior.


Assuntos
Fígado/embriologia , Fígado/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/embriologia , Peixe-Zebra/metabolismo , Animais , Animais Geneticamente Modificados , Sequência de Bases , Primers do DNA/genética , Endoderma/embriologia , Endoderma/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Técnicas de Silenciamento de Genes , Hibridização In Situ , Mucosa Intestinal/metabolismo , Intestinos/embriologia , Fígado/anormalidades , Fígado/inervação , Modelos Biológicos , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/genética , Organogênese/genética , Organogênese/fisiologia , RNA Antissenso/genética , Transdução de Sinais , Proteínas Wnt/antagonistas & inibidores , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/antagonistas & inibidores , Proteínas de Peixe-Zebra/genética
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