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1.
Nature ; 629(8011): 426-434, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38658764

RESUMEN

Expansion of antigen-experienced CD8+ T cells is critical for the success of tumour-infiltrating lymphocyte (TIL)-adoptive cell therapy (ACT) in patients with cancer1. Interleukin-2 (IL-2) acts as a key regulator of CD8+ cytotoxic T lymphocyte functions by promoting expansion and cytotoxic capability2,3. Therefore, it is essential to comprehend mechanistic barriers to IL-2 sensing in the tumour microenvironment to implement strategies to reinvigorate IL-2 responsiveness and T cell antitumour responses. Here we report that prostaglandin E2 (PGE2), a known negative regulator of immune response in the tumour microenvironment4,5, is present at high concentrations in tumour tissue from patients and leads to impaired IL-2 sensing in human CD8+ TILs via the PGE2 receptors EP2 and EP4. Mechanistically, PGE2 inhibits IL-2 sensing in TILs by downregulating the IL-2Rγc chain, resulting in defective assembly of IL-2Rß-IL2Rγc membrane dimers. This results in impaired IL-2-mTOR adaptation and PGC1α transcriptional repression, causing oxidative stress and ferroptotic cell death in tumour-reactive TILs. Inhibition of PGE2 signalling to EP2 and EP4 during TIL expansion for ACT resulted in increased IL-2 sensing, leading to enhanced proliferation of tumour-reactive TILs and enhanced tumour control once the cells were transferred in vivo. Our study reveals fundamental features that underlie impairment of human TILs mediated by PGE2 in the tumour microenvironment. These findings have therapeutic implications for cancer immunotherapy and cell therapy, and enable the development of targeted strategies to enhance IL-2 sensing and amplify the IL-2 response in TILs, thereby promoting the expansion of effector T cells with enhanced therapeutic potential.


Asunto(s)
Linfocitos T CD8-positivos , Proliferación Celular , Dinoprostona , Interleucina-2 , Linfocitos Infiltrantes de Tumor , Mitocondrias , Transducción de Señal , Animales , Humanos , Ratones , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Dinoprostona/metabolismo , Regulación hacia Abajo , Ferroptosis , Subunidad gamma Común de Receptores de Interleucina/biosíntesis , Subunidad gamma Común de Receptores de Interleucina/deficiencia , Subunidad gamma Común de Receptores de Interleucina/metabolismo , Interleucina-2/antagonistas & inhibidores , Interleucina-2/inmunología , Interleucina-2/metabolismo , Subunidad beta del Receptor de Interleucina-2/metabolismo , Linfocitos Infiltrantes de Tumor/citología , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Mitocondrias/metabolismo , Estrés Oxidativo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Subtipo EP2 de Receptores de Prostaglandina E/metabolismo , Subtipo EP2 de Receptores de Prostaglandina E/antagonistas & inhibidores , Subtipo EP4 de Receptores de Prostaglandina E/metabolismo , Subtipo EP4 de Receptores de Prostaglandina E/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/metabolismo , Microambiente Tumoral/inmunología
2.
J Allergy Clin Immunol Glob ; 3(1): 100195, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38187863

RESUMEN

Background: Telazorlimab is a humanized anti-OX40 monoclonal antibody being studied for treatment of T-cell-mediated diseases. Objective: This randomized, placebo-controlled, phase 2b dose-range finding study investigated efficacy, safety, pharmacokinetics, and immunogenicity of telazorlimab in subjects with atopic dermatitis. Methods: In this 2-part study (NCT03568162), adults (≥18 years) with moderate-to-severe disease were randomized to various regimens of subcutaneous telazorlimab or placebo for 16 weeks' blinded treatment, followed by 38 weeks' open-label treatment and 12 weeks' drug-free follow-up. Telazorlimab treatment groups (following a loading dose) in part 1 were 300 mg every 2 weeks; 300 mg every 4 weeks; or 75 mg every 4 weeks. Part 2 evaluated telazorlimab 600 mg every 2 weeks. The primary end point was percentage change from baseline in Eczema Area and Severity Index (EASI) at week 16. Safety assessments included incidence of treatment-emergent adverse events. Results: The study randomized 313 subjects in part 1 and 149 in part 2. At 16 weeks, the least squares mean percentage change from baseline in EASI was significantly greater in subjects receiving telazorlimab 300 mg every 2 weeks (part 1) and 600 mg every 2 weeks (part 2) versus placebo (-54.4% vs -34.2% for part 1 and -59.0% vs -41.8% for part 2, P = .008 for both). Telazorlimab was well tolerated, with similar distribution of adverse events between telazorlimab- and placebo-treated subjects in both part 1 and part 2. Conclusion: Telazorlimab, administered subcutaneously at 300 mg every 2 weeks or 600 mg every 2 weeks following a loading dose, was well tolerated and induced significant and progressive clinical improvement in adults with moderate-to-severe atopic dermatitis.

3.
Blood ; 142(3): 260-273, 2023 07 20.
Artículo en Inglés | MEDLINE | ID: mdl-37192303

RESUMEN

Although treatment of multiple myeloma (MM) with daratumumab significantly extends the patient's lifespan, resistance to therapy is inevitable. ISB 1342 was designed to target MM cells from patients with relapsed/refractory MM (r/r MM) displaying lower sensitivity to daratumumab. ISB 1342 is a bispecific antibody with a high-affinity Fab binding to CD38 on tumor cells on a different epitope than daratumumab and a detuned scFv domain affinity binding to CD3ε on T cells, to mitigate the risk of life-threatening cytokine release syndrome, using the Bispecific Engagement by Antibodies based on the TCR (BEAT) platform. In vitro, ISB 1342 efficiently killed cell lines with different levels of CD38, including those with a lower sensitivity to daratumumab. In a killing assay where multiple modes of action were enabled, ISB 1342 showed higher cytotoxicity toward MM cells compared with daratumumab. This activity was retained when used in sequential or concomitant combinations with daratumumab. The efficacy of ISB 1342 was maintained in daratumumab-treated bone marrow patient samples showing lower sensitivity to daratumumab. ISB 1342 induced complete tumor control in 2 therapeutic mouse models, unlike daratumumab. Finally, in cynomolgus monkeys, ISB 1342 displayed an acceptable toxicology profile. These data suggest that ISB 1342 may be an option in patients with r/r MM refractory to prior anti-CD38 bivalent monoclonal antibody therapies. It is currently being developed in a phase 1 clinical study.


Asunto(s)
Anticuerpos Biespecíficos , Mieloma Múltiple , Animales , Ratones , ADP-Ribosil Ciclasa 1/metabolismo , Anticuerpos Biespecíficos/farmacología , Anticuerpos Biespecíficos/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Linfocitos T/patología
4.
Brain Behav Immun Health ; 28: 100568, 2023 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-36704658

RESUMEN

Background: Studies in rodents and humans have indicated that inflammation outside CNS (systemic inflammation) affects brain homeostasis contributing to neurodevelopmental disorders. Itis becoming increasingly evident that such early insults may also belinked to neurodegenerative diseases like late-onset Alzheimer's disease (AD). Importantly, lifestyle and stress, such as viral or bacterial infection causing chronic inflammation, may contribute to neurodegenerative dementia. Systemic inflammatory response triggers a cascade of neuroinflammatory responses, altering brain transcriptome, cell death characteristic of AD, and vascular dementia. Our study aimed to assess the temporal evolution of the pathological impact of systemic inflammation evoked by prenatal and early postnatal peripheral exposure of viral mimetic Polyinosinic:polycytidylic acid (PolyI:C) and compare the hippocampal transcriptomic changes with the profiles of human post-mortem AD and vascular dementia brain specimens. Methods: We have engineered the PolyI:C sterile infection model in wildtype C57BL6 mice to achieve chronic low-grade systemic inflammation. We have conducted a cross-sectional analysis of aging PolyI:C and Saline control mice (3 months, 6 months, 9 months, and 16 months), taking the hippocampus as a reference brain region, and compared the brain aging phenotype to AD progression in humans with mild AD, severe AD, and Controls (CTL), in parallel to Vascular dementia (VaD) patients' specimens. Results: We found that PolyI:C mice display both peripheral and central inflammation with a peak at 6 months, associated with memory deficits. The hippocampus is characterized by a pronounced and progressive tauopathy. In PolyI:C brains, microglia undergo aging-dependent morphological shifts progressively adopting a phagocytic phenotype. Transcriptomic analysis reveals a profound change in gene expression throughout aging, with a peak in differential expression at 9 months. We show that the proinflammatory marker Lcn2 is one of the genes with the strongest upregulation in PolyI:C mice upon aging. Validation in brains from patients with increasing severity of AD and VaD shows the reproducibility of some gene targets in vascular dementia specimens as compared to AD ones. Conclusions: The PolyI:C model of sterile infection demonstrates that peripheral chronic inflammation causes progressive tau hyperphosphorylation, changes in microglia morphology, astrogliosis and gene reprogramming reflecting increased neuroinflammation, vascular remodeling, and the loss of neuronal functionality seen to some extent in human AD and Vascular dementia suggesting early immune insults could be crucial in neurodegenerative diseases.

5.
Cancer Cell ; 39(12): 1623-1642.e20, 2021 12 13.
Artículo en Inglés | MEDLINE | ID: mdl-34739845

RESUMEN

The mechanisms regulating exhaustion of tumor-infiltrating lymphocytes (TIL) and responsiveness to PD-1 blockade remain partly unknown. In human ovarian cancer, we show that tumor-specific CD8+ TIL accumulate in tumor islets, where they engage antigen and upregulate PD-1, which restrains their functions. Intraepithelial PD-1+CD8+ TIL can be, however, polyfunctional. PD-1+ TIL indeed exhibit a continuum of exhaustion states, with variable levels of CD28 costimulation, which is provided by antigen-presenting cells (APC) in intraepithelial tumor myeloid niches. CD28 costimulation is associated with improved effector fitness of exhausted CD8+ TIL and is required for their activation upon PD-1 blockade, which also requires tumor myeloid APC. Exhausted TIL lacking proper CD28 costimulation in situ fail to respond to PD-1 blockade, and their response may be rescued by local CTLA-4 blockade and tumor APC stimulation via CD40L.


Asunto(s)
Células Presentadoras de Antígenos/metabolismo , Antígenos CD28/metabolismo , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Células Mieloides/metabolismo , Neoplasias/tratamiento farmacológico , Nicho de Células Madre/genética , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Neoplasias/inmunología
6.
Alzheimers Dement (Amst) ; 12(1): e12000, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32775594

RESUMEN

INTRODUCTION: There is increasing evidence linking periodontal infections to Alzheimer's disease (AD). Saliva sampling can reveal information about the host and pathogen interactions that can inform about physiological and pathological brain states. METHODS: A cross-sectional cohort of age-matched participants (78) was segmented according to their chemosensory (University of Pennsylvania Smell Identification Test; UPSIT) and cognitive scores (Mini-Mental State Exam; MMSE and clinical dementia rating; CDR). Mid-morning saliva was sampled from each participant and processed for microbiome composition and cytokine analysis. Linear discriminant analysis (LDA) was used to unravel specific changes in microbial and immunological signatures and logistic regression analysis (LRA) was employed to identify taxa that varied in abundance among patient groups. RESULTS: Using olfaction we distinguish in the cognitively normal population a segment with high chemosensory scores (CNh, 27) and another segment with chemosensory scores (CNr, 16) as low as mild cognitive impairment (MCI, 21) but higher than the AD group (17). We could identify stage-specific microbial signatures changes but no clearly distinct cytokine profiles. Periodontal pathogen species as Filifactor villosus decline with the increasing severity of AD, whereas opportunistic oral bacteria such as Leptotrichia wadei show a significant enrichment in MCI. CONCLUSIONS: The salivary microbiome indicates stage-dependent changes in oral bacteria favoring opportunistic species at the expense of periodontal bacteria, whereas the inflammatory profiles remain mainly unchanged in the sampled population.

7.
Sci Rep ; 10(1): 200, 2020 01 13.
Artículo en Inglés | MEDLINE | ID: mdl-31932697

RESUMEN

The metabolic shift induced in human CD4+ T lymphocytes by stimulation is characterized by an upregulation of glycolysis, leading to an augmentation in lactate production. This adaptation has already been highlighted with various techniques and reported in several previous studies. We herein propose a method to rapidly and noninvasively detect the associated increase in flux from pyruvate to lactate catalyzed by lactate dehydrogenase using hyperpolarized 13C magnetic resonance, a technique which can be used for in vivo imaging. It was shown that the conversion of hyperpolarized 13C-pyruvate to 13C-lactate during the one-minute measurement increased by a mean factor of 3.6 in T cells stimulated for 5 days as compared to resting T cells. This method can be extended to other metabolic substrates and is therefore a powerful tool to noninvasively analyze T cell metabolism, possibly in vivo.


Asunto(s)
Adaptación Fisiológica , Isótopos de Carbono/análisis , Glucólisis , Leucocitos Mononucleares/metabolismo , Activación de Linfocitos , Imagen por Resonancia Magnética/métodos , Linfocitos T/metabolismo , Humanos , Ácido Láctico/metabolismo , Leucocitos Mononucleares/inmunología , Complejo Piruvato Deshidrogenasa/metabolismo , Ácido Pirúvico/metabolismo , Linfocitos T/inmunología
8.
Trends Biotechnol ; 37(1): 86-99, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30126620

RESUMEN

In 2006, the group of Dr C.M. Lieber pioneered the field of nanowire sensors by fabricating devices for the ultra-sensitive label-free detection of biological macromolecules. Since then, nanowire sensors have demonstrated their ability to detect cancer-associated analytes in peripheral blood, tumor tissue, and the exhaled breath of cancer patients. These innovative developments have marked a new era with unprecedented detection performance, capable of addressing crucial needs such as cancer diagnosis and monitoring disease progression and patient response to therapy. The ability of nanowire sensors to identify molecular features of patient tumor represents a first step toward precision medicine, and their integration into portable devices has the potential to revolutionize cancer diagnosis and patient monitoring.


Asunto(s)
Técnicas Biosensibles/instrumentación , Técnicas Biosensibles/métodos , Técnicas de Diagnóstico Molecular/instrumentación , Técnicas de Diagnóstico Molecular/métodos , Nanocables , Antígenos de Neoplasias/análisis , Neoplasias de la Mama/diagnóstico , Femenino , Humanos , Silicio
9.
Front Immunol ; 8: 1564, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29187853

RESUMEN

Redirecting CD8 T cell immunity with self/tumor-specific affinity-matured T cell receptors (TCRs) is a promising approach for clinical adoptive T cell therapy, with the aim to improve treatment efficacy. Despite numerous functional-based studies, little is known about the characteristics of TCR signaling (i.e., intensity, duration, and amplification) and the regulatory mechanisms underlying optimal therapeutic T cell responses. Using a panel of human SUP-T1 and primary CD8 T cells engineered with incremental affinity TCRs against the cancer-testis antigen NY-ESO-1, we found that upon activation, T cells with optimal-affinity TCRs generated intense and sustained proximal (CD3ζ, LCK) signals associated with distal (ERK1/2) amplification-gain and increased function. In contrast, in T cells with very high affinity TCRs, signal initiation was rapid and strong yet only transient, resulting in poor MAPK activation and low proliferation potential even at high antigen stimulation dose. Under resting conditions, the levels of surface TCR/CD3ε, CD8ß, and CD28 expression and of CD3ζ phosphorylation were significantly reduced in those hyporesponsive cells, suggesting the presence of TCR affinity-related activation thresholds. We also show that SHP phosphatases were involved along the TCR affinity gradient, but displayed spatially distinct regulatory roles. While PTPN6/SHP-1 phosphatase activity controlled TCR signaling initiation and subsequent amplification by counteracting CD3ζ and ERK1/2 phosphorylation, PTPN11/SHP-2 augmented MAPK activation without affecting proximal TCR signaling. Together, our findings indicate that optimal TCR signaling can be finely tuned by TCR affinity-dependent SHP-1 and SHP-2 activity, and this may readily be determined at the TCR/CD3 complex level. We propose that these TCR affinity-associated regulations represent potential protective mechanisms preventing high affinity TCR-mediated autoimmune diseases.

10.
Oncoimmunology ; 6(4): e1303585, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28507810

RESUMEN

Tumor-associated macrophages (TAM) are well known as a key player in the tumor microenvironment, which support cancer progression. More recently, a lineage of monocytes characterized by the expression of the TIE-2/Tek angiopoietin receptor identified a subset of circulating and tumor-associated monocytes endowed with proangiogenic activity. TIE-2 expressing monocytes (TEM) were found both in humans and mice. Here, we review the phenotypes and functions of TEM reported so far in human cancer and their potential use as markers of cancer progression and metastasis. Finally, we discuss the therapeutic approaches currently used or proposed to target TEM.

12.
Oncoimmunology ; 5(2): e1073882, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-27057438

RESUMEN

In experimental mouse models of cancer, increasingly compelling evidence point toward a contribution of tumor associated macrophages (TAM) to tumor lymphangiogenesis. Corresponding experimental observations in human cancer remain scarce although lymphatic metastasis is widely recognized as a predominant route for tumor spread. We previously showed that, in malignant tumors of untreated breast cancer (BC) patients, TIE-2-expressing monocytes (TEM) are highly proangiogenic immunosuppressive cells and that TIE-2 and VEGFR signaling pathways drive TEM immunosuppressive function. We report here that, in human BC, TEM express the canonical lymphatic markers LYVE-1, Podoplanin, VEGFR-3 and PROX-1. Critically, both TEM acquisition of lymphatic markers and insertion into lymphatic vessels were observed in tumors but not in adjacent non-neoplastic tissues, suggesting that the tumor microenvironment shapes both TEM phenotype and spatial distribution. We assessed the lymphangiogenic activity of TEM isolated from dissociated primary breast tumors in vitro and in vivo using endothelial cells (EC) sprouting assay and corneal vascularization assay, respectively. We show that, in addition to their known hemangiogenic function, TEM isolated from breast tumor display a lymphangiogenic activity. Importantly, TIE-2 and VEGFR pathways display variable contributions to TEM angiogenic and lymphangiogenic activities across BC patients; however, combination of TIE-2 and VEGFR kinase inhibitors abrogated these activities and overcame inter-patient variability. These results highlight the direct contribution of tumor TEM to the breast tumor lymphatic network and suggest a combined use of TIE-2 and VEGFR kinase inhibitors as a therapeutic approach to block hem- and lymphangiogenesis in BC.

13.
BMC Res Notes ; 9: 168, 2016 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-26979239

RESUMEN

BACKGROUND: Networks have become a popular way to conceptualize a system of interacting elements, such as electronic circuits, social communication, metabolism or gene regulation. Network inference, analysis, and modeling techniques have been developed in different areas of science and technology, such as computer science, mathematics, physics, and biology, with an active interdisciplinary exchange of concepts and approaches. However, some concepts seem to belong to a specific field without a clear transferability to other domains. At the same time, it is increasingly recognized that within some biological systems--such as the tumor microenvironment--where different types of resident and infiltrating cells interact to carry out their functions, the complexity of the system demands a theoretical framework, such as statistical inference, graph analysis and dynamical models, in order to asses and study the information derived from high-throughput experimental technologies. RESULTS: In this article we propose to adopt and adapt the concepts of influence and investment from the world of social network analysis to biological problems, and in particular to apply this approach to infer causality in the tumor microenvironment. We showed that constructing a bidirectional network of influence between cell and cell communication molecules allowed us to determine the direction of inferred regulations at the expression level and correctly recapitulate cause-effect relationships described in literature. CONCLUSIONS: This work constitutes an example of a transfer of knowledge and concepts from the world of social network analysis to biomedical research, in particular to infer network causality in biological networks. This causality elucidation is essential to model the homeostatic response of biological systems to internal and external factors, such as environmental conditions, pathogens or treatments.


Asunto(s)
Redes Reguladoras de Genes , Red Social , Microambiente Tumoral/genética , Algoritmos , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias/genética
14.
NPJ Syst Biol Appl ; 2: 16037, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-28725481

RESUMEN

Survival analyses based on the Kaplan-Meier estimate have been pervasively used to support or validate the relevance of biological mechanisms in cancer research. Recently, with the appearance of gene expression high-throughput technologies, this kind of analysis has been applied to tumor transcriptomics data. In a 'bottom-up' approach, gene-expression profiles that are associated with a deregulated pathway hypothetically involved in cancer progression are first identified and then subsequently correlated with a survival effect, which statistically supports or requires the rejection of such a hypothesis. In this work, we propose a 'top-down' approach, in which the clinical outcome (survival) is the starting point that guides the identification of deregulated biological mechanisms in cancer by a non-hypothesis-driven iterative survival analysis. We show that the application of our novel method to a population of ~2,000 breast cancer patients of the METABRIC consortium allows the identification of several well-known cancer mechanisms, such as ERBB4, HNF3A and TGFB pathways, and the investigation of their paradoxical dual effect. In addition, several novel biological mechanisms are proposed as potentially involved in cancer progression. The proposed exploratory methodology can be considered both alternative and complementary to classical 'bottom-up' approaches for validation of biological hypotheses. We propose that our method may be used to better characterize cancer, and may therefore impact the future design of therapies that are truly molecularly tailored to individual patients. The method, named SURCOMED, was implemented as a web-based tool, which is publicly available at http://surcomed.vital-it.ch. R scripts are also available at http://surcomed.sourceforge.net).

15.
Oncoimmunology ; 4(11): e1046674, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26451320

RESUMEN

By merging computational systems modeling and experimental approaches, we have uncovered treatments reprogramming pro-angiogenic monocytes present in breast tumor into immunologically potent cells capable of mediating an anti-tumor immune response. The unraveled pathways and ligands which underlie monocyte pro-angiogenic activity have a strong predictive value for breast cancer patient relapse - free survival.

16.
PLoS Comput Biol ; 11(3): e1004050, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25768678

RESUMEN

Angiogenesis plays a key role in tumor growth and cancer progression. TIE-2-expressing monocytes (TEM) have been reported to critically account for tumor vascularization and growth in mouse tumor experimental models, but the molecular basis of their pro-angiogenic activity are largely unknown. Moreover, differences in the pro-angiogenic activity between blood circulating and tumor infiltrated TEM in human patients has not been established to date, hindering the identification of specific targets for therapeutic intervention. In this work, we investigated these differences and the phenotypic reversal of breast tumor pro-angiogenic TEM to a weak pro-angiogenic phenotype by combining Boolean modelling and experimental approaches. Firstly, we show that in breast cancer patients the pro-angiogenic activity of TEM increased drastically from blood to tumor, suggesting that the tumor microenvironment shapes the highly pro-angiogenic phenotype of TEM. Secondly, we predicted in silico all minimal perturbations transitioning the highly pro-angiogenic phenotype of tumor TEM to the weak pro-angiogenic phenotype of blood TEM and vice versa. In silico predicted perturbations were validated experimentally using patient TEM. In addition, gene expression profiling of TEM transitioned to a weak pro-angiogenic phenotype confirmed that TEM are plastic cells and can be reverted to immunological potent monocytes. Finally, the relapse-free survival analysis showed a statistically significant difference between patients with tumors with high and low expression values for genes encoding transitioning proteins detected in silico and validated on patient TEM. In conclusion, the inferred TEM regulatory network accurately captured experimental TEM behavior and highlighted crosstalk between specific angiogenic and inflammatory signaling pathways of outstanding importance to control their pro-angiogenic activity. Results showed the successful in vitro reversion of such an activity by perturbation of in silico predicted target genes in tumor derived TEM, and indicated that targeting tumor TEM plasticity may constitute a novel valid therapeutic strategy in breast cancer.


Asunto(s)
Neoplasias de la Mama/fisiopatología , Modelos Biológicos , Monocitos/fisiología , Neovascularización Patológica/fisiopatología , Animales , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/mortalidad , Línea Celular , Biología Computacional , Citocinas/metabolismo , Citocinas/fisiología , Femenino , Humanos , Estimación de Kaplan-Meier , Ratones , Ratones Transgénicos , Persona de Mediana Edad , Monocitos/química , Monocitos/clasificación , Neoplasias Experimentales , Fenotipo , Transducción de Señal/fisiología
17.
Oncoimmunology ; 3: e29080, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25101222

RESUMEN

Bone marrow-derived endothelial progenitor cells (EPCs) infiltrate into sites of neovascularization in adult tissues and mature into functional blood endothelial cells (BECs) during a process called vasculogenesis. Human marrow-derived EPCs have recently been reported to display a mixed myeloid and lymphatic endothelial cell (LEC) phenotype during inflammation-induced angiogenesis; however, their role in cancer remains poorly understood. We report the in vitro differentiation of human cord blood CD133+CD34+ progenitors into podoplanin+ cells expressing both myeloid markers (CD11b, CD14) and the canonical LEC markers vascular endothelium growth factor receptor 3 (VEGFR-3), lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1), and prospero homeobox 1 (PROX-1). These podoplanin+ cells displayed sprouting behavior comparable to that of LECs in vitro and a dual hemangiogenic and lymphangiogenic activity in vivo in an endothelial cell sprouting assay and corneal vascularization assay, respectively. Furthermore, these cells expressed vascular endothelium growth factor (VEGF) family members A, -C, and -D. Thus, bone-marrow derived EPCs stimulate hemangiogenesis and lymphangiogenesis through their ability to differentiate into LECs and to produce angiogenic factors. Importantly, plasma from patients with breast cancer induced differentiation of CD34+ cord blood progenitors into hemangiogenic and lymphangiogenic CD11b+ myeloid cells, whereas plasma from healthy women did not have this effect. Consistent with these findings, circulating CD11b+ cells from breast cancer patients, but not from healthy women, displayed a similar dual angiogenic activity. Taken together, our results show that marrow-derived EPCs become hemangiogenic and lymphangiogenic upon exposure to cancer plasma. These newly identified functions of bone-marrow derived EPCs are expected to influence the diagnosis and treatment of breast cancer.

18.
IEEE Trans Nanobioscience ; 13(1): 19-30, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24594511

RESUMEN

We attempt to examine the potential of silicon nanowire memristors in the field of nanobiosensing. The memristive devices are crystalline Silicon (Si) Nanowires (NWs) with Nickel Silicide (NiSi) terminals. The nanowires are fabricated on a Silicon-on-Insulator (SOI) wafer by an Ebeam Lithography Technique (EBL) process that allows high resolution at the nanoscale. A Deep Reactive Ion Etching (DRIE) technique is used to define free-standing nanowires. The close alignment between Silicon (Si) and Nickel-Silicide (NiSi) terminals forms a Schottky-barrier at their junction. The memristive effect of the fabricated devices matches well with the memristor theory. An equivalent circuit reproducing the memristive effect in current-voltage (I-V) characteristics of our silicon nanowires is presented too. The memristive silicon nanowire devices are then functionalized with anti-human VEGF (Vascular Endothelial Growth Factor) antibody and I-V characteristics are examined for the nanowires prior to and after protein functionalization. The uptake of bio-molecules linked to the surface of the memristive NWs is confirmed by the increased voltage gap in the hysteresis curve. The effects of varying humidity conditions on the conductivity of bio-modified memristive silicon nanowires are deeply investigated.


Asunto(s)
Anticuerpos/química , Técnicas Biosensibles , Nanocables/química , Níquel/química , Compuestos de Silicona/química , Silicio/química , Anticuerpos/inmunología , Humanos , Humedad , Microscopía Electrónica de Rastreo , Modelos Teóricos , Nanocables/ultraestructura , Imagen Óptica , Factor A de Crecimiento Endotelial Vascular/inmunología
19.
Clin Cancer Res ; 19(13): 3439-49, 2013 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-23649001

RESUMEN

PURPOSE: Tumor-associated TIE-2-expressing monocytes (TEM) are highly proangiogenic cells critical for tumor vascularization. We previously showed that, in human breast cancer, TIE-2 and VEGFR pathways control proangiogenic activity of TEMs. Here, we examine the contribution of these pathways to immunosuppressive activity of TEMs. EXPERIMENTAL DESIGN: We investigated the changes in immunosuppressive activity of TEMs and gene expression in response to specific kinase inhibitors of TIE-2 and VEGFR. The ability of tumor TEMs to suppress tumor-specific T-cell response mediated by tumor dendritic cells (DC) was measured in vitro. Characterization of TEM and DC phenotype in addition to their interaction with T cells was done using confocal microscopic images analysis of breast carcinomas. RESULTS: TEMs from breast tumors are able to suppress tumor-specific immune responses. Importantly, proangiogenic and suppressive functions of TEMs are similarly driven by TIE-2 and VEGFR kinase activity. Furthermore, we show that tumor TEMs can function as antigen-presenting cells and elicit a weak proliferation of T cells. Blocking TIE-2 and VEGFR kinase activity induced TEMs to change their phenotype into cells with features of myeloid dendritic cells. We show that immunosuppressive activity of TEMs is associated with high CD86 surface expression and extensive engagement of T regulatory cells in breast tumors. TIE-2 and VEGFR kinase activity was also necessary to maintain high CD86 surface expression levels and to convert T cells into regulatory cells. CONCLUSIONS: These results suggest that TEMs are plastic cells that can be reverted from suppressive, proangiogenic cells into cells that are able to mediate an antitumoral immune response.


Asunto(s)
Neoplasias de la Mama/inmunología , Neoplasias de la Mama/metabolismo , Monocitos/inmunología , Monocitos/metabolismo , Receptor TIE-2/metabolismo , Receptores de Factores de Crecimiento Endotelial Vascular/metabolismo , Inhibidores de la Angiogénesis/farmacología , Células Presentadoras de Antígenos/inmunología , Células Presentadoras de Antígenos/metabolismo , Antígeno B7-2/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Antígeno CD11c/metabolismo , Análisis por Conglomerados , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Femenino , Perfilación de la Expresión Génica , Humanos , Inmunofenotipificación , Activación de Linfocitos/inmunología , Monocitos/efectos de los fármacos , Neovascularización Patológica/metabolismo , Fenotipo , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo
20.
PLoS One ; 7(3): e32803, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22403712

RESUMEN

Although the pathology of Morbillivirus in the central nervous system (CNS) is well described, the molecular basis of neurodegenerative events still remains poorly understood. As a model to explore Morbillivirus-mediated CNS dysfunctions, we used canine distemper virus (CDV) that we inoculated into two different cell systems: a monkey cell line (Vero) and rat primary hippocampal neurons. Importantly, the recombinant CDV used in these studies not only efficiently infects both cell types but recapitulates the uncommon, non-cytolytic cell-to-cell spread mediated by virulent CDVs in brain of dogs. Here, we demonstrated that both CDV surface glycoproteins (F and H) markedly accumulated in the endoplasmic reticulum (ER). This accumulation triggered an ER stress, characterized by increased expression of the ER resident chaperon calnexin and the proapoptotic transcription factor CHOP/GADD 153. The expression of calreticulin (CRT), another ER resident chaperon critically involved in the response to misfolded proteins and in Ca(2+) homeostasis, was also upregulated. Transient expression of recombinant CDV F and H surface glycoproteins in Vero cells and primary hippocampal neurons further confirmed a correlation between their accumulation in the ER, CRT upregulation, ER stress and disruption of ER Ca(2+) homeostasis. Furthermore, CDV infection induced CRT fragmentation with re-localisation of a CRT amino-terminal fragment, also known as vasostatin, on the surface of infected and neighbouring non-infected cells. Altogether, these results suggest that ER stress, CRT fragmentation and re-localization on the cell surface may contribute to cytotoxic effects and ensuing cell dysfunctions triggered by Morbillivirus, a mechanism that might potentially be relevant for other neurotropic viruses.


Asunto(s)
Calcio/metabolismo , Calreticulina/metabolismo , Virus del Moquillo Canino/genética , Estrés del Retículo Endoplásmico , Glicoproteínas/genética , Homeostasis , Fragmentos de Péptidos/metabolismo , Proteínas Virales/genética , Animales , Membrana Celular/metabolismo , Chlorocebus aethiops , Virus del Moquillo Canino/fisiología , Expresión Génica , Hipocampo/citología , Neuronas/metabolismo , Neuronas/virología , Transporte de Proteínas , Ratas , Regulación hacia Arriba , Células Vero
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