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1.
Nat Immunol ; 14(9): 959-65, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23852275

RESUMEN

Foxp3⁺ regulatory T (Treg) cells are a crucial immunosuppressive population of CD4⁺ T cells, yet the homeostatic processes and survival programs that maintain the Treg cell pool are poorly understood. Here we report that peripheral Treg cells markedly alter their proliferative and apoptotic rates to rapidly restore numerical deficit through an interleukin 2-dependent and costimulation-dependent process. By contrast, excess Treg cells are removed by attrition, dependent on the Bim-initiated Bak- and Bax-dependent intrinsic apoptotic pathway. The antiapoptotic proteins Bcl-xL and Bcl-2 were dispensable for survival of Treg cells, whereas Mcl-1 was critical for survival of Treg cells, and the loss of this antiapoptotic protein caused fatal autoimmunity. Together, these data define the active processes by which Treg cells maintain homeostasis via critical survival pathways.


Asunto(s)
Apoptosis/inmunología , Factores de Transcripción Forkhead/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Animales , Apoptosis/genética , Supervivencia Celular/genética , Supervivencia Celular/inmunología , Femenino , Factores de Transcripción Forkhead/genética , Eliminación de Gen , Homeostasis/inmunología , Interleucina-2/metabolismo , Recuento de Linfocitos , Masculino , Ratones , Ratones Noqueados , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Proteínas Proto-Oncogénicas c-bcl-2/genética , Transducción de Señal
2.
Proc Natl Acad Sci U S A ; 119(15): e2120149119, 2022 04 12.
Artículo en Inglés | MEDLINE | ID: mdl-35394861

RESUMEN

Immunological tolerance is established and maintained by a diverse array of safeguards that work together to protect against autoimmunity. Despite the identification of numerous tolerogenic processes, the basis for cooperation among them remains poorly understood. We sought to identify synergy among several well-defined tolerance mediators that alone provide protection only from mild autoimmune symptoms in C57BL/6 mice: BIM, AIRE, CBL-B, and PD-1. Survey of a range of compound mutant mice revealed that the combined loss of the autoimmune regulator, AIRE, with PD-1 unleashed a spontaneous, lethal autoimmune disease. Pdcd1−/−Aire−/− mice succumbed to cachexia before adulthood, with near-complete destruction of the exocrine pancreas. Such fatal autoimmunity was not observed in Pdcd1−/−Bim−/−, Bim−/−Aire−/−, or Cblb−/−Bim−/− mice, suggesting that the cooperation between AIRE-mediated and PD-1­mediated tolerance was particularly potent. Immune profiling revealed largely normal development of FOXP3+ regulatory T (Treg) cells in Pdcd1−/−Aire−/− mice, yet excessive, early activation of effector T cells. Adoptive transfer experiments demonstrated that autoimmune exocrine pancreatitis was driven by conventional CD4+ T cells and could not be prevented by the cotransfer of Treg cells from wild-type mice. The development of autoimmunity in mixed bone marrow chimeras supported these observations, indicating that failure of recessive tolerance was responsible for disease. These findings reveal a potent tolerogenic axis between AIRE and PD-1 that has implications for our understanding of how immune checkpoint blockade might synergize with subclinical defects in central tolerance to elicit autoimmune disease.


Asunto(s)
Pancreatitis Autoinmune , Tolerancia Inmunológica , Tolerancia Periférica , Receptor de Muerte Celular Programada 1 , Factores de Transcripción , Animales , Pancreatitis Autoinmune/genética , Pancreatitis Autoinmune/inmunología , Autoinmunidad/genética , Tolerancia Inmunológica/genética , Ratones , Ratones Endogámicos C57BL , Tolerancia Periférica/genética , Tolerancia Periférica/inmunología , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/fisiología , Timo/inmunología , Factores de Transcripción/genética , Factores de Transcripción/fisiología , Proteína AIRE
3.
Blood ; 133(16): 1729-1741, 2019 04 18.
Artículo en Inglés | MEDLINE | ID: mdl-30755422

RESUMEN

Somatically acquired mutations in PHF6 (plant homeodomain finger 6) frequently occur in hematopoietic malignancies and often coincide with ectopic expression of TLX3. However, there is no functional evidence to demonstrate whether these mutations contribute to tumorigenesis. Similarly, the role of PHF6 in hematopoiesis is unknown. We report here that Phf6 deletion in mice resulted in a reduced number of hematopoietic stem cells (HSCs), an increased number of hematopoietic progenitor cells, and an increased proportion of cycling stem and progenitor cells. Loss of PHF6 caused increased and sustained hematopoietic reconstitution in serial transplantation experiments. Interferon-stimulated gene expression was upregulated in the absence of PHF6 in hematopoietic stem and progenitor cells. The numbers of hematopoietic progenitor cells and cycling hematopoietic stem and progenitor cells were restored to normal by combined loss of PHF6 and the interferon α and ß receptor subunit 1. Ectopic expression of TLX3 alone caused partially penetrant leukemia. TLX3 expression and loss of PHF6 combined caused fully penetrant early-onset leukemia. Our data suggest that PHF6 is a hematopoietic tumor suppressor and is important for fine-tuning hematopoietic stem and progenitor cell homeostasis.


Asunto(s)
Células Madre Hematopoyéticas/citología , Proteínas de Homeodominio/metabolismo , Leucemia/etiología , Proteínas Represoras/fisiología , Animales , Carcinogénesis , Regulación de la Expresión Génica , Humanos , Ratones , Ratones Noqueados , Receptores de Interferón , Proteínas Represoras/genética , Proteínas Supresoras de Tumor
4.
Immunity ; 36(4): 646-57, 2012 Apr 20.
Artículo en Inglés | MEDLINE | ID: mdl-22483802

RESUMEN

The immune system must distinguish viable cells from cells damaged by physical and infective processes. The damaged cell-recognition molecule Clec9A is expressed on the surface of the mouse and human dendritic cell subsets specialized for the uptake and processing of material from dead cells. Clec9A recognizes a conserved component within nucleated and nonnucleated cells, exposed when cell membranes are damaged. We have identified this Clec9A ligand as a filamentous form of actin in association with particular actin-binding domains of cytoskeletal proteins. We have determined the crystal structure of the human CLEC9A C-type lectin domain and propose a functional dimeric structure with conserved tryptophans in the ligand recognition site. Mutation of these residues ablated CLEC9A binding to damaged cells and to the isolated ligand complexes. We propose that Clec9A provides targeted recruitment of the adaptive immune system during infection and can also be utilized to enhance immune responses generated by vaccines.


Asunto(s)
Citoesqueleto de Actina/metabolismo , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Lectinas Tipo C/metabolismo , Receptores Inmunológicos/metabolismo , Receptores Mitogénicos/metabolismo , Actinas/metabolismo , Inmunidad Adaptativa , Animales , Sitios de Unión , Línea Celular , Membrana Celular/metabolismo , Células Dendríticas/citología , Femenino , Humanos , Lectinas Tipo C/química , Lectinas Tipo C/genética , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Estructura Secundaria de Proteína , Receptores Inmunológicos/genética , Receptores Mitogénicos/química , Receptores Mitogénicos/genética , Espectrina/metabolismo
5.
Immunol Cell Biol ; 97(8): 740-752, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31087793

RESUMEN

FOXP3+ regulatory T (Treg) cells are essential for immunological tolerance and immune homeostasis. Despite a great deal of interest in modulating their number and function for the treatment of autoimmune disease or cancer, the precise mechanisms that control the homeostasis of Treg cells remain unclear. We report a new ENU-induced mutant mouse, lack of costimulation (loco), with atopic dermatitis and Treg cell deficiency typical of Card11 loss-of-function mutants. Three distinct single nucleotide variants were found in the Card11 introns 2, 10 and 20 that cause the loss of CARD11 expression in these mutant mice. These mutations caused the loss of thymic-derived, Neuropilin-1+ (NRP1+ ) Treg cells in neonatal and adult loco mice; however, residual peripherally induced NRP1- Treg cells remained. These peripherally generated Treg cells could be expanded in vivo by the administration of IL-2:anti-IL-2 complexes, indicating that this key homeostatic signaling axis remained intact in CARD11-deficient Treg cells. Furthermore, these expanded Treg cells could mediate near-normal suppression of activated, conventional CD4+ T cells, suggesting that CARD11 is dispensable for Treg cell function. In addition to shedding light on the requirements for CARD11 in Treg cell homeostasis and function, these data reveal novel noncoding Card11 loss-of-function mutations that impair the expression of this critical immune-regulatory protein.


Asunto(s)
Proteínas Adaptadoras de Señalización CARD/deficiencia , Dermatitis Atópica/inmunología , Homeostasis/inmunología , Transducción de Señal/inmunología , Linfocitos T Reguladores/inmunología , Animales , Proteínas Adaptadoras de Señalización CARD/genética , Proteínas Adaptadoras de Señalización CARD/inmunología , Dermatitis Atópica/genética , Modelos Animales de Enfermedad , Etilnitrosourea/toxicidad , Factores de Transcripción Forkhead/inmunología , Factores de Transcripción Forkhead/metabolismo , Homeostasis/genética , Humanos , Intrones/efectos de los fármacos , Intrones/genética , Intrones/inmunología , Mutación con Pérdida de Función/efectos de los fármacos , Mutación con Pérdida de Función/inmunología , Ratones , Ratones Transgénicos , Mutagénesis/inmunología , Mutágenos/toxicidad , Neuropilina-1/inmunología , Neuropilina-1/metabolismo , Polimorfismo de Nucleótido Simple/efectos de los fármacos , Polimorfismo de Nucleótido Simple/inmunología , Transducción de Señal/genética , Linfocitos T Reguladores/metabolismo
6.
Blood ; 130(23): 2504-2515, 2017 12 07.
Artículo en Inglés | MEDLINE | ID: mdl-28972012

RESUMEN

T-cell differentiation is governed by interactions with thymic epithelial cells (TECs) and defects in this process undermine immune function and tolerance. To uncover new strategies to restore thymic function and adaptive immunity in immunodeficiency, we sought to determine the molecular mechanisms that control life and death decisions in TECs. Guided by gene expression profiling, we created mouse models that specifically deleted prosurvival genes in TECs. We found that although BCL-2 and BCL-XL were dispensable for TEC homeostasis, MCL-1 deficiency impacted on TECs as early as embryonic day 15.5, resulting in early thymic atrophy and T-cell lymphopenia, with near complete loss of thymic tissue by 2 months of age. MCL-1 was not necessary for TEC differentiation but was continually required for the survival of mature cortical and medullary TECs and the maintenance of thymic architecture. A screen of TEC trophic factors in organ cultures showed that epidermal growth factor upregulated MCL-1 via MAPK/ERK kinase activity, providing a molecular mechanism for the support of TEC survival. This signaling axis governing TEC survival and thymic function represents a new target for strategies for thymic protection and regeneration.


Asunto(s)
Supervivencia Celular/genética , Células Epiteliales/metabolismo , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/genética , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Timo/fisiología , Animales , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Supervivencia Celular/efectos de los fármacos , Factor de Crecimiento Epidérmico/farmacología , Células Epiteliales/efectos de los fármacos , Femenino , Expresión Génica , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Homeostasis/genética , Inmunofenotipificación , Linfopenia/genética , Masculino , Ratones , Ratones Noqueados , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Subgrupos de Linfocitos T/citología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Timocitos/citología , Timocitos/inmunología , Timocitos/metabolismo , Timo/patología , Proteína bcl-X/genética , Proteína bcl-X/metabolismo
7.
J Immunol ; 199(4): 1490-1504, 2017 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-28710252

RESUMEN

Natural killer cells constitute potent innate lymphoid cells that play a major role in both tumor immunosurveillance and viral clearance via their effector functions. A four-stage model of NK cell functional maturation has been established according to the expression of CD11b and CD27, separating mature NK (mNK) cells into distinct populations that exhibit specific phenotypic and functional properties. To identify genetic factors involved in the regulation of NK cell functional maturation, we performed a linkage analysis on F2 (B6.Rag1-/- × NOD.Rag1-/- intercross) mice. We identified six loci on chromosomes 2, 4, 7, 10, 11, and 18 that were linked to one or more mNK cell subsets. Subsequently, we performed an in silico analysis exploiting mNK cell subset microarray data, highlighting various genes and microRNAs as potential regulators of the functional maturation of NK cells. Together, the combination of our unbiased genetic linkage study and the in silico analysis positions genes known to affect NK cell biology along the specific stages of NK cell functional maturation. Moreover, this approach allowed us to uncover a novel candidate gene in the regulation of NK cell maturation, namely Trp53 Using mice deficient for Trp53, we confirm that this tumor suppressor regulates NK cell functional maturation. Additional candidate genes revealed in this study may eventually serve as targets for the modulation of NK cell functional maturation to potentiate both tumor immunosurveillance and viral clearance.


Asunto(s)
Regulación de la Expresión Génica , Ligamiento Genético , Células Asesinas Naturales/fisiología , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Animales , Antígeno CD11b/inmunología , Diferenciación Celular , Procesos de Crecimiento Celular , Células Cultivadas , Simulación por Computador , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/inmunología , Células Asesinas Naturales/inmunología , Ratones , Ratones Endogámicos NOD , MicroARNs/genética , MicroARNs/inmunología , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/inmunología
8.
Proc Natl Acad Sci U S A ; 109(40): 16270-5, 2012 Oct 02.
Artículo en Inglés | MEDLINE | ID: mdl-22988114

RESUMEN

Synthetic CpG oligonucleotides (ODN) have potent immunostimulatory properties exploited in clinical vaccine trials. How CpG ODN are captured and delivered to the intracellular receptor TLR9, however, has been elusive. Here we show that DEC-205, a multilectin receptor expressed by a variety of cells, is a receptor for CpG ODN. When CpG ODN are used as an adjuvant, mice deficient in DEC-205 have impaired dendritic cell (DC) and B-cell maturation, are unable to make some cytokines such as IL-12, and display suboptimal cytotoxic T-cell responses. We reveal that DEC-205 directly binds class B CpG ODN and enhances their uptake. The CpG-ODN binding function of DEC-205 is conserved between mouse and man, although human DEC-205 preferentially binds a specific class B CpG ODN that has been selected for human clinical trials. Our findings identify an important receptor for class B CpG ODN and reveal a unique function for DEC-205.


Asunto(s)
Antígenos CD/metabolismo , Linfocitos B/metabolismo , Células Dendríticas/metabolismo , Lectinas Tipo C/metabolismo , Oligodesoxirribonucleótidos/metabolismo , Receptores de Superficie Celular/metabolismo , Animales , Antígenos CD/genética , Células CHO , Cromatografía de Afinidad , Cromatografía en Gel , Clonación Molecular , Cricetinae , Cricetulus , Citocinas/sangre , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Humanos , Lectinas Tipo C/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microscopía Confocal , Antígenos de Histocompatibilidad Menor , Oligodesoxirribonucleótidos/genética , Receptores de Superficie Celular/genética , Especificidad de la Especie , Resonancia por Plasmón de Superficie
9.
Sci Immunol ; 7(69): eabn8041, 2022 03 25.
Artículo en Inglés | MEDLINE | ID: mdl-35333545

RESUMEN

Targeting the potent immunosuppressive properties of FOXP3+ regulatory T cells (Tregs) has substantial therapeutic potential for treating autoimmune and inflammatory diseases. Yet, the molecular mechanisms controlling Treg homeostasis, particularly during inflammation, remain unclear. We report that caspase-8 is a central regulator of Treg homeostasis in a context-specific manner that is decisive during immune responses. In mouse genetic models, targeting caspase-8 in Tregs led to accumulation of effector Tregs resistant to apoptotic cell death. Conversely, inflammation induced the MLKL-dependent necroptosis of caspase-8-deficient lymphoid and tissue Tregs, which enhanced immunity to a variety of chronic infections to promote clearance of viral or parasitic pathogens. However, improved immunity came at the risk of lethal inflammation in overwhelming infections. Caspase-8 inhibition using a clinical-stage compound revealed that human Tregs have heightened sensitivity to necroptosis compared with conventional T cells. These findings reveal a fundamental mechanism in Tregs that could be targeted to manipulate the balance between immune tolerance versus response for therapeutic benefit.


Asunto(s)
Caspasa 8/metabolismo , Tolerancia Inmunológica , Linfocitos T Reguladores , Animales , Homeostasis , Inflamación/metabolismo , Ratones
10.
Clin Cancer Res ; 26(15): 4120-4134, 2020 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-32245900

RESUMEN

PURPOSE: Although cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors significantly extend tumor response in patients with metastatic estrogen receptor-positive (ER+) breast cancer, relapse is almost inevitable. This may, in part, reflect the failure of CDK4/6 inhibitors to induce apoptotic cell death. We therefore evaluated combination therapy with ABT-199 (venetoclax), a potent and selective BCL2 inhibitor. EXPERIMENTAL DESIGN: BCL2 family member expression was assessed following treatment with endocrine therapy and the CDK4/6 inhibitor palbociclib. Functional assays were used to determine the impact of adding ABT-199 to fulvestrant and palbociclib in ER+ breast cancer cell lines, patient-derived organoid (PDO), and patient-derived xenograft (PDX) models. A syngeneic ER+ mouse mammary tumor model was used to study the effect of combination therapy on the immune system. RESULTS: Triple therapy was well tolerated and produced a superior and more durable tumor response compared with single or doublet therapy. This was associated with marked apoptosis, including of senescent cells, indicative of senolysis. Unexpectedly, ABT-199 resulted in Rb dephosphorylation and reduced G1-S cyclins, most notably at high doses, thereby intensifying the fulvestrant/palbociclib-induced cell-cycle arrest. Interestingly, a CRISPR/Cas9 screen suggested that ABT-199 could mitigate loss of Rb (and potentially other mechanisms of acquired resistance) to palbociclib. ABT-199 did not abrogate the favorable immunomodulatory effects of palbociclib in a syngeneic ER+ mammary tumor model and extended tumor response when combined with anti-PD1 therapy. CONCLUSIONS: This study illustrates the potential for targeting BCL2 in combination with CDK4/6 inhibitors and supports investigation of combination therapy in ER+ breast cancer.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias de la Mama/terapia , Terapia Neoadyuvante/métodos , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Adulto , Anciano , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apoptosis/efectos de los fármacos , Mama/patología , Mama/cirugía , Neoplasias de la Mama/patología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Línea Celular Tumoral , Quimioterapia Adyuvante/métodos , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Modelos Animales de Enfermedad , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Fulvestrant/farmacología , Fulvestrant/uso terapéutico , Humanos , Mastectomía , Ratones , Persona de Mediana Edad , Organoides , Piperazinas/farmacología , Piperazinas/uso terapéutico , Cultivo Primario de Células , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/farmacología , Piridinas/uso terapéutico , Receptores de Estrógenos/análisis , Receptores de Estrógenos/metabolismo , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto
11.
Elife ; 92020 12 02.
Artículo en Inglés | MEDLINE | ID: mdl-33264090

RESUMEN

The dendritic cell receptor Clec9A facilitates processing of dead cell-derived antigens for cross-presentation and the induction of effective CD8+ T cell immune responses. Here, we show that this process is regulated by E3 ubiquitin ligase RNF41 and define a new ubiquitin-mediated mechanism for regulation of Clec9A, reflecting the unique properties of Clec9A as a receptor specialized for delivery of antigens for cross-presentation. We reveal RNF41 is a negative regulator of Clec9A and the cross-presentation of dead cell-derived antigens by mouse dendritic cells. Intriguingly, RNF41 regulates the downstream fate of Clec9A by directly binding and ubiquitinating the extracellular domains of Clec9A. At steady-state, RNF41 ubiquitination of Clec9A facilitates interactions with ER-associated proteins and degradation machinery to control Clec9A levels. However, Clec9A interactions are altered following dead cell uptake to favor antigen presentation. These findings provide important insights into antigen cross-presentation and have implications for development of approaches to modulate immune responses.


Asunto(s)
Antígenos/inmunología , Células Dendríticas/fisiología , Lectinas Tipo C/metabolismo , Receptores Inmunológicos/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Animales , Linfocitos T CD4-Positivos , Linfocitos T CD8-positivos , Células CHO , Cricetinae , Cricetulus , Regulación de la Expresión Génica/fisiología , Lectinas Tipo C/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Unión Proteica , Receptores Inmunológicos/genética , Ubiquitina-Proteína Ligasas/genética
12.
Cancer Discov ; 9(3): 354-369, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30518523

RESUMEN

Venetoclax, a potent and selective BCL2 inhibitor, synergizes with endocrine therapy in preclinical models of ER-positive breast cancer. Using a phase Ib 3 + 3 dose-escalation and expansion study design, 33 patients with ER and BCL2-positive metastatic disease (mean prior regimens, 2; range, 0-8) were treated with daily tamoxifen (20 mg) and venetoclax (200-800 mg). Apart from uncomplicated "on-target" lymphopenia, no dose-limiting toxicities or high-grade adverse events were observed in the escalation phase (15 patients), and 800 mg was selected as the recommended phase II dose (RP2D). In the expansion phase (18 patients), few high-grade treatment-related adverse events were observed. For 24 patients treated at the RP2D, the confirmed radiologic response rate was 54% and the clinical benefit rate was 75%. Treatment responses were preempted by metabolic responses (FDG-PET) at 4 weeks and correlated with serial changes in circulating tumor DNA. Radiologic responses (40%) and clinical benefit (70%) were observed in 10 patients with plasma-detected ESR1 mutations. SIGNIFICANCE: In the first clinical study to evaluate venetoclax in a solid tumor, we demonstrate that combining venetoclax with endocrine therapy has a tolerable safety profile and elicits notable activity in ER and BCL2-positive metastatic breast cancer. These findings support further investigation of combination therapy for patients with BCL2-positive tumors.See related commentary by Drago et al., p. 323.This article is highlighted in the In This Issue feature, p. 305.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Receptor alfa de Estrógeno/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , ADN Tumoral Circulante/análisis , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Receptor alfa de Estrógeno/metabolismo , Femenino , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Sulfonamidas/administración & dosificación , Tamoxifeno/administración & dosificación , Distribución Tisular
13.
Cell Metab ; 27(4): 935-943.e4, 2018 04 03.
Artículo en Inglés | MEDLINE | ID: mdl-29526543

RESUMEN

The lung presents a highly oxidative environment, which is tolerated through engagement of tightly controlled stress response pathways. A critical stress response mediator is the transcription factor nuclear factor erythroid-2-related factor 2 (NFE2L2/NRF2), which is negatively regulated by Kelch-like ECH-associated protein 1 (KEAP1). Alterations in the KEAP1/NRF2 pathway have been identified in 23% of lung adenocarcinomas, suggesting that deregulation of the pathway is a major cancer driver. We demonstrate that inactivation of Keap1 and Pten in the mouse lung promotes adenocarcinoma formation. Notably, metabolites identified in the plasma of Keap1f/f/Ptenf/f tumor-bearing mice indicate that tumorigenesis is associated with reprogramming of the pentose phosphate pathway. Furthermore, the immune milieu was dramatically changed by Keap1 and Pten deletion, and tumor regression was achieved utilizing immune checkpoint inhibition. Thus, our study highlights the ability to exploit both metabolic and immune characteristics in the detection and treatment of lung tumors harboring KEAP1/NRF2 pathway alterations.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Proteína 1 Asociada A ECH Tipo Kelch/fisiología , Neoplasias Pulmonares , Factor 2 Relacionado con NF-E2/fisiología , Fosfohidrolasa PTEN/fisiología , Fosfatidilinositol 3-Quinasas/metabolismo , Adenocarcinoma del Pulmón/inmunología , Adenocarcinoma del Pulmón/metabolismo , Animales , Carcinogénesis , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Proteína 1 Asociada A ECH Tipo Kelch/genética , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Mutación con Pérdida de Función , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/metabolismo , Ratones Mutantes , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Vía de Pentosa Fosfato
14.
Cell Rep ; 21(4): 934-942, 2017 Oct 24.
Artículo en Inglés | MEDLINE | ID: mdl-29069601

RESUMEN

Evidence suggests that a stem-cell-driven differentiation hierarchy maintains the dynamic thymic epithelial cell (TEC) network that governs T lymphocyte development. The identification of TEC stem/progenitor cells has been a major focus in the field, and several candidates with contrasting phenotypes have been described. We sought to determine the provenance and function of the only population reported to exhibit TEC stem cell properties in the adult, a Foxn1- EpCAM- cell that generates so-called thymospheres. We provide evidence that the thymosphere-forming cell (TSFC) is not a TEC stem cell but can incorporate bystander TECs into thymospheres, providing an explanation for the epithelial activity ascribed to these structures. TSFCs were found to share a phenotype, transcriptional profile, and developmental origin with thymic fibroblasts and can generate adipocytes. In summary, this study redefines the nature of bipotent TEC stem/progenitor cells in the adult thymus and highlights a potentially important mesenchymal progenitor population.


Asunto(s)
Adipocitos/citología , Diferenciación Celular , Células Epiteliales/citología , Células Madre Mesenquimatosas/citología , Timo/citología , Adipocitos/metabolismo , Animales , Células Cultivadas , Células Epiteliales/metabolismo , Femenino , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Masculino , Células Madre Mesenquimatosas/metabolismo , Ratones , Ratones Endogámicos C57BL , Transcriptoma
15.
Sci Transl Med ; 9(393)2017 06 07.
Artículo en Inglés | MEDLINE | ID: mdl-28592566

RESUMEN

Immune checkpoint inhibitors have emerged as a potent new class of anticancer therapy. They have changed the treatment landscape for a range of tumors, particularly those with a high mutational load. To date, however, modest results have been observed in breast cancer, where tumors are rarely hypermutated. Because BRCA1-associated tumors frequently exhibit a triple-negative phenotype with extensive lymphocyte infiltration, we explored their mutational load, immune profile, and response to checkpoint inhibition in a Brca1-deficient tumor model. BRCA1-mutated triple-negative breast cancers (TNBCs) exhibited an increased somatic mutational load and greater numbers of tumor-infiltrating lymphocytes, with increased expression of immunomodulatory genes including PDCD1 (PD-1) and CTLA4, when compared to TNBCs from BRCA1-wild-type patients. Cisplatin treatment combined with dual anti-programmed death-1 and anti-cytotoxic T lymphocyte-associated antigen 4 therapy substantially augmented antitumor immunity in Brca1-deficient mice, resulting in an avid systemic and intratumoral immune response. This response involved enhanced dendritic cell activation, reduced suppressive FOXP3+ regulatory T cells, and concomitant increase in the activation of tumor-infiltrating cytotoxic CD8+ and CD4+ T cells, characterized by the induction of polyfunctional cytokine-producing T cells. Dual (but not single) checkpoint blockade together with cisplatin profoundly attenuated the growth of Brca1-deficient tumors in vivo and improved survival. These findings provide a rationale for clinical studies of combined immune checkpoint blockade in BRCA1-associated TNBC.


Asunto(s)
Proteína BRCA1/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/inmunología , Mutación/genética , Proteínas Supresoras de Tumor/genética , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antígeno B7-H1/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Proliferación Celular , Femenino , Humanos , Linfocitos Infiltrantes de Tumor/inmunología , Ratones , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/inmunología
16.
Nat Commun ; 7: 13353, 2016 11 18.
Artículo en Inglés | MEDLINE | ID: mdl-27857075

RESUMEN

The linear ubiquitin chain assembly complex (LUBAC) is essential for innate immunity in mice and humans, yet its role in adaptive immunity is unclear. Here we show that the LUBAC components HOIP, HOIL-1 and SHARPIN have essential roles in late thymocyte differentiation, FOXP3+ regulatory T (Treg)-cell development and Treg cell homeostasis. LUBAC activity is not required to prevent TNF-induced apoptosis or necroptosis but is necessary for the transcriptional programme of the penultimate stage of thymocyte differentiation. Treg cell-specific ablation of HOIP causes severe Treg cell deficiency and lethal immune pathology, revealing an ongoing requirement of LUBAC activity for Treg cell homeostasis. These data reveal stage-specific requirements for LUBAC in coordinating the signals required for T-cell differentiation.


Asunto(s)
Diferenciación Celular/fisiología , Homeostasis/fisiología , Linfocitos T/fisiología , Timo/citología , Ubiquitina/metabolismo , Animales , Secuencia de Bases , Células Cultivadas , Biología Computacional , Regulación de la Expresión Génica/fisiología , Genotipo , Ratones , Multimerización de Proteína , Procesamiento Proteico-Postraduccional , ARN/genética , Análisis de Secuencia de ARN , Linfocitos T/clasificación , Ubiquitina/química , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitinación
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