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1.
J Immunol ; 210(9): 1281-1291, 2023 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-36920384

RESUMEN

Diacylglycerol is a potent element of intracellular secondary signaling cascades whose production is enhanced by cell-surface receptor agonism and function is regulated by enzymatic degradation by diacylglycerol kinases (DGKs). In T cells, stringent regulation of the activity of this second messenger maintains an appropriate balance between effector function and anergy. In this article, we demonstrate that DGKα is an indispensable regulator of TCR-mediated activation of CD8 T cells in lymphocytic choriomeningitis virus Clone 13 viral infection. In the absence of DGKα, Clone 13 infection in a murine model results in a pathologic, proinflammatory state and a multicellular immunopathologic host death that is predominantly driven by CD8 effector T cells.


Asunto(s)
Coriomeningitis Linfocítica , Virus de la Coriomeningitis Linfocítica , Ratones , Animales , Diacilglicerol Quinasa/genética , Diacilglicerol Quinasa/metabolismo , Diglicéridos/metabolismo , Coriomeningitis Linfocítica/metabolismo , Linfocitos T CD8-positivos/metabolismo , Células Clonales , Ratones Endogámicos C57BL , Ratones Noqueados
2.
Crit Rev Immunol ; 41(2): 21-33, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34348000

RESUMEN

Natural killer (NK) cells are major innate lymphocytes. NK cells do not require prior antigen exposure to mediate antitumor cytotoxicity or proinflammatory cytokine production. Since they use only nonclonotypic receptors, they possess high clinical value in treatment against a broad spectrum of malignancies. Irrespective of this potential, however, the transcriptional regulation that governs human NK cell development remains far from fully defined. Various environmental cues initiate a complex network of transcription factors (TFs) during their early development, one of which is GATA2, a master regulator that drives the commitment of common lymphoid progenitors (CLPs) into immature NK progenitors (NKPs). GATA2 forms a core heptad complex with six other TFs (TAL1, FLI1, RUNX1, LYL1, LMO2, and ERG) to mediate its transcriptional regulation in various cell types. Patients with GATA2 haploinsufficiency specifically lose CD56bright NK cells, with or without a reduced number of CD56dlm NK cells. Here, we review the recent progress in understanding GATA2 and its role in human NK cell development and functions.


Asunto(s)
Factor de Transcripción GATA2 , Regulación de la Expresión Génica , Células Asesinas Naturales , Factor de Transcripción GATA2/genética , Humanos
3.
Crit Rev Immunol ; 41(2): 35-44, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34348001

RESUMEN

Fanconi anemia (FA) is an inherited disorder characterized by diverse congenital malformations, progressive pancytopenia, and predisposition to hematological malignancies and solid tumors. The role of the Fanconi anemia pathway in DNA repair mechanisms and genome instability is well studied. However, the consequences of inherited mutations in genes encoding the FA proteins and the acquired mutations due to impaired DNA repair complex in immune cells are far from understood. Patients with FA show bone marrow failure (BMF) and have a higher risk of developing myelodysplasia (MDS) or acute myeloid leukemia (AML) which are directly related to having chromosomal instability in hematopoietic stem cells and their subsequent progeny. However, immune dysregulation can also be seen in FA. As mature descendants of the common lymphoid progenitor line, NK cells taken from FA patients are dysfunctional in both NK cell-mediated cytotoxicity and cytokine production. The molecular bases for these defects are yet to be determined. However, recent studies have provided directions to define the cause and effect of inherited and acquired mutations in FA patients. Here, we summarize the recent studies in the hematopoietic dysfunction, focusing on the impairment in the development and functions of NK cells in FA patients, and discuss the possible mechanisms and future directions.


Asunto(s)
Anemia de Fanconi , Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Anemia de Fanconi/genética , Humanos , Células Asesinas Naturales , Mutación
4.
Int J Mol Sci ; 20(23)2019 Nov 20.
Artículo en Inglés | MEDLINE | ID: mdl-31756921

RESUMEN

It is well established that extracellular proteins that negatively regulate T cell function, such as Cytotoxic T-Lymphocyte-Associated protein 4 (CTLA-4) and Programmed Cell Death protein 1 (PD-1), can be effectively targeted to enhance cancer immunotherapies and Chimeric Antigen Receptor T cells (CAR-T cells). Intracellular proteins that inhibit T cell receptor (TCR) signal transduction, though less well studied, are also potentially useful therapeutic targets to enhance T cell activity against tumor. Four major classes of enzymes that attenuate TCR signaling include E3 ubiquitin kinases such as the Casitas B-lineage lymphoma proteins (Cbl-b and c-Cbl), and Itchy (Itch), inhibitory tyrosine phosphatases, such as Src homology region 2 domain-containing phosphatases (SHP-1 and SHP-2), inhibitory protein kinases, such as C-terminal Src kinase (Csk), and inhibitory lipid kinases such as Src homology 2 (SH2) domain-containing inositol polyphosphate 5-phosphatase (SHIP) and Diacylglycerol kinases (DGKs). This review describes the mechanism of action of eighteen intracellular inhibitory regulatory proteins in T cells within these four classes, and assesses their potential value as clinical targets to enhance the anti-tumor activity of endogenous T cells and CAR-T cells.


Asunto(s)
Proteínas Inhibidoras de las Quinasas Dependientes de la Ciclina/metabolismo , Inmunoterapia Adoptiva/métodos , Neoplasias/terapia , Linfocitos T/inmunología , Animales , Humanos
5.
Oncologist ; 22(4): 369-374, 2017 04.
Artículo en Inglés | MEDLINE | ID: mdl-28314841

RESUMEN

Multiple factors critical to the effectiveness of academic phase I cancer programs were assessed among 16 academic centers in the U.S. Successful cancer centers were defined as having broad phase I and I/II clinical trial portfolios, multiple investigator-initiated studies, and correlative science. The most significant elements were institutional philanthropic support, experienced clinical research managers, robust institutional basic research, institutional administrative efforts to reduce bureaucratic regulatory delays, phase I navigators to inform patients and physicians of new studies, and a large cancer center patient base. New programs may benefit from a separate stand-alone operation, but mature phase I programs work well when many of the activities are transferred to disease-oriented teams. The metrics may be useful as a rubric for new and established academic phase I programs. The Oncologist 2017;22:369-374.


Asunto(s)
Centros Médicos Académicos , Neoplasias/epidemiología , Ensayos Clínicos como Asunto , Humanos , Neoplasias/genética , Desarrollo de Programa , Estados Unidos
6.
J Immunol ; 194(9): 4362-70, 2015 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-25821220

RESUMEN

Regulatory T cells (Tregs) are a subset of CD4(+) T cells that maintain immune tolerance in part by their ability to inhibit the proliferation of conventional CD4(+) T cells (Tconvs). The role of the TCR and the downstream signaling pathways required for this suppressive function of Tregs are not fully understood. To yield insight into how TCR-mediated signals influence Treg suppressive function, we assessed the ability of Tregs with altered TCR-mediated signaling capacity to inhibit Tconv proliferation. Mature Tregs deficient in Src homology 2 domain containing leukocyte protein of 76 kDa (SLP-76), an adaptor protein that nucleates the proximal signaling complex downstream of the TCR, were unable to inhibit Tconv proliferation, suggesting that TCR signaling is required for Treg suppressive function. Moreover, Tregs with defective phospholipase C γ (PLCγ) activation due to a Y145F mutation of SLP-76 were also defective in their suppressive function. Conversely, enhancement of diacylglycerol-mediated signaling downstream of PLCγ by genetic ablation of a negative regulator of diacylglycerol kinase ζ increased the suppressive ability of Tregs. Because SLP-76 is also important for integrin activation and signaling, we tested the role of integrin activation in Treg-mediated suppression. Tregs lacking the adaptor proteins adhesion and degranulation promoting adapter protein or CT10 regulator of kinase/CT10 regulator of kinase-like, which are required for TCR-mediated integrin activation, inhibited Tconv proliferation to a similar extent as wild-type Tregs. Together, these data suggest that TCR-mediated PLCγ activation, but not integrin activation, is required for Tregs to inhibit Tconv proliferation.


Asunto(s)
Inmunomodulación , Receptores de Antígenos de Linfocitos T/metabolismo , Transducción de Señal , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Diglicéridos/metabolismo , Integrinas/metabolismo , Ratones , Ratones Transgénicos , Fosfoproteínas/metabolismo , Receptores de Antígenos de Linfocitos T/genética
7.
J Biol Chem ; 286(7): 5254-65, 2011 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-21138839

RESUMEN

Modulation of T cell receptor signal transduction in CD8(+) T cells represents a novel strategy toward enhancing the immune response to tumor. Recently, levels of guanine exchange factors, RasGRP and SOS, within T cells have been shown to represent a key determinant in the regulation of the analog to the digital activation threshold of Ras. One important for regulating activation levels of RasGRP is diacylglycerol (DAG), and its levels are influenced by diacylglycerol kinase-ζ (DGKζ), which metabolizes DAG into phosphatidic acid, terminating DAG-mediated Ras signaling. We sought to determine whether DGKζ-deficient CD8(+) T cells demonstrated enhanced in vitro responses in a manner predicted by the current model of Ras activation and to evaluate whether targeting this threshold confers enhanced CD8(+) T cell responsiveness to tumor. We observed that DGKζ-deficient CD8(+) T cells conform to most predictions of the current model of how RasGRP levels influence Ras activation. But our results differ in that the EC(50) value of stimulation is not altered for any T cell receptor stimulus, a finding that suggests a further degree of complexity to how DGKζ deficiency affects signals important for Ras and ERK activation. Additionally, we found that DGKζ-deficient CD8(+) T cells demonstrate enhanced responsiveness in a subcutaneous lymphoma model, implicating the analog to a digital conversion threshold as a novel target for potential therapeutic manipulation.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Diacilglicerol Quinasa/inmunología , Diglicéridos/inmunología , Quinasas MAP Reguladas por Señal Extracelular/inmunología , Linfoma/inmunología , Modelos Inmunológicos , Neoplasias Experimentales/inmunología , Animales , Linfocitos T CD8-positivos/enzimología , Linfocitos T CD8-positivos/metabolismo , Diacilglicerol Quinasa/genética , Diacilglicerol Quinasa/metabolismo , Diglicéridos/genética , Diglicéridos/metabolismo , Activación Enzimática/genética , Activación Enzimática/inmunología , Quinasas MAP Reguladas por Señal Extracelular/genética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Linfoma/enzimología , Linfoma/genética , Linfoma/terapia , Ratones , Ratones Noqueados , Neoplasias Experimentales/enzimología , Neoplasias Experimentales/genética , Neoplasias Experimentales/terapia , Proteínas ras/inmunología , Proteínas ras/metabolismo
8.
Eur J Immunol ; 41(7): 2064-73, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21469089

RESUMEN

The adaptor protein Src homology 2 domain-containing leukocyte-specific protein of 76 kDa (SLP-76) is central to the organization of intracellular signaling downstream of the T-cell receptor (TCR). Evaluation of its role in mature, primary T cells has been hampered by developmental defects that occur in the absence of WT SLP-76 protein in thymocytes. Here, we show that following tamoxifen-regulated conditional deletion of SLP-76, mature, antigen-inexperienced T cells maintain normal TCR surface expression but fail to transduce TCR-generated signals. Conditionally deficient T cells fail to proliferate in response to antigenic stimulation or a lymphopenic environment. Mice with induced deletion of SLP-76 are resistant to induction of the CD4+ T-cell-mediated autoimmune disease experimental autoimmune encephalomyelitis. Altogether, our findings demonstrate the critical role of SLP-76-mediated signaling in initiating T-cell-directed immune responses both in vitro and in vivo and highlight the ability to analyze signaling processes in mature T cells in the absence of developmental defects.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Linfocitos T CD4-Positivos/inmunología , Fosfoproteínas/metabolismo , Transducción de Señal , Linfocitos T/inmunología , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Linfocitos T CD4-Positivos/metabolismo , Proliferación Celular , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/inmunología , Citometría de Flujo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fosfoproteínas/genética , Reacción en Cadena de la Polimerasa , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Linfocitos T/metabolismo , Tamoxifeno/farmacología
9.
Cell Mol Gastroenterol Hepatol ; 12(1): 41-58, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33548597

RESUMEN

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDA) is a lethal chemoresistant cancer that exhibits early metastatic spread. The highly immunosuppressive PDA tumor microenvironment renders patients resistant to emerging immune-targeted therapies. Building from our prior work, we evaluated stimulator of interferon genes (STING) agonist activation of PDA cell interferon-α/ß-receptor (IFNAR) signaling in systemic antitumor immune responses. METHODS: PDA cells were implanted subcutaneously to wild-type, IFNAR-, or CXCR3-knockout mice. Tumor growth was monitored, and immune responses were comprehensively profiled. RESULTS: Human and mouse STING agonist ADU-S100 reduced local and distal tumor burden and activated systemic antitumor immune responses in PDA-bearing mice. Effector T-cell infiltration and inflammatory cytokine and chemokine production, including IFN-dependent CXCR3-agonist chemokines, were elevated, whereas suppressive immune populations were decreased in treated tumors. Intratumoral STING agonist treatment also generated inflammation in distal noninjected tumors and peripheral immune tissues. STING agonist treatment of type I IFN-responsive PDA tumors engrafted to IFNAR-/- recipient mice was sufficient to contract tumors and stimulate local and systemic T-cell activation. Tumor regression and CD8+ T-cell infiltration were abolished in PDA engrafted to CXCR3-/- mice treated with STING agonist. CONCLUSIONS: These data indicate that STING agonists promote T-cell infiltration and counteract immune suppression in locally treated and distant tumors. Tumor-intrinsic type I IFN signaling initiated systemic STING-mediated antitumor inflammation and required CXCR3 expression. STING-mediated induction of systemic immune responses provides an approach to harness the immune system to treat primary and disseminated pancreatic cancers.


Asunto(s)
Proteínas de la Membrana/metabolismo , Receptor de Interferón alfa y beta/metabolismo , Receptores CXCR3/metabolismo , Animales , Línea Celular Tumoral , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptor de Interferón alfa y beta/deficiencia , Receptores CXCR3/deficiencia , Transducción de Señal
10.
Oncoimmunology ; 10(1): 1941566, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34350062

RESUMEN

Two isoforms of diacylglycerol kinases (DGKs), DGKα and DGKζ, are primarily responsible for terminating DAG-mediated activation of Ras and PKCθ pathways in T cells. A direct comparison of tumor growth between mice lacking each isoform has not been undertaken. We evaluated the growth of three syngeneic tumor cell lines in mice lacking either DGKα or DGKζ in the presence or absence of treatment with anti-PD1 and determined that (i) mice deficient in DGKζ conferred enhanced control of tumor relative to mice deficient in DGKα and (ii) deficiency of DGKζ acted additively with anti-PD1 in tumor control. Consistent with this finding, functional and RNA-sequencing analyses revealed greater changes in stimulated DGKζ-deficient T cells compared with DGKα-deficient T cells, which were enhanced relative to wildtype T cells. DGKζ also imparted greater regulation than DGKα in human T cells. Together, these data support targeting the ζ isoform of DGKs to therapeutically enhance T cell anti-tumor activity.


Asunto(s)
Diacilglicerol Quinasa , Linfocitos T , Animales , Linfocitos T CD8-positivos , Línea Celular Tumoral , Diacilglicerol Quinasa/genética , Ratones
11.
Mol Immunol ; 137: 94-104, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34242922

RESUMEN

The signaling adapter MyD88 is critical for immune cell activation in response to viral or bacterial pathogens via several TLRs, IL-1ßR and IL-18R. However, the essential role of MyD88 during activations mediated by germline-encoded NK cell receptors (NKRs), such as Ly49H or NKG2D, has yet to be investigated. To define the NK cell-intrinsic function of MyD88, we generated a novel NK cell conditional knockout mouse for MyD88 (Myd88fl/flNcr1Cre/+). Phenotypic characterization of these mice demonstrated that MyD88 is dispensable for NK cell development and maturation. However, the MyD88-deficient NK cells exhibited significantly reduced cytotoxic potentials in vivo. In addition, the lack of MyD88 significantly reduced the NKG2D-mediated inflammatory cytokine production in vitro. Consistent with this, mice lacking MyD88 were unable to respond and clear MCMV infection. Transcriptomic analyses of splenic NK cells following MCMV infection revealed that inflammatory gene signatures were upregulated in Ly49H+. In contrast, Ly49H- NK cells have significant enrichment in G2M checkpoint genes, revealing distinct transcriptomic profiles of these subsets. Our results identify a central role for MyD88 in Ly49H-dependent gene signatures, including alterations in genes regulating proliferation in Ly49H+ NK cells. In summary, our study reveals a previously unknown function of MyD88 in Ly49H-dependent signaling and in vivo functions of NK cells.


Asunto(s)
Infecciones por Herpesviridae/inmunología , Células Asesinas Naturales/inmunología , Muromegalovirus/inmunología , Factor 88 de Diferenciación Mieloide/inmunología , Animales , Proliferación Celular/fisiología , Citocinas/inmunología , Femenino , Inflamación/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Subfamilia K de Receptores Similares a Lectina de Células NK/inmunología , Receptores de Células Asesinas Naturales/inmunología , Transducción de Señal/inmunología , Transcriptoma/inmunología
12.
J Immunother Cancer ; 9(1)2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33462140

RESUMEN

BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy is an emerging option for cancer treatment, but its efficacy is limited, especially in solid tumors. This is partly because the CAR T cells become dysfunctional and exhausted in the tumor microenvironment. However, the key pathways responsible for impaired function of exhausted cells remain unclear, which is essential to overcome CAR T-cell exhaustion. METHODS: Analysis of RNA-sequencing data from CD8+ tumor-infiltrating lymphocytes (TILs) led to identification of Cbl-b as a potential target. The sequencing data were validated using a syngeneic MC38 colon cancer model. To analyze the in vivo role of Cbl-b in T-cell exhaustion, tumor growth, % PD1+Tim3+ cells, and expression of effector cytokines were analyzed in cbl-b+/+ and cbl-b-/- mice. To evaluate the therapeutic potential of Cbl-b depletion, we generated a new CAR construct, hCEAscFv-CD28-CD3ζ.GFP, that recognizes human carcinoembryonic antigen (CEA). cbl-b+/+ and cbl-b-/- CEA-CAR T cells were generated by retroviral transduction. Rag-/- mice bearing MC38-CEA cells were injected with cbl-b+/+ and cbl-b-/- ; CEA-CAR T cells, tumor growth, % PD1+Tim3+ cells and expression of effector cytokines were analyzed. RESULTS: Our results show that the E3 ubiquitin ligase Cbl-b is upregulated in exhausted (PD1+Tim3+) CD8+ TILs. CRISPR-Cas9-mediated inhibition of Cbl-b restores the effector function of exhausted CD8+ TILs. Importantly, the reduced growth of syngeneic MC38 tumors in cbl-b-/- mice was associated with a marked reduction of PD1+Tim3+ CD8+ TILs. Depletion of Cbl-b inhibited CAR T-cell exhaustion, resulting in reduced MC38-CEA tumor growth, reduced PD1+Tim3+ cells and increased expression of interferon gamma, tumor necrosis factor alpha, and increased tumor cell killing. CONCLUSION: Our studies demonstrate that deficiency of Cbl-b overcomes endogenous CD8+ T-cell exhaustion, and deletion of Cbl-b in CAR T cells renders them resistant to exhaustion. Our results could facilitate the development of efficient CAR T-cell therapy for solid tumors by targeting Cbl-b.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Neoplasias del Colon/genética , Neoplasias del Colon/terapia , Proteínas Proto-Oncogénicas c-cbl/genética , Receptores Quiméricos de Antígenos/metabolismo , Regulación hacia Arriba , Animales , Linfocitos T CD8-positivos/inmunología , Antígeno Carcinoembrionario/metabolismo , Neoplasias del Colon/inmunología , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunoterapia Adoptiva , Interferón gamma/metabolismo , Linfocitos Infiltrantes de Tumor/inmunología , Ratones , Trasplante de Neoplasias , Análisis de Secuencia de ARN , Microambiente Tumoral , Factor de Necrosis Tumoral alfa/metabolismo
13.
iScience ; 23(10): 101580, 2020 Oct 23.
Artículo en Inglés | MEDLINE | ID: mdl-33083746

RESUMEN

Immunotherapy with monoclonal antibodies targeting immune checkpoint molecules, including programmed death-1 (PD-1), PD ligand-1 (PD-L1), and cytotoxic T-lymphocyte-associated antigen (CTLA)-4, has become prominent in the treatment of many types of cancer. However, a significant number of patients treated with immune checkpoint inhibitors (ICIs) develop immune-related adverse events (irAEs). irAEs can affect any organ system, and although most are clinically manageable, irAEs can result in mortality or long-term morbidity. Factors that can predict irAEs remain elusive. Understanding the etiology of ICI-induced irAEs and ways to limit these adverse events are needed. In this review, we provide basic science and clinical insights on the mechanisms responsible for ICI efficacy and ICI-induced irAEs. We further provide insights into approaches that may uncouple irAEs from the ability of ICIs to kill tumor cells.

14.
iScience ; 23(9): 101454, 2020 Sep 25.
Artículo en Inglés | MEDLINE | ID: mdl-32858341

RESUMEN

During an immune response, natural killer (NK) cells activate specific metabolic pathways to meet the increased energetic and biosynthetic demands associated with effector functions. Here, we found in vivo activation of NK cells during Listeria monocytogenes infection-augmented transcription of genes encoding mitochondria-associated proteins in a manner dependent on the transcriptional coactivator PGC-1α. Using an Ncr1Cre-based conditional knockout mouse, we found that PGC-1α was crucial for optimal NK cell effector functions and bioenergetics, as the deletion of PGC-1α was associated with decreased cytotoxic potential and cytokine production along with altered ADP/ATP ratios. Lack of PGC-1α also significantly impaired the ability of NK cells to control B16F10 tumor growth in vivo, and subsequent gene expression analysis showed that PGC-1α mediates transcription required to maintain mitochondrial activity within the tumor microenvironment. Together, these data suggest that PGC-1α-dependent transcription of specific target genes is required for optimal NK cell function during the response to infection or tumor growth.

15.
Elife ; 92020 05 14.
Artículo en Inglés | MEDLINE | ID: mdl-32406817

RESUMEN

The transcriptional activation and repression during NK cell ontology are poorly understood. Here, using single-cell RNA-sequencing, we reveal a novel role for T-bet in suppressing the immature gene signature during murine NK cell development. Based on transcriptome, we identified five distinct NK cell clusters and define their relative developmental maturity in the bone marrow. Transcriptome-based machine-learning classifiers revealed that half of the mTORC2-deficient NK cells belongs to the least mature NK cluster. Mechanistically, loss of mTORC2 results in an increased expression of signature genes representing immature NK cells. Since mTORC2 regulates the expression of T-bet through AktS473-FoxO1 axis, we further characterized the T-bet-deficient NK cells and found an augmented immature transcriptomic signature. Moreover, deletion of Foxo1 restores the expression of T-bet and corrects the abnormal expression of immature NK genes. Collectively, our study reveals a novel role for mTORC2-AktS473-FoxO1-T-bet axis in suppressing the transcriptional signature of immature NK cells.


Asunto(s)
Células de la Médula Ósea/metabolismo , Perfilación de la Expresión Génica , Células Asesinas Naturales/metabolismo , Aprendizaje Automático , RNA-Seq , Análisis de la Célula Individual , Proteínas de Dominio T Box/genética , Transcriptoma , Animales , Células de la Médula Ósea/inmunología , Análisis por Conglomerados , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Regulación de la Expresión Génica , Genotipo , Células Asesinas Naturales/inmunología , Diana Mecanicista del Complejo 2 de la Rapamicina/deficiencia , Diana Mecanicista del Complejo 2 de la Rapamicina/genética , Ratones Endogámicos C57BL , Ratones Noqueados , Fenotipo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteína Asociada al mTOR Insensible a la Rapamicina/deficiencia , Proteína Asociada al mTOR Insensible a la Rapamicina/genética , Proteína Reguladora Asociada a mTOR/deficiencia , Proteína Reguladora Asociada a mTOR/genética , Proteínas de Dominio T Box/metabolismo
16.
Front Oncol ; 10: 460, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32351886

RESUMEN

Introduction/Background: Multimodal neoadjuvant therapy has resulted in increased rates of histologic response in pancreatic tumors and adjacent lymph nodes. The biologic significance of the collective response in the primary tumor and lymph nodes is not understood. Methods: Patients with localized PC who received neoadjuvant therapy and surgery with histologic assessment of the primary tumor and local-regional lymph nodes were included. Histopathologic response was classified using the modified Ryan score as follows: no viable cancer cells (CR), rare groups of cancer cells (nCR), residual cancer with evident tumor regression (PR), and extensive residual cancer with no evident tumor regression (NR). Nodal status was defined by number of lymph nodes (LN) with tumor metastases: N0 (0 LN), N1 (1-3), N2 (≥4). Results: Of 341 patients with localized PC who received neoadjuvant therapy and surgery, 107 (31%) received chemoradiation alone, 44 (13%) received chemotherapy alone, and 190 (56%) received chemotherapy and chemoradiation. Histopathologic response consisted of 15 (4%) CRs, 59 (17%) nCRs, 188 (55%) PRs, and 79 (23%) NRs. Patients who received chemotherapy alone had the worst responses (n = 21 for NR, 48%) as compared to patients who received chemoradiation alone (n = 25 for NR, 24%) or patients who received both therapies (n = 33 for NR, 17%) (Table 1; p = 0.001). Median overall survival for all 341 patients was 39 months; OS by histopathologic subtype was not reached (CR), 49 months (nCR), 38 months (PR), and 34 months (NR), respectively (p = 0.004). Of the 341 patients, 208 (61%) had N0 disease, 97 (28%) had N1 disease, and 36 (11%) had N2 disease. In an adjusted hazards model, modified Ryan score of PR or NR (HR: 1.71; 95% CI: 1.15-2.54; p = 0.008) and N1 (HR: 1.42; 95% CI: 1.1.02-2.01; p = 0.04), or N2 disease (HR: 2.54, 95% CI: 1.64-3.93; p < 0.001) were associated with increased risk of death. Conclusions: Neoadjuvant chemotherapy alone is associated with lower rates of pathologic response. Patients with CR or nCR have a significantly improved OS as compared to patients with PR or NR. Nodal status is the most important pathologic prognostic factor. Neoadjuvant chemoradiation may be an important driver of pathologic response.

17.
Cancer Discov ; 10(1): 40-53, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31732494

RESUMEN

Adenosine mediates immunosuppression within the tumor microenvironment through triggering adenosine 2A receptors (A2AR) on immune cells. To determine whether this pathway could be targeted as an immunotherapy, we performed a phase I clinical trial with a small-molecule A2AR antagonist. We find that this molecule can safely block adenosine signaling in vivo. In a cohort of 68 patients with renal cell cancer (RCC), we also observe clinical responses alone and in combination with an anti-PD-L1 antibody, including subjects who had progressed on PD-1/PD-L1 inhibitors. Durable clinical benefit is associated with increased recruitment of CD8+ T cells into the tumor. Treatment can also broaden the circulating T-cell repertoire. Clinical responses are associated with an adenosine-regulated gene-expression signature in pretreatment tumor biopsies. A2AR signaling, therefore, represents a targetable immune checkpoint distinct from PD-1/PD-L1 that restricts antitumor immunity. SIGNIFICANCE: This first-in-human study of an A2AR antagonist for cancer treatment establishes the safety and feasibility of targeting this pathway by demonstrating antitumor activity with single-agent and anti-PD-L1 combination therapy in patients with refractory RCC. Responding patients possess an adenosine-regulated gene-expression signature in pretreatment tumor biopsies.See related commentary by Sitkovsky, p. 16.This article is highlighted in the In This Issue feature, p. 1.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias Renales/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Receptor de Adenosina A2A/química , Terapia Recuperativa , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Carcinoma de Células Renales/patología , Femenino , Estudios de Seguimiento , Furanos/administración & dosificación , Humanos , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Pronóstico , Piridinas/administración & dosificación , Pirimidinas/administración & dosificación , Receptor de Adenosina A2A/metabolismo , Tasa de Supervivencia
18.
World J Urol ; 27(4): 471-6, 2009 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-19330334

RESUMEN

Germ cell tumors (GCTs) are the most common solid malignancy in young adult males. Approximately 28% of metastatic non-seminomatous GCTs have features that confer a poor prognosis, as defined by the International Germ Cell Consensus Classification. Five-year survival rates in poor prognosis GCTs remain about 50%. Despite numerous clinical trials testing a range of approaches, four cycles of bleomycin, etoposide, and cisplatin remain the standard of care for patients with poor-risk disease. Further improvements in the outcomes of patients with poor-risk GCTs might be achieved by incorporating targeted therapies into existing regimens, and by improving our understanding of the mechanism of cisplatin insensitivity.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de Células Germinales y Embrionarias/tratamiento farmacológico , Neoplasias Testiculares/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Bleomicina/administración & dosificación , Cisplatino/administración & dosificación , Etopósido/administración & dosificación , Humanos , Ifosfamida/administración & dosificación , Masculino , Neoplasias de Células Germinales y Embrionarias/diagnóstico , Pronóstico , Neoplasias Testiculares/diagnóstico , Vinblastina/administración & dosificación
19.
Blood Adv ; 3(7): 1154-1166, 2019 04 09.
Artículo en Inglés | MEDLINE | ID: mdl-30967391

RESUMEN

Diacylglycerol kinases (DGKs) are a family of enzymes that convert diacylglycerol (DAG) into phosphatidic acid (PA). The ζ isoform of DGK (DGKζ) has been reported to inhibit T-cell responsiveness by downregulating intracellular levels of DAG. However, its role in platelet function remains undefined. In this study, we show that DGKζ was expressed at significant levels in both platelets and megakaryocytes and that DGKζ-knockout (DGKζ-KO) mouse platelets were hyperreactive to glycoprotein VI (GPVI) agonists, as assessed by aggregation, spreading, granule secretion, and activation of relevant signal transduction molecules. In contrast, they were less responsive to thrombin. Platelets from DGKζ-KO mice accumulated faster on collagen-coated microfluidic surfaces under conditions of arterial shear and stopped blood flow faster after ferric chloride-induced carotid artery injury. Other measures of hemostasis, as measured by tail bleeding time and rotational thromboelastometry analysis, were normal. Interestingly, DGKζ deficiency led to increased GPVI expression on the platelet and megakaryocyte surfaces without affecting the expression of other platelet surface receptors. These results implicate DGKζ as a novel negative regulator of GPVI-mediated platelet activation that plays an important role in regulating thrombus formation in vivo.


Asunto(s)
Diacilglicerol Quinasa/farmacología , Activación Plaquetaria/efectos de los fármacos , Glicoproteínas de Membrana Plaquetaria/farmacología , Animales , Plaquetas/metabolismo , Diacilglicerol Quinasa/deficiencia , Diacilglicerol Quinasa/genética , Diacilglicerol Quinasa/metabolismo , Hemostasis , Humanos , Megacariocitos/metabolismo , Ratones , Ratones Noqueados , Glicoproteínas de Membrana Plaquetaria/efectos de los fármacos , Trombosis/etiología
20.
J Immunother Cancer ; 7(1): 115, 2019 04 29.
Artículo en Inglés | MEDLINE | ID: mdl-31036082

RESUMEN

Pancreatic cancer is characterized by an immune suppressive stromal reaction that creates a barrier to therapy. A murine transgenic pancreatic cancer cell line that recapitulates human disease was used to test whether a STimulator of Interferon Genes (STING) agonist could reignite immunologically inert pancreatic tumors. STING agonist treatment potently changed the tumor architecture, altered the immune profile, and increased the survival of tumor-bearing mice. Notably, STING agonist increased numbers and activity of cytotoxic T cells within tumors and decreased levels of suppressive regulatory T cells. Further, STING agonist treatment upregulated costimulatory molecule expression on cross-presenting dendritic cells and reprogrammed immune-suppressive macrophages into immune-activating subtypes. STING agonist promoted the coordinated and differential cytokine production by dendritic cells, macrophages, and pancreatic cancer cells. Cumulatively, these data demonstrate that pancreatic cancer progression is potently inhibited by STING agonist, which reignited immunologically cold pancreatic tumors to promote trafficking and activation of tumor-killing T cells.


Asunto(s)
Antineoplásicos/farmacología , Proteínas de la Membrana/agonistas , Neoplasias Pancreáticas/tratamiento farmacológico , Escape del Tumor/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos , Animales , Antineoplásicos/uso terapéutico , Línea Celular Tumoral/trasplante , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Modelos Animales de Enfermedad , Femenino , Proteínas de Homeodominio/genética , Humanos , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/inmunología , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Masculino , Proteínas de la Membrana/inmunología , Ratones , Ratones Noqueados , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/inmunología , Carga Tumoral/efectos de los fármacos , Carga Tumoral/inmunología , Microambiente Tumoral/inmunología , Xantonas/farmacología , Xantonas/uso terapéutico
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