Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 220
Filtrar
Más filtros

Banco de datos
País/Región como asunto
Tipo del documento
Intervalo de año de publicación
1.
Nat Immunol ; 23(11): 1588-1599, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-36266363

RESUMEN

Dysfunctional CD8+ T cells, which have defective production of antitumor effectors, represent a major mediator of immunosuppression in the tumor microenvironment. Here, we show that SUSD2 is a negative regulator of CD8+ T cell antitumor function. Susd2-/- effector CD8+ T cells showed enhanced production of antitumor molecules, which consequently blunted tumor growth in multiple syngeneic mouse tumor models. Through a quantitative mass spectrometry assay, we found that SUSD2 interacted with interleukin (IL)-2 receptor α through sushi domain-dependent protein interactions and that this interaction suppressed the binding of IL-2, an essential cytokine for the effector functions of CD8+ T cells, to IL-2 receptor α. SUSD2 was not expressed on regulatory CD4+ T cells and did not affect the inhibitory function of these cells. Adoptive transfer of Susd2-/- chimeric antigen receptor T cells induced a robust antitumor response in mice, highlighting the potential of SUSD2 as an immunotherapy target for cancer.


Asunto(s)
Linfocitos T CD8-positivos , Neoplasias , Animales , Ratones , Línea Celular Tumoral , Inmunoterapia/métodos , Ratones Endogámicos C57BL , Neoplasias/metabolismo , Receptores de Interleucina-2/metabolismo , Transducción de Señal , Microambiente Tumoral
2.
Nature ; 619(7970): 624-631, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-37344596

RESUMEN

Loss of the Y chromosome (LOY) is observed in multiple cancer types, including 10-40% of bladder cancers1-6, but its clinical and biological significance is unknown. Here, using genomic and transcriptomic studies, we report that LOY correlates with poor prognoses in patients with bladder cancer. We performed in-depth studies of naturally occurring LOY mutant bladder cancer cells as well as those with targeted deletion of Y chromosome by CRISPR-Cas9. Y-positive (Y+) and Y-negative (Y-) tumours grew similarly in vitro, whereas Y- tumours were more aggressive than Y+ tumours in immune-competent hosts in a T cell-dependent manner. High-dimensional flow cytometric analyses demonstrated that Y- tumours promote striking dysfunction or exhaustion of CD8+ T cells in the tumour microenvironment. These findings were validated using single-nuclei RNA sequencing and spatial proteomic evaluation of human bladder cancers. Of note, compared with Y+ tumours, Y- tumours exhibited an increased response to anti-PD-1 immune checkpoint blockade therapy in both mice and patients with cancer. Together, these results demonstrate that cancer cells with LOY mutations alter T cell function, promoting T cell exhaustion and sensitizing them to PD-1-targeted immunotherapy. This work provides insights into the basic biology of LOY mutation and potential biomarkers for improving cancer immunotherapy.


Asunto(s)
Linfocitos T CD8-positivos , Deleción Cromosómica , Cromosomas Humanos Y , Escape del Tumor , Neoplasias de la Vejiga Urinaria , Animales , Humanos , Ratones , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Cromosomas Humanos Y/genética , Proteómica , Microambiente Tumoral/inmunología , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/inmunología , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/terapia , Escape del Tumor/genética , Escape del Tumor/inmunología , Perfilación de la Expresión Génica , Genómica , Pronóstico , Sistemas CRISPR-Cas , Edición Génica , Técnicas In Vitro , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Citometría de Flujo , Inmunoterapia
3.
Proc Natl Acad Sci U S A ; 121(12): e2309326121, 2024 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-38483986

RESUMEN

Hsp90s are ATP-dependent chaperones that collaborate with co-chaperones and Hsp70s to remodel client proteins. Grp94 is the ER Hsp90 homolog essential for folding multiple secretory and membrane proteins. Grp94 interacts with the ER Hsp70, BiP, although the collaboration of the ER chaperones in protein remodeling is not well understood. Grp94 undergoes large-scale conformational changes that are coupled to chaperone activity. Within Grp94, a region called the pre-N domain suppresses ATP hydrolysis and conformational transitions to the active chaperone conformation. In this work, we combined in vivo and in vitro functional assays and structural studies to characterize the chaperone mechanism of Grp94. We show that Grp94 directly collaborates with the BiP chaperone system to fold clients. Grp94's pre-N domain is not necessary for Grp94-client interactions. The folding of some Grp94 clients does not require direct interactions between Grp94 and BiP in vivo, suggesting that the canonical collaboration may not be a general chaperone mechanism for Grp94. The BiP co-chaperone DnaJB11 promotes the interaction between Grp94 and BiP, relieving the pre-N domain suppression of Grp94's ATP hydrolysis activity. In structural studies, we find that ATP binding by Grp94 alters the ATP lid conformation, while BiP binding stabilizes a partially closed Grp94 intermediate. Together, BiP and ATP push Grp94 into the active closed conformation for client folding. We also find that nucleotide binding reduces Grp94's affinity for clients, which is important for productive client folding. Alteration of client affinity by nucleotide binding may be a conserved chaperone mechanism for a subset of ER chaperones.


Asunto(s)
Proteínas HSP70 de Choque Térmico , Pliegue de Proteína , Humanos , Proteínas HSP70 de Choque Térmico/metabolismo , Proteínas de la Membrana/metabolismo , Chaperonas Moleculares/metabolismo , Nucleótidos , Adenosina Trifosfato/metabolismo
5.
J Immunol ; 211(5): 895-902, 2023 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-37459051

RESUMEN

IL-27 is a pleiotropic cytokine that exhibits stimulatory/regulatory functions on multiple lineages of immune cells and has a potential to be used as a therapeutic for cancer. We have recently demonstrated that administration of IL-27 producing adeno-associated virus (AAV-IL-27) exhibits potent inhibition of tumor growth in mouse models. In this study, we demonstrate that AAV-IL-27 treatment leads to significant expansion of CD11b+Gr1+ myeloid cells. AAV-IL-27-induced expansion of CD11b+Gr1+ cells is IL-27R-dependent and requires Stat3 signaling, but it is inhibited by Stat1 signaling. AAV-IL-27 treatment does not increase the self-renewal capacity of CD11b+Gr1+ cells but induces significant expansion of Lin-Sca1+c-Kit+ (LSK) and granulocyte-monocyte progenitor cells. Despite exhibiting significant suppression of T cells in vitro, IL-27-induced CD11b+Gr1+ cells lost the tumor-promoting activity in vivo and overall play an antitumor role. In tumors from AAV-IL-27-treated mice, CD11b+Gr1+ cells are largely F4/80+ and express high levels of MHC class I/II and M1 macrophage markers. Thus, IL-27 gene therapy induces Stat3-mediated expansion of CD11b+Gr1+ myeloid cells and promotes accumulation of M1 macrophages in the tumor microenvironment.


Asunto(s)
Interleucina-27 , Ratones , Animales , Microambiente Tumoral , Macrófagos , Células Mieloides , Linfocitos T , Antígeno CD11b
7.
Mol Cancer ; 23(1): 97, 2024 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-38730427

RESUMEN

DLL3 acts as an inhibitory ligand that downregulates Notch signaling and is upregulated by ASCL1, a transcription factor prevalent in the small-cell lung cancer (SCLC) subtype SCLC-A. Currently, the therapeutic strategies targeting DLL3 are varied, including antibody-drug conjugates (ADCs), bispecific T-cell engagers (BiTEs), and chimeric antigen receptor (CAR) T-cell therapies. Although rovalpituzumab tesirine (Rova-T) showed promise in a phase II study, it failed to produce favorable results in subsequent phase III trials, leading to the cessation of its development. Conversely, DLL3-targeted BiTEs have garnered significant clinical interest. Tarlatamab, for instance, demonstrated enhanced response rates and progression-free survival compared to the standard of care in a phase II trial; its biologics license application (BLA) is currently under US Food and Drug Administration (FDA) review. Numerous ongoing phase III studies aim to further evaluate tarlatamab's clinical efficacy, alongside the development of novel DLL3-targeted T-cell engagers, both bispecific and trispecific. CAR-T cell therapies targeting DLL3 have recently emerged and are undergoing various preclinical and early-phase clinical studies. Additionally, preclinical studies have shown promising efficacy for DLL3-targeted radiotherapy, which employs ß-particle-emitting therapeutic radioisotopes conjugated to DLL3-targeting antibodies. DLL3-targeted therapies hold substantial potential for SCLC management. Future clinical trials will be crucial for comparing treatment outcomes among various approaches and exploring combination therapies to improve patient survival outcomes.


Asunto(s)
Inmunoconjugados , Péptidos y Proteínas de Señalización Intracelular , Neoplasias Pulmonares , Radioinmunoterapia , Carcinoma Pulmonar de Células Pequeñas , Humanos , Carcinoma Pulmonar de Células Pequeñas/terapia , Carcinoma Pulmonar de Células Pequeñas/patología , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/radioterapia , Inmunoconjugados/uso terapéutico , Inmunoconjugados/farmacología , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/radioterapia , Radioinmunoterapia/métodos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Animales , Proteínas de la Membrana/metabolismo , Inmunoterapia/métodos , Medicina de Precisión , Terapia Molecular Dirigida
8.
Cancer Immunol Immunother ; 73(3): 52, 2024 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-38349405

RESUMEN

INTRODUCTION: As one of the major components of the tumor microenvironment, tumor-associated macrophages (TAMs) possess profound inhibitory activity against T cells and facilitate tumor escape from immune checkpoint blockade therapy. Converting this pro-tumorigenic toward the anti-tumorigenic phenotype thus is an important strategy for enhancing adaptive immunity against cancer. However, a plethora of mechanisms have been described for pro-tumorigenic differentiation in cancer, metabolic switches to program the anti-tumorigenic property of TAMs are elusive. MATERIALS AND METHODS: From an unbiased analysis of single-cell transcriptome data from multiple tumor models, we discovered that anti-tumorigenic TAMs uniquely express elevated levels of a specific fatty acid receptor, G-protein-coupled receptor 84 (GPR84). Genetic ablation of GPR84 in mice leads to impaired pro-inflammatory polarization of macrophages, while enhancing their anti-inflammatory phenotype. By contrast, GPR84 activation by its agonist, 6-n-octylaminouracil (6-OAU), potentiates pro-inflammatory phenotype via the enhanced STAT1 pathway. Moreover, 6-OAU treatment significantly retards tumor growth and increases the anti-tumor efficacy of anti-PD-1 therapy. CONCLUSION: Overall, we report a previously unappreciated fatty acid receptor, GPR84, that serves as an important metabolic sensing switch for orchestrating anti-tumorigenic macrophage polarization. Pharmacological agonists of GPR84 hold promise to reshape and reverse the immunosuppressive TME, and thereby restore responsiveness of cancer to overcome resistance to immune checkpoint blockade.


Asunto(s)
Inhibidores de Puntos de Control Inmunológico , Inmunoterapia , Animales , Ratones , Carcinogénesis , Ácidos Grasos , Macrófagos , Microambiente Tumoral , Macrófagos Asociados a Tumores
9.
J Immunol ; 208(9): 2239-2245, 2022 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-35418466

RESUMEN

IL-27 is a pleiotropic cytokine that exhibits stimulatory/regulatory functions on multiple lineages of immune cells including T lymphocytes. In this study, we demonstrate that IL-27 directly induces CCL5 production by T lymphocytes, particularly CD8+ T cells in vitro and in vivo. IL-27-induced CCL5 production is IL-27R-dependent. In CD4+ T cells, IL-27-induced CCL5 production was primarily dependent on Stat1 activation, whereas in CD8+ T cells, Stat1 deficiency does not abrogate CCL5 induction. A chromatin immunoprecipitation assay revealed that in the CCL5 promoter region, both putative Stat3 binding sites exhibit significant binding to Stat3, whereas only one out of four Stat1 binding sites displays moderate binding to Stat1. In tumor-bearing mice, IL-27 induced dramatic production of CCL5 in tumor-infiltrating T cells. IL-27-induced CCL5 appears to contribute to an IL-27-mediated antitumor effect. This is signified by diminished tumor inhibition in anti-CCL5- and IL-27-treated mice. Additionally, intratumor delivery of CCL5 mRNA using lipid nanoparticles significantly inhibited tumor growth. Thus, IL-27 induces robust CCL5 production by T cells, which contributes to antitumor activity.


Asunto(s)
Interleucina-27 , Animales , Linfocitos T CD8-positivos , Citocinas , Expresión Génica , Liposomas , Ratones , Nanopartículas
10.
Cancer Immunol Immunother ; 72(7): 2067-2074, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-36795122

RESUMEN

INTRODUCTION: Patients treated with immune checkpoint inhibitors (ICIs) may not response to treatment and are at risk for immune-related adverse events (irAEs). Platelet function has been linked to both oncogenesis and immune evasion. We studied the association between the change in mean platelet volume (MPV), platelet count, survival, and the risk of developing irAEs in patients with metastatic non-small cell lung cancer (NSCLC) who have received first-line ICI. METHODS: In this retrospective study, delta (∆) MPV was defined as the difference between cycle 2 and baseline MPV. Patient data were collected via chart review, and Cox proportional hazard and Kaplan-Meier method were used to assess the risk and estimate median overall survival. RESULTS: We identified 188 patients treated with first-line pembrolizumab, with or without concurrent chemotherapy. There were 80 (42.6%) patients received pembrolizumab monotherapy, and 108 (57.4%) received pembrolizumab in combination with platinum-based chemotherapy. Patients whose MPV (∆MPV ≤ 0) decreased had hazard ratio (HR) = 0.64 (95% CI 0.43-0.94) for death with p = 0.023. Patients with ∆MPV ≤ - 0.2 fL (median), there was a 58% increase in the risk of developing irAE (HR = 1.58, 95% CI 1.04-2.40, p = 0.031). Thrombocytosis at baseline and cycle 2 was associated with shorter OS with p = 0.014 and 0.039, respectively. CONCLUSION: Change in MPV after 1 cycle of pembrolizumab-based treatment was significantly associated with overall survival as well as the occurrence of irAEs in patients with metastatic NSCLC in the first-line setting. In addition, thrombocytosis was associated with poor survival.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Trombocitosis , Humanos , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , Volúmen Plaquetario Medio , Estudios Retrospectivos , Trombocitosis/tratamiento farmacológico
11.
Hepatology ; 76(6): 1587-1601, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-34986508

RESUMEN

BACKGROUD AND AIMS: Abnormalities in the tumor protein P53 (p53) gene and overexpression of mouse double minute 2 homolog (MDM2), a negative regulator of p53, are commonly observed in cancers. p53 destabilization is regulated by endoplasmic reticulum (ER) stress and unfolded protein response (UPR) in cancer. However, the mechanisms remain enigmatic. Canopy homolog 2 (CNPY2) is a key UPR initiator that primarily involved in ER stress and is highly expressed in the liver, but its functional role in regulating liver carcinogenesis is poorly understood. Therefore, we aimed to investigate the role of CNPY2 in hepartocarcinogenesis through URP-dependent p53 destabilization. APPROACH AND RESULTS: Here, we showed that CNPY2 expression is up-regulated in HCC and negatively correlated with survival rate in liver cancer patients. Deletion of Cnpy2 obliterates diethylnitrosamine (DEN)-induced HCC in mice. Mechanistic studies demonstrated that CNPY2 binds and prevents ribosome proteins from inhibiting MDM2 and enhances the UPR activity of protein kinase RNA-like endoplasmic reticulum kinase and inositol-requiring transmembrane kinase endoribonuclease-1α, leading to p53 destabilization and cell-cycle progression. In addition, transcriptome analyses uncovered that CNPY2 is also required for DEN-induced expression of oncogenes, including c-Jun and fibroblast growth factor 21. Intratumoral injection of nanoparticle-based CRISPR single-guide RNA/CRISPR-associated protein 9 mRNA against Cnpy2 has antitumor effects in HCC. CONCLUSIONS: These findings demonstrate that CNPY2 is crucial for liver oncogenesis through UPR-dependent repression of p53 and activation of oncogenes, providing insights into the design of a therapeutic target for HCC.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animales , Ratones , Carcinogénesis/genética , Carcinoma Hepatocelular/patología , Proliferación Celular , Estrés del Retículo Endoplásmico , Neoplasias Hepáticas/patología , Proteína p53 Supresora de Tumor/metabolismo , Respuesta de Proteína Desplegada
12.
Biometrics ; 79(3): 1775-1787, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-35895854

RESUMEN

High throughput spatial transcriptomics (HST) is a rapidly emerging class of experimental technologies that allow for profiling gene expression in tissue samples at or near single-cell resolution while retaining the spatial location of each sequencing unit within the tissue sample. Through analyzing HST data, we seek to identify sub-populations of cells within a tissue sample that may inform biological phenomena. Existing computational methods either ignore the spatial heterogeneity in gene expression profiles, fail to account for important statistical features such as skewness, or are heuristic-based network clustering methods that lack the inferential benefits of statistical modeling. To address this gap, we develop SPRUCE: a Bayesian spatial multivariate finite mixture model based on multivariate skew-normal distributions, which is capable of identifying distinct cellular sub-populations in HST data. We further implement a novel combination of Pólya-Gamma data augmentation and spatial random effects to infer spatially correlated mixture component membership probabilities without relying on approximate inference techniques. Via a simulation study, we demonstrate the detrimental inferential effects of ignoring skewness or spatial correlation in HST data. Using publicly available human brain HST data, SPRUCE outperforms existing methods in recovering expertly annotated brain layers. Finally, our application of SPRUCE to human breast cancer HST data indicates that SPRUCE can distinguish distinct cell populations within the tumor microenvironment. An R package spruce for fitting the proposed models is available through The Comprehensive R Archive Network.


Asunto(s)
Modelos Estadísticos , Transcriptoma , Humanos , Teorema de Bayes , Simulación por Computador , Perfilación de la Expresión Génica
13.
Cancer Immunol Immunother ; 71(5): 1157-1165, 2022 May.
Artículo en Inglés | MEDLINE | ID: mdl-34618180

RESUMEN

INTRODUCTION: Immune checkpoint inhibitors (ICI) are associated with unique immune-related adverse events (irAEs). Immune-related thrombocytopenia (irTCP) is an understudied and poorly understood toxicity; little data are available regarding either risk of irTCP or the effect of irTCP on clinical outcomes of patients treated with ICI. METHODS: We conducted a retrospective review of sequential cancer patients treated with ICI between 2011 and 2017 at our institution. All patients who received ICI alone or in combination with other systemic therapy in any line of treatment were included; those with thrombocytopenia ≥ grade 3 at baseline were excluded. We calculated the incidence of ≥ grade 3 irTCP and overall survival (OS). Patient factors associated with irTCP were assessed. RESULTS: We identified 1,038 patients that met eligibility criteria. Overall, 89 (8.6%) patients developed grade ≥ 3 thrombocytopenia; eighteen were attributed to ICI (1.73% overall). Patients who developed grade ≥ 3 irTCP had worse overall survival compared to those whose thrombocytopenia was unrelated to ICI (4.17 vs. 10.8 month; HR. 1.94, 95% CI 1.13, 3.33; log-rank p = 0.0164). Patients with grade ≥ 3 irTCP also had worse survival compared to those without thrombocytopenia (4.17 vs. 13.31 months; HR 2.22, 95% CI 1.36, 3.62; log-rank p = 0.001). The incidence of irTCP appeared lowest among those treated with PD-1/L1 monotherapy (p = 0.059) and was not associated with cancer type, smoking status, age, gender, race, or line of therapy. CONCLUSIONS: Unlike other irAEs, we found that irTCP was associated with worse overall survival. The incidence of irTCP appeared lowest among those treated with PD-1/L1 monotherapy.


Asunto(s)
Neoplasias , Trombocitopenia , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Incidencia , Neoplasias/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/uso terapéutico , Estudios Retrospectivos , Factores de Riesgo , Trombocitopenia/inducido químicamente , Trombocitopenia/tratamiento farmacológico , Trombocitopenia/epidemiología
14.
Bioinformatics ; 37(18): 3045-3047, 2021 09 29.
Artículo en Inglés | MEDLINE | ID: mdl-33595622

RESUMEN

SUMMARY: Single-cell RNA-Seq (scRNA-Seq) data is useful in discovering cell heterogeneity and signature genes in specific cell populations in cancer and other complex diseases. Specifically, the investigation of condition-specific functional gene modules (FGM) can help to understand interactive gene networks and complex biological processes in different cell clusters. QUBIC2 is recognized as one of the most efficient and effective biclustering tools for condition-specific FGM identification from scRNA-Seq data. However, its limited availability to a C implementation restricted its application to only a few downstream analysis functionalities. We developed an R package named IRIS-FGM (Integrative scRNA-Seq Interpretation System for Functional Gene Module analysis) to support the investigation of FGMs and cell clustering using scRNA-Seq data. Empowered by QUBIC2, IRIS-FGM can effectively identify condition-specific FGMs, predict cell types/clusters, uncover differentially expressed genes and perform pathway enrichment analysis. It is noteworthy that IRIS-FGM can also take Seurat objects as input, facilitating easy integration with the existing analysis pipeline. AVAILABILITY AND IMPLEMENTATION: IRIS-FGM is implemented in the R environment (as of version 3.6) with the source code freely available at https://github.com/BMEngineeR/IRISFGM. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Asunto(s)
Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Análisis de Secuencia de ARN , Programas Informáticos , Análisis de Expresión Génica de una Sola Célula , Análisis de la Célula Individual , Análisis por Conglomerados
15.
Immunol Invest ; 51(8): 2176-2214, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-36259611

RESUMEN

T-cell bispecific antibodies (T-BsAbs) are a new class of cancer immunotherapy drugs that can simultaneously bind to tumor-associated antigens on target cells and to the CD3 subunit of the T-cell receptor (TCR) on T cells. In the last decade, numerous T-BsAbs have been developed for the treatment of both hematological malignancies and solid tumors. Among them, blinatumomab has been successfully used to treat CD19 positive malignancies and has been approved by the FDA as standard care for acute lymphoblastic leukemia (ALL). However, in many clinical scenarios, the efficacy of T-BsAbs remains unsatisfactory. To further improve T-BsAb therapy, it will be crucial to better understand the factors affecting treatment efficacy and the nature of the T-BsAb-induced immune response. Herein, we first review the studies on the potential mechanisms by which T-BsAbs activate T-cells and how they elicit efficient target killing despite suboptimal costimulatory support. We focus on analyzing reports from clinical trials and preclinical studies, and summarize the factors that have been identified to impact the efficacy of T-BsAbs. Lastly, we review current and propose new approaches to improve the clinical efficacy of T-BsAbs.


Asunto(s)
Anticuerpos Biespecíficos , Neoplasias , Humanos , Anticuerpos Biespecíficos/uso terapéutico , Neoplasias/terapia , Linfocitos T , Antígenos de Neoplasias , Inmunoterapia
16.
Hepatology ; 72(3): 1073-1084, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-31860744

RESUMEN

BACKGROUND AND AIMS: Moesin, an ezrin/radixin/moesin family member, is involved in the regulation of cell adhesion, polarity, and migration by cross-linking between the actin cytoskeleton and plasma membrane. The primary effector cell in hepatic fibrosis is the hepatic stellate cell (HSC), which undergoes activation during liver injury leading to increased extracellular matrix production. APPROACH AND RESULTS: Here, we have hypothesized that moesin plays a critical role in linking the HSC cytoskeleton to the fibrogenic cascade during HSC activation. Moesin phosphorylation was up-regulated during HSC activation and fibrogenesis. Using moesin wild-type (WT) and mutant constructs (phosphomimicking T558D and nonphosphorylatable T558A), we found that cellular motility and contraction were increased in moesin WT-infected and T558D-infected cells, paralleled by an increase in smooth muscle α-actin and collagen 1 expression. In contrast, overexpression of nonphosphorylatable moesin and moesin knockout (KO) decreased cellular motility and contraction. Most importantly, moesin KO led to abrogation of liver fibrosis. The mechanism of moesin's effect was a reduction in myocardin-related transcription factor-A and serum-response factor (SRF)-mediated changes in the actin cytoskeleton, which in turn modulated the expression of matrix genes. CONCLUSIONS: Taken together, our findings suggest that the linkage between cytoskeletal dynamics and the correlated MRTF/SRF signaling pathway has a pivotal role in HSC activation and fibrogenesis.


Asunto(s)
Citoesqueleto de Actina/metabolismo , Células Estrelladas Hepáticas , Cirrosis Hepática , Proteínas de Microfilamentos/metabolismo , Factor de Respuesta Sérica/metabolismo , Transactivadores/metabolismo , Factores de Transcripción/metabolismo , Animales , Adhesión Celular , Membrana Celular/fisiología , Movimiento Celular , Polaridad Celular , Modelos Animales de Enfermedad , Matriz Extracelular/metabolismo , Células Estrelladas Hepáticas/metabolismo , Células Estrelladas Hepáticas/ultraestructura , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Ratones , Ratones Noqueados , Fragmentos de Péptidos , Fosforilación , Ratas
17.
J Immunol ; 203(5): 1105-1110, 2019 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-31358658

RESUMEN

Aside from their roles in hemostasis and thrombosis, thrombocytes or platelets also promote tumor growth via immune suppression. However, the extent to which platelet activation shapes the immunosuppressive tumor microenvironment (TME) and whether platelet inhibition can be leveraged to improve checkpoint blockade are unknown. We show in this study that platelet function in mice mediates suppression of CD8+ T cell function within the TME but not in the draining lymph nodes. Tempering platelet activation genetically reduced TGF-ß signaling in both immune and nonimmune cells in the TME, enhanced T cell frequency and function, and decreased CD11b+ myeloid cell infiltration in the tumor. Targeting platelet function pharmacologically in tumor-bearing mice with aspirin and clopidogrel in combination with PD-1 blockade improved tumor control. These results suggest that platelet function represents a continuous, supplemental mechanism of immune evasion co-opted by tumors to evade antitumor immunity and offers an attractive target for combination with immunotherapy.


Asunto(s)
Plaquetas/efectos de los fármacos , Neoplasias/inmunología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Microambiente Tumoral , Animales , Plaquetas/fisiología , Línea Celular Tumoral , Femenino , Ratones , Ratones Endogámicos C57BL , Neoplasias/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/farmacología , Linfocitos T/inmunología , Factor de Crecimiento Transformador beta1/fisiología
18.
Am J Physiol Endocrinol Metab ; 318(6): E1004-E1013, 2020 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-32208002

RESUMEN

Macrophage polarization contributes to obesity-induced insulin resistance. Glucose-regulated protein 94 (GRP94) is an endoplasmic reticulum (ER) chaperone specialized for folding and quality control of secreted and membrane proteins. To determine the role of GRP94 in macrophage polarization and insulin resistance, macrophage-specific GRP94 conditional knockout (KO) mice were challenged with a high-fat diet (HFD). Glucose tolerance, insulin sensitivity, and macrophage composition were compared with control mice. KO mice showed better glucose tolerance and increased insulin sensitivity. Adipose tissues from HFD-KO mice contained lower numbers of M1 macrophages, with lower expression of M1 macrophage markers, than wild-type (WT) mice. In vitro, WT adipocytes cocultured with KO macrophages retained insulin sensitivity, whereas those cultured with WT macrophages did not. In addition, compared with WT bone marrow-derived macrophages (BMDMs), BMDMs from GRP94 KO mice exhibited lower expression of M1 macrophage marker genes following stimulation with LPS or IFN-γ, and exhibited partially increased expression of M2 macrophage marker genes following stimulation with interleukin-4. These findings identify GRP94 as a novel regulator of M1 macrophage polarization and insulin resistance and inflammation.


Asunto(s)
Dieta Alta en Grasa , Resistencia a la Insulina/genética , Activación de Macrófagos/genética , Macrófagos/inmunología , Glicoproteínas de Membrana/genética , Obesidad/inmunología , Células 3T3-L1 , Adipocitos/metabolismo , Animales , Técnicas de Cocultivo , Citocinas/genética , Citocinas/inmunología , Prueba de Tolerancia a la Glucosa , Inflamación/genética , Inflamación/inmunología , Resistencia a la Insulina/inmunología , Interferón gamma/farmacología , Lipopolisacáridos/farmacología , Activación de Macrófagos/inmunología , Macrófagos/efectos de los fármacos , Glicoproteínas de Membrana/inmunología , Ratones , Ratones Noqueados , Obesidad/genética , Obesidad/metabolismo , ARN Mensajero/metabolismo
19.
Biol Blood Marrow Transplant ; 26(10): e247-e255, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32589921

RESUMEN

The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Myeloma Intergroup has organized an annual workshop focused on minimal residual disease (MRD) testing and immune profiling (IP) in multiple myeloma since 2016. In 2019, the workshop took place as an American Society of Hematology (ASH) Friday Scientific Workshop titled "Immune Profiling and Minimal Residual Disease Testing in Multiple Myeloma." This workshop focused on 4 main topics: the molecular and immunologic evolution of plasma cell disorders, development of new laboratory- and imaging-based MRD assessment approaches, chimeric antigen receptor T cell therapy research, and statistical and regulatory issues associated with novel clinical endpoints. In this report, we provide a summary of the workshop and discuss future directions.


Asunto(s)
Mieloma Múltiple , Médula Ósea , Humanos , Mieloma Múltiple/terapia , Neoplasia Residual
20.
J Immunol ; 211(7): 1065-1066, 2023 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-37722094
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA