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1.
Cell ; 184(25): 6081-6100.e26, 2021 12 09.
Artículo en Inglés | MEDLINE | ID: mdl-34861191

RESUMEN

Chimeric antigen receptor (CAR) T cell therapy has achieved remarkable success in hematological malignancies but remains ineffective in solid tumors, due in part to CAR T cell exhaustion in the solid tumor microenvironment. To study dysfunction of mesothelin-redirected CAR T cells in pancreatic cancer, we establish a robust model of continuous antigen exposure that recapitulates hallmark features of T cell exhaustion and discover, both in vitro and in CAR T cell patients, that CAR dysregulation is associated with a CD8+ T-to-NK-like T cell transition. Furthermore, we identify a gene signature defining CAR and TCR dysregulation and transcription factors, including SOX4 and ID3 as key regulators of CAR T cell exhaustion. Our findings shed light on the plasticity of human CAR T cells and demonstrate that genetic downmodulation of ID3 and SOX4 expression can improve the efficacy of CAR T cell therapy in solid tumors by preventing or delaying CAR T cell dysfunction.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Inmunoterapia Adoptiva/métodos , Neoplasias Pancreáticas/terapia , Receptores Quiméricos de Antígenos/inmunología , Animales , Linfocitos T CD8-positivos/citología , Línea Celular Tumoral , Células HEK293 , Humanos , Proteínas Inhibidoras de la Diferenciación/inmunología , Masculino , Ratones , Ratones Noqueados , Ratones Desnudos , Ratones SCID , Proteínas de Neoplasias/inmunología , Factores de Transcripción SOXC/inmunología
2.
Immunity ; 48(5): 1029-1045.e5, 2018 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-29768164

RESUMEN

Exhausted CD8 T (Tex) cells are immunotherapy targets in chronic infection and cancer, but a comprehensive assessment of Tex cell diversity in human disease is lacking. Here, we developed a transcriptomic- and epigenetic-guided mass cytometry approach to define core exhaustion-specific genes and disease-induced changes in Tex cells in HIV and human cancer. Single-cell proteomic profiling identified 9 distinct Tex cell clusters using phenotypic, functional, transcription factor, and inhibitory receptor co-expression patterns. An exhaustion severity metric was developed and integrated with high-dimensional phenotypes to define Tex cell clusters that were present in healthy subjects, common across chronic infection and cancer or enriched in either disease, linked to disease severity, and changed with HIV therapy. Combinatorial patterns of immunotherapy targets on different Tex cell clusters were also defined. This approach and associated datasets present a resource for investigating human Tex cell biology, with implications for immune monitoring and immunomodulation in chronic infections, autoimmunity, and cancer.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Epigenómica/métodos , Citometría de Flujo/métodos , Perfilación de la Expresión Génica/métodos , Infecciones por VIH/inmunología , Neoplasias Pulmonares/inmunología , Linfocitos T CD8-positivos/metabolismo , Infecciones por VIH/genética , Infecciones por VIH/metabolismo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Proteómica/métodos , Factores de Transcripción/genética , Factores de Transcripción/inmunología , Factores de Transcripción/metabolismo
3.
Proc Natl Acad Sci U S A ; 121(13): e2319856121, 2024 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-38513098

RESUMEN

The use of lipid nanoparticles (LNP) to encapsulate and deliver mRNA has become an important therapeutic advance. In addition to vaccines, LNP-mRNA can be used in many other applications. For example, targeting the LNP with anti-CD5 antibodies (CD5/tLNP) can allow for efficient delivery of mRNA payloads to T cells to express protein. As the percentage of protein expressing T cells induced by an intravenous injection of CD5/tLNP is relatively low (4-20%), our goal was to find ways to increase mRNA-induced translation efficiency. We showed that T cell activation using an anti-CD3 antibody improved protein expression after CD5/tLNP transfection in vitro but not in vivo. T cell health and activation can be increased with cytokines, therefore, using mCherry mRNA as a reporter, we found that culturing either mouse or human T cells with the cytokine IL7 significantly improved protein expression of delivered mRNA in both CD4+ and CD8+ T cells in vitro. By pre-treating mice with systemic IL7 followed by tLNP administration, we observed significantly increased mCherry protein expression by T cells in vivo. Transcriptomic analysis of mouse T cells treated with IL7 in vitro revealed enhanced genomic pathways associated with protein translation. Improved translational ability was demonstrated by showing increased levels of protein expression after electroporation with mCherry mRNA in T cells cultured in the presence of IL7, but not with IL2 or IL15. These data show that IL7 selectively increases protein translation in T cells, and this property can be used to improve expression of tLNP-delivered mRNA in vivo.


Asunto(s)
Linfocitos T CD4-Positivos , Linfocitos T CD8-positivos , Interleucina-7 , Liposomas , Nanopartículas , Biosíntesis de Proteínas , ARN Mensajero , Animales , Humanos , Ratones , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/metabolismo , Interleucina-7/farmacología , Biosíntesis de Proteínas/efectos de los fármacos , ARN Mensajero/metabolismo , Ratones Endogámicos C57BL , Células Cultivadas , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología
4.
Nature ; 573(7774): 430-433, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31511695

RESUMEN

Fibrosis is observed in nearly every form of myocardial disease1. Upon injury, cardiac fibroblasts in the heart begin to remodel the myocardium by depositing excess extracellular matrix, resulting in increased stiffness and reduced compliance of the tissue. Excessive cardiac fibrosis is an important factor in the progression of various forms of cardiac disease and heart failure2. However, clinical interventions and therapies that target fibrosis remain limited3. Here we demonstrate the efficacy of redirected T cell immunotherapy to specifically target pathological cardiac fibrosis in mice. We find that cardiac fibroblasts that express a xenogeneic antigen can be effectively targeted and ablated by adoptive transfer of antigen-specific CD8+ T cells. Through expression analysis of the gene signatures of cardiac fibroblasts obtained from healthy and diseased human hearts, we identify an endogenous target of cardiac fibroblasts-fibroblast activation protein. Adoptive transfer of T cells that express a chimeric antigen receptor against fibroblast activation protein results in a significant reduction in cardiac fibrosis and restoration of function after injury in mice. These results provide proof-of-principle for the development of immunotherapeutic drugs for the treatment of cardiac disease.


Asunto(s)
Linfocitos T CD8-positivos , Fibrosis Endomiocárdica/terapia , Inmunoterapia Adoptiva , Animales , Antígenos de Superficie/inmunología , Linfocitos T CD8-positivos/inmunología , Fibrosis Endomiocárdica/inmunología , Fibroblastos/inmunología , Humanos , Masculino , Ratones , Ovalbúmina/inmunología , Cicatrización de Heridas
6.
Am J Physiol Lung Cell Mol Physiol ; 326(5): L646-L650, 2024 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-38529551

RESUMEN

Novel screening techniques for early detection of lung cancer are urgently needed. Profiling circulating tumor cell-free DNA (ctDNA) has emerged as a promising tool for biopsy-free tumor genotyping. However, both the scarcity and short half-life of ctDNA substantially limit the sensitivity and clinical utility of ctDNA detection methodologies. Our discovery that red blood cells (RBCs) sequester mitochondrial DNA opens a new avenue for detecting circulating nucleic acids, as RBCs represent an unrecognized reservoir of circulating nucleic acid. Here, we show that RBCs acquire tumor DNA following coculture with lung cancer cell lines harboring Kirsten rat sarcoma viral oncogene homolog (KRAS) and epidermal growth factor receptor (EGFR) mutations. RBC-bound tumor DNA is detectable in patients with early-stage non-small cell lung cancer (NSCLC) but not in healthy controls by qPCR. Our results collectively uncover a previously unrecognized yet easily accessible reservoir of tumor DNA, offering a promising foundation for future RBC-based tumor diagnostics.NEW & NOTEWORTHY We present a novel method for lung cancer detection by revealing RBCs as a reservoir for tumor DNA, overcoming the limitations of current circulating tumor ctDNA methodologies. By demonstrating that RBCs can capture tumor DNA, including critical mutations found in lung cancer, we provide a promising, biopsy-free avenue for early cancer diagnostics. This discovery opens up exciting possibilities for developing RBC-based diagnostic tools, significantly enhancing the sensitivity and clinical utility of noninvasive cancer detection.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , ADN Tumoral Circulante , Eritrocitos , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/diagnóstico , Eritrocitos/metabolismo , ADN Tumoral Circulante/genética , ADN Tumoral Circulante/sangre , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/sangre , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Mutación , Línea Celular Tumoral , Receptores ErbB/genética , Receptores ErbB/metabolismo , ADN Mitocondrial/genética , ADN Mitocondrial/sangre , Proteínas Proto-Oncogénicas p21(ras)/genética , Masculino , Femenino , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/sangre , ADN de Neoplasias/sangre , ADN de Neoplasias/genética
7.
Mol Ther ; 31(12): 3564-3578, 2023 Dec 06.
Artículo en Inglés | MEDLINE | ID: mdl-37919903

RESUMEN

Chimeric antigen receptor (CAR) T cell therapy has been successful for hematological malignancies. Still, a lack of efficacy and potential toxicities have slowed its application for other indications. Furthermore, CAR T cells undergo dynamic expansion and contraction in vivo that cannot be easily predicted or controlled. Therefore, the safety and utility of such therapies could be enhanced by engineered mechanisms that engender reversible control and quantitative monitoring. Here, we use a genetic tag based on the enzyme Escherichia coli dihydrofolate reductase (eDHFR), and derivatives of trimethoprim (TMP) to modulate and monitor CAR expression and T cell activity. We fused eDHFR to the CAR C terminus, allowing regulation with TMP-based proteolysis-targeting chimeric small molecules (PROTACs). Fusion of eDHFR to the CAR does not interfere with cell signaling or its cytotoxic function, and the addition of TMP-based PROTACs results in a reversible and dose-dependent inhibition of CAR activity via the proteosome. We show the regulation of CAR expression in vivo and demonstrate imaging of the cells with TMP radiotracers. In vitro immunogenicity assays using primary human immune cells and overlapping peptide fragments of eDHFR showed no memory immune repertoire for eDHFR. Overall, this translationally-orientied approach allows for temporal monitoring and image-guided control of cell-based therapies.


Asunto(s)
Inmunoterapia Adoptiva , Linfocitos T , Humanos , Inmunoterapia Adoptiva/métodos , Tetrahidrofolato Deshidrogenasa/genética , Tetrahidrofolato Deshidrogenasa/metabolismo , Receptores de Antígenos de Linfocitos T/genética
8.
Mol Ther ; 31(8): 2309-2325, 2023 08 02.
Artículo en Inglés | MEDLINE | ID: mdl-37312454

RESUMEN

Multiple clinical studies have treated mesothelin (MSLN)-positive solid tumors by administering MSLN-directed chimeric antigen receptor (CAR) T cells. Although these products are generally safe, efficacy is limited. Therefore, we generated and characterized a potent, fully human anti-MSLN CAR. In a phase 1 dose-escalation study of patients with solid tumors, we observed two cases of severe pulmonary toxicity following intravenous infusion of this product in the high-dose cohort (1-3 × 108 T cells per m2). Both patients demonstrated progressive hypoxemia within 48 h of infusion with clinical and laboratory findings consistent with cytokine release syndrome. One patient ultimately progressed to grade 5 respiratory failure. An autopsy revealed acute lung injury, extensive T cell infiltration, and accumulation of CAR T cells in the lungs. RNA and protein detection techniques confirmed low levels of MSLN expression by benign pulmonary epithelial cells in affected lung and lung samples obtained from other inflammatory or fibrotic conditions, indicating that pulmonary pneumocyte and not pleural expression of mesothelin may lead to dose-limiting toxicity. We suggest patient enrollment criteria and dosing regimens of MSLN-directed therapies consider the possibility of dynamic expression of mesothelin in benign lung with a special concern for patients with underlying inflammatory or fibrotic conditions.


Asunto(s)
Mesotelina , Neoplasias , Humanos , Proteínas Ligadas a GPI/genética , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Neoplasias/terapia , Linfocitos T
9.
Nat Immunol ; 12(8): 761-9, 2011 Jun 26.
Artículo en Inglés | MEDLINE | ID: mdl-21706006

RESUMEN

The migration of neutrophils into inflamed tissues is a fundamental component of innate immunity. A decisive step in this process is the polarized migration of blood neutrophils through endothelial cells (ECs) lining the venular lumen (transendothelial migration (TEM)) in a luminal-to-abluminal direction. By real-time confocal imaging, we found that neutrophils had disrupted polarized TEM ('hesitant' and 'reverse') in vivo. We noted these events in inflammation after ischemia-reperfusion injury, characterized by lower expression of junctional adhesion molecule C (JAM-C) at EC junctions, and they were enhanced by blockade or genetic deletion of JAM-C in ECs. Our results identify JAM-C as a key regulator of polarized neutrophil TEM in vivo and suggest that reverse TEM of neutrophils can contribute to the dissemination of systemic inflammation.


Asunto(s)
Moléculas de Adhesión Celular/inmunología , Endotelio Vascular/inmunología , Inmunoglobulinas/inmunología , Inflamación/inmunología , Neutrófilos/inmunología , Migración Transendotelial y Transepitelial/inmunología , Animales , Endotelio Vascular/citología , Endotelio Vascular/patología , Procesamiento de Imagen Asistido por Computador , Inflamación/patología , Ratones , Microscopía Confocal , Daño por Reperfusión/inmunología , Daño por Reperfusión/patología
10.
Mol Ther ; 29(2): 658-670, 2021 02 03.
Artículo en Inglés | MEDLINE | ID: mdl-33160076

RESUMEN

Gene-mediated cytotoxic immunotherapy (GMCI) is an immuno-oncology approach involving local delivery of a replication-deficient adenovirus expressing herpes simplex thymidine kinase (AdV-tk) followed by anti-herpetic prodrug activation that promotes immunogenic tumor cell death, antigen-presenting cell activation, and T cell stimulation. This phase I dose-escalation pilot trial assessed bronchoscopic delivery of AdV-tk in patients with suspected lung cancer who were candidates for surgery. A single intra-tumoral AdV-tk injection in three dose cohorts (maximum 1012 viral particles) was performed during diagnostic staging, followed by a 14-day course of the prodrug valacyclovir, and subsequent surgery 1 week later. Twelve patients participated after appropriate informed consent. Vector-related adverse events were minimal. Immune biomarkers were evaluated in tumor and blood before and after GMCI. Significantly increased infiltration of CD8+ T cells was found in resected tumors. Expression of activation, inhibitory, and proliferation markers, such as human leukocyte antigen (HLA)-DR, CD38, Ki67, PD-1, CD39, and CTLA-4, were significantly increased in both the tumor and peripheral CD8+ T cells. Thus, intratumoral AdV-tk injection into non-small-cell lung cancer (NSCLC) proved safe and feasible, and it effectively induced CD8+ T cell activation. These data provide a foundation for additional clinical trials of GMCI for lung cancer patients with potential benefit if combined with other immune therapies.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/terapia , Terapia Genética , Inmunoterapia/métodos , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/terapia , Adenoviridae/genética , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Citotoxicidad Inmunológica , Terapia Genética/métodos , Vectores Genéticos/administración & dosificación , Vectores Genéticos/genética , Humanos , Neoplasias Pulmonares/patología , Terapia Neoadyuvante , Timidina Quinasa/genética
11.
Int J Mol Sci ; 23(17)2022 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-36077483

RESUMEN

Although alveolar macrophages play a critical role in malignant transformation of mesothelial cells following asbestos exposure, inflammatory and oxidative processes continue to occur in the mesothelial cells lining the pleura that may contribute to the carcinogenic process. Malignant transformation of mesothelial cells following asbestos exposure occurs over several decades; however, amelioration of DNA damage, inflammation, and cell injury may impede the carcinogenic process. We have shown in an in vitro model of asbestos-induced macrophage activation that synthetic secoisolariciresinol diglucoside (LGM2605), given preventively, reduced inflammatory cascades and oxidative/nitrosative cell damage. Therefore, it was hypothesized that LGM2605 could also be effective in reducing asbestos-induced activation and the damage of pleural mesothelial cells. LGM2605 treatment (50 µM) of huma n pleural mesothelial cells was initiated 4 h prior to exposure to asbestos (crocidolite, 20 µg/cm2). Supernatant and cells were evaluated at 0, 2, 4, and 8 h post asbestos exposure for reactive oxygen species (ROS) generation, DNA damage (oxidized guanine), inflammasome activation (caspase-1 activity) and associated pro-inflammatory cytokine release (IL-1ß, IL-18, IL-6, TNFα, and HMGB1), and markers of oxidative stress (malondialdehyde (MDA) and 8-iso-prostaglandin F2a (8-iso-PGF2α). Asbestos induced a time-dependent ROS increase that was significantly (p < 0.0001) reduced (29.4%) by LGM2605 treatment. LGM2605 pretreatment also reduced levels of asbestos-induced DNA damage by 73.6% ± 1.0%. Although levels of inflammasome-activated cytokines, IL-1ß and IL-18, reached 29.2 pg/mL ± 0.7 pg/mL and 43.9 pg/mL ± 0.8 pg/mL, respectively, LGM2605 treatment significantly (p < 0.0001) reduced cytokine levels comparable to baseline (non-asbestos exposed) values (3.8 pg/mL ± 0.2 pg/mL and 5.4 pg/mL ± 0.2 pg/mL, respectively). Furthermore, levels of IL-6 and TNFα in asbestos-exposed mesothelial cells were high (289.1 pg/mL ± 2.9 pg/mL and 511.3 pg/mL ± 10.2 pg/mL, respectively), while remaining undetectable with LGM2605 pretreatment. HMGB1 (a key inflammatory mediator and initiator of malignant transformation) release was reduced 75.3% ± 0.4% by LGM2605. Levels of MDA and 8-iso-PGF2α, markers of oxidative cell injury, were significantly (p < 0.001) reduced by 80.5% ± 0.1% and 76.6% ± 0.3%, respectively. LGM2605, given preventively, reduced ROS generation, DNA damage, and inflammasome-activated cytokine release and key inflammatory mediators implicated in asbestos-induced malignant transformation of normal mesothelial cells.


Asunto(s)
Amianto , Proteína HMGB1 , Amianto/toxicidad , Butileno Glicoles , Citocinas , Daño del ADN , Glucósidos , Humanos , Inflamasomas , Inflamación/patología , Inflamación/prevención & control , Interleucina-18 , Interleucina-6 , Especies Reactivas de Oxígeno , Factor de Necrosis Tumoral alfa
12.
Mol Ther ; 28(7): 1600-1613, 2020 07 08.
Artículo en Inglés | MEDLINE | ID: mdl-32559430

RESUMEN

Chimeric antigen receptor (CAR)-modified T cells are endowed with novel antigen specificity and are most often administered to patients without an engineered mechanism to control the CAR T cells once infused. "Suicide switches" such as the small molecule-controlled, inducible caspase-9 (iCas9) system afford the ability to selectively eliminate engineered T cells; however, these approaches are designed for all-or-none, irreversible termination of an ongoing immune response. In order to permit reversible and adjustable modulation, we have created a CAR that is capable of on-demand downregulation by fusing the CAR to a previously developed ligand-induced degradation (LID) domain. Addition of a small molecule ligand triggers exposure of a cryptic degron within the LID domain, resulting in proteasomal degradation of the CAR-LID fusion protein and loss of CAR on the surface of T cells. This fusion construct allowed for reversible and "tunable" inhibition of CAR T cell activity in vitro. Delivery of the triggering molecule in CAR-LID-treated tumor-bearing mice temporarily reduced CAR activity through modulation of CAR surface expression. The ability to more flexibly modulate CAR T cell expression through a small molecule provides a platform for controlling possible adverse side effects, as well as preclinical investigations of CAR T cell biology.


Asunto(s)
Morfolinas/química , Neoplasias/terapia , Receptores Quiméricos de Antígenos/metabolismo , Proteínas Recombinantes de Fusión/química , Bibliotecas de Moléculas Pequeñas/administración & dosificación , Linfocitos T/trasplante , Animales , Línea Celular Tumoral , Proliferación Celular , Femenino , Humanos , Inmunoterapia Adoptiva , Ligandos , Ratones , Trasplante de Neoplasias , Neoplasias/inmunología , Complejo de la Endopetidasa Proteasomal/metabolismo , Dominios Proteicos , Proteolisis , Receptores Quiméricos de Antígenos/química , Proteínas Recombinantes de Fusión/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacología , Linfocitos T/citología , Linfocitos T/metabolismo
13.
Mol Ther ; 27(11): 1919-1929, 2019 11 06.
Artículo en Inglés | MEDLINE | ID: mdl-31420241

RESUMEN

This phase I study investigated the safety and activity of lentiviral-transduced chimeric antigen receptor (CAR)-modified autologous T cells redirected against mesothelin (CART-meso) in patients with malignant pleural mesothelioma, ovarian carcinoma, and pancreatic ductal adenocarcinoma. Fifteen patients with chemotherapy-refractory cancer (n = 5 per indication) were treated with a single CART-meso cell infusion. CART-meso cells were engineered by lentiviral transduction with a construct composed of the anti-mesothelin single-chain variable fragment derived from the mouse monoclonal antibody SS1 fused to intracellular signaling domains of 4-1BB and CD3zeta. Patients received 1-3 × 107 or 1-3 × 108 CART-meso cells/m2 with or without 1.5 g/m2 cyclophosphamide. Lentiviral-transduced CART-meso cells were well tolerated; one dose-limiting toxicity (grade 4, sepsis) occurred at 1-3 × 107/m2 CART-meso without cyclophosphamide. The best overall response was stable disease (11/15 patients). CART-meso cells expanded in the blood and reached peak levels by days 6-14 but persisted transiently. Cyclophosphamide pre-treatment enhanced CART-meso expansion but did not improve persistence beyond 28 days. CART-meso DNA was detected in 7/10 tumor biopsies. Human anti-chimeric antibodies (HACA) were detected in the blood of 8/14 patients. CART-meso cells were well tolerated and expanded in the blood of all patients but showed limited clinical activity. Studies evaluating a fully human anti-mesothelin CAR are ongoing.


Asunto(s)
Proteínas Ligadas a GPI/inmunología , Inmunoterapia Adoptiva , Neoplasias/inmunología , Neoplasias/terapia , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores Quiméricos de Antígenos/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Anciano , Biomarcadores , Femenino , Proteínas Ligadas a GPI/antagonistas & inhibidores , Terapia Genética , Vectores Genéticos/genética , Humanos , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Lentivirus/genética , Masculino , Mesotelina , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias/diagnóstico , Receptores de Antígenos de Linfocitos T/genética , Receptores Quiméricos de Antígenos/genética , Tomografía Computarizada por Rayos X
14.
Am J Physiol Lung Cell Mol Physiol ; 317(2): L271-L282, 2019 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-31188013

RESUMEN

Fibroblast activation protein (FAP), a cell surface serine protease, is upregulated on a subset of activated fibroblasts (often distinct from α-smooth muscle actin-expressing myofibroblasts) associated with matrix remodeling, including fibroblasts in idiopathic pulmonary fibrosis (Acharya PS, Zukas A, Chandan V, Katzenstein AL, Puré E. Hum Pathol 37: 352-360, 2006.). As FAP+ fibroblasts could be pivotal in either breakdown and/or production of collagen and other matrix components, the goal of this study was to define the role of FAP+ cells in pulmonary fibrosis in two established, but different, mouse models of chronic lung fibrosis: repetitive doses of intratracheal bleomycin and a single dose of an adenoviral vector encoding constitutively active TGF-ß1 (Ad-TGFß). To determine their role in fibrotic remodeling, FAP-expressing cells were depleted by injection of T cells expressing a chimeric antigen receptor specific for murine FAP in mice with established fibrosis. The contribution of FAP to the function of FAP-expressing cells was assessed in FAP knockout mice. Using histological analyses, quantification of soluble collagen content, and flow cytometry, we found that loss of FAP+ cells exacerbated fibrosis in the bleomycin model, a phenotype largely recapitulated by the genetic deletion of FAP, indicating that FAP plays a role in this model. In contrast, depletion of FAP+ cells or genetic deletion of FAP had little effect in the Ad-TGFß model highlighting the potential for distinct mechanisms driving fibrosis depending on the initiating insult. The role of FAP in human lung fibrosis will need to be well understood to guide the use of FAP-targeted therapeutics that are being developed.


Asunto(s)
Diferenciación Celular/efectos de los fármacos , Fibroblastos/metabolismo , Fibrosis/inducido químicamente , Factor de Crecimiento Transformador beta/metabolismo , Animales , Bleomicina/farmacología , Colágeno/metabolismo , Fibrosis Pulmonar Idiopática/patología , Pulmón/patología , Ratones Endogámicos C57BL , Ratones Transgénicos , Miofibroblastos/efectos de los fármacos , Miofibroblastos/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo
15.
Annu Rev Med ; 68: 139-152, 2017 01 14.
Artículo en Inglés | MEDLINE | ID: mdl-27860544

RESUMEN

The field of cancer immunotherapy has been re-energized by the application of chimeric antigen receptor (CAR) T cell therapy in cancers. These CAR T cells are engineered to express synthetic receptors that redirect polyclonal T cells to surface antigens for subsequent tumor elimination. Many CARs are designed with elements that augment T cell persistence and activity. To date, CAR T cells have demonstrated tremendous success in eradicating hematologic malignancies (e.g., CD19 CARs in leukemias). However, this success has yet to be extrapolated to solid tumors, and the reasons for this are being actively investigated. We characterize some of the challenges that CAR T cells have to surmount in the solid tumor microenvironment and new approaches that are being considered to overcome these hurdles.


Asunto(s)
Antígenos de Neoplasias/inmunología , Inmunoterapia Adoptiva/métodos , Neoplasias/inmunología , Neoplasias/terapia , Receptores de Antígenos de Linfocitos T/uso terapéutico , Linfocitos T/inmunología , Microambiente Tumoral/inmunología , Humanos , Tolerancia Inmunológica , Inmunidad Celular , Linfocitos Infiltrantes de Tumor/inmunología , Receptores de Antígenos de Linfocitos T/inmunología
16.
Toxicol Appl Pharmacol ; 375: 81-93, 2019 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-31022494

RESUMEN

BACKGROUND: Exposure to the Libby amphibole (LA) asbestos-like fibers found in Libby, Montana, is associated with inflammatory responses in mice and humans, and an increased risk of developing mesothelioma, asbestosis, pleural disease, and systemic autoimmune disease. Flaxseed-derived secoisolariciresinol diglucoside (SDG) has anti-inflammatory, anti-fibrotic, and antioxidant properties. We have previously identified potent protective properties of SDG against crocidolite asbestos exposure modeled in mice. The current studies aimed to extend those findings by evaluating the immunomodulatory effects of synthetic SDG (LGM2605) on LA-exposed mice. METHODS: Male and female C57BL/6 mice were given LGM2605 via gavage initiated 3 days prior to and continued for 3 days after a single intraperitoneal dose of LA fibers (200 µg) and evaluated on day 3 for inflammatory cell influx in the peritoneal cavity using flow cytometry. RESULTS: LA exposure induced a significant increase (p < 0.0001) in spleen weight and peritoneal influx of white blood cells, all of which were reduced with LGM2605 with similar trends among males and females. Levels of peritoneal PMN cells were significantly (p < 0.0001) elevated post LA exposure, and were significantly (p < 0.0001) blunted by LGM2605. Importantly, LGM2605 significantly ameliorated the LA-induced mobilization of peritoneal B1a B cells. CONCLUSIONS: LGM2605 reduced LA-induced acute inflammation and WBC trafficking supporting its possible use in mitigating downstream LA fiber-associated diseases. SUMMARY: Following acute exposure to Libby amphibole (LA) asbestos-like fibers, synthetic SDG (LGM2605), a small synthetic molecule, significantly reduced the LA-induced increase in spleen weight and peritoneal inflammation in C57BL/6 male and female mice. Our findings highlight that LGM2605 has immunomodulatory properties and may, thus, likely be a chemopreventive agent for LA-induced diseases.


Asunto(s)
Asbestos Anfíboles/toxicidad , Butileno Glicoles/farmacología , Glucósidos/farmacología , Inflamación/inducido químicamente , Inflamación/prevención & control , Animales , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Tamaño de los Órganos , Peritoneo/efectos de los fármacos , Peritoneo/patología , Bazo/efectos de los fármacos , Bazo/patología
17.
Mol Ther ; 26(5): 1198-1205, 2018 05 02.
Artículo en Inglés | MEDLINE | ID: mdl-29550074

RESUMEN

Gene-mediated cytotoxic immunotherapy (GMCI) is an immune strategy implemented through local delivery of an adenovirus-based vector expressing the thymidine kinase gene (aglatimagene besadenovec, AdV-tk) followed by anti-herpetic prodrug valacyclovir. A phase I dose escalation trial of GMCI followed by chemotherapy was conducted in patients with malignant pleural effusion (MPE). AdV-tk was administered intrapleurally (IP) in three cohorts at a dose of 1 × 1012 to 1013 vector particles. Primary endpoint was safety; secondary endpoints included response rate, progression-free survival, and overall survival. Nineteen patients were enrolled: median age 67 years; 14 with malignant mesothelioma, 4 non-small-cell lung cancer (NSCLC), and 1 breast cancer. There were no dose limiting toxicities. All 3 patients in cohort 2 experienced transient cytokine release syndrome (CRS). Addition of celecoxib in cohort 3 reduced the incidence and severity of CRS (none > grade 2). Three patients are alive (23-33 months after GMCI), and 3 of 4 NSCLC patients had prolonged disease stabilization; one is alive 29 months after GMCI, 3.6 years after initial diagnosis. GMCI was safe and well tolerated in combination with chemotherapy in patients with MPE and showed encouraging response. Further studies are warranted to determine efficacy.


Asunto(s)
Terapia Genética , Inmunoterapia , Derrame Pleural Maligno/inmunología , Derrame Pleural Maligno/terapia , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/metabolismo , Adenoviridae/genética , Anciano , Anciano de 80 o más Años , Biomarcadores , Terapia Combinada , Femenino , Terapia Genética/efectos adversos , Terapia Genética/métodos , Vectores Genéticos/genética , Humanos , Inmunoterapia/efectos adversos , Inmunoterapia/métodos , Masculino , Persona de Mediana Edad , Derrame Pleural Maligno/diagnóstico , Derrame Pleural Maligno/metabolismo , Tomografía Computarizada por Tomografía de Emisión de Positrones , Pruebas de Función Respiratoria , Resultado del Tratamiento
18.
Lancet Oncol ; 19(3): e161-e172, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29508763

RESUMEN

Malignant pleural mesothelioma is a rare cancer that is typically associated with exposure to asbestos. Patients with malignant pleural mesothelioma have poor outcomes with suboptimal therapeutic options and currently no treatment is curative. The standard frontline treatment, cisplatin plus pemetrexed chemotherapy, has only short and insufficient efficacy, and no validated treatment beyond first-line therapy is available. New therapeutic strategies are therefore needed. The addition of bevacizumab (an anti-VEGF antibody) combined with cisplatin plus pemetrexed has shown some promise. However, immunotherapy, especially immune checkpoint inhibitors, has generated a lot of excitement because of data suggesting the potential value of immune checkpoint inhibitors for patients who have failed chemotherapy. In this Review, we describe immune checkpoint inhibitors, other immunotherapies, targeted therapies, or combinations of novel drugs being investigated in malignant pleural mesothelioma, as well as the issues surrounding the selection of the best candidates for these treatments.


Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Mesotelioma/tratamiento farmacológico , Terapia Molecular Dirigida/métodos , Neoplasias Pleurales/tratamiento farmacológico , Inhibidores de la Angiogénesis/efectos adversos , Animales , Antineoplásicos Inmunológicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Humanos , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Mesotelioma/inmunología , Mesotelioma/metabolismo , Mesotelioma/patología , Mesotelioma Maligno , Terapia Molecular Dirigida/efectos adversos , Neoplasias Pleurales/inmunología , Neoplasias Pleurales/metabolismo , Neoplasias Pleurales/patología , Transducción de Señal/efectos de los fármacos , Resultado del Tratamiento
19.
Lasers Surg Med ; 50(5): 440-450, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29799130

RESUMEN

OBJECTIVE: Inflammation is a well-known consequence of surgery. Although surgical debulking of tumor is beneficial to patients, the onset of inflammation in injured tissue may impede the success of adjuvant therapies. One marker for postoperative inflammation is IL-6, which is released as a consequence of surgical injuries. IL-6 is predictive of response to many cancer therapies, and it is linked to various molecular and cellular resistance mechanisms. The purpose of this study was to establish a murine model by which therapeutic responses to photodynamic therapy (PDT) can be studied in the context of surgical inflammation. MATERIALS AND METHODS: Murine models with AB12 mesothelioma tumors were treated with either surgical resection or sham surgery with tumor incision but no resection. The timing and extent of IL-6 release in the tumor and/or serum was measured using enzyme-linked immunosorbent assay (ELISA) and compared to that measured in the serum of 27 consecutive, prospectively enrolled patients with malignant pleural mesothelioma (MPM) who underwent macroscopic complete resection (MCR). RESULTS: MPM patients showed a significant increase in IL-6 at the time MCR was completed. Similarly, IL-6 increased in the tumor and serum of mice treated with surgical resections. However, investigations that combine resection with another therapy make it necessary to grow tumors for resection to a larger volume than those that receive secondary therapy alone. As the larger size may alter tumor biology independent of the effects of surgical injury, we assessed the tumor incision model. In this model, tumor levels of IL-6 significantly increased after tumor incision. CONCLUSION: The tumor incision model induces IL-6 release as is seen in the surgical setting, yet it avoids the limitations of surgical resection models. Potential mechanisms by which surgical induction of inflammation and IL-6 could alter the nature and efficacy of tumor response to PDT are reviewed. These include a wide spectrum of molecular and cellular mechanisms through which surgically-induced IL-6 could change the effectiveness of therapies that are combined with surgery. The tumor incision model can be employed for novel investigations of the effects of surgically-induced, acute inflammation on therapeutic response to PDT (or potentially other therapies). Lasers Surg. Med. 50:440-450, 2018. © 2018 Wiley Periodicals, Inc.


Asunto(s)
Inflamación/etiología , Interleucina-6/metabolismo , Mesotelioma/terapia , Fotoquimioterapia , Neoplasias Pleurales/terapia , Complicaciones Posoperatorias/etiología , Animales , Modelos Animales de Enfermedad , Humanos , Mesotelioma/metabolismo , Ratones , Neoplasias Pleurales/metabolismo
20.
Carcinogenesis ; 37(2): 177-87, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26678224

RESUMEN

Malignant mesothelioma (MM), linked to asbestos exposure, is a highly lethal form of thoracic cancer with a long latency period, high mortality and poor treatment options. Chronic inflammation and oxidative tissue damage caused by asbestos fibers are linked to MM development. Flaxseed lignans, enriched in secoisolariciresinol diglucoside (SDG), have antioxidant, anti-inflammatory and cancer chemopreventive properties. As a prelude to chronic chemoprevention studies for MM development, we tested the ability of flaxseed lignan component (FLC) to prevent acute asbestos-induced inflammation in MM-prone Nf2(+/mu) mice. Mice (n = 16-17 per group) were placed on control (CTL) or FLC-supplemented diets initiated 7 days prior to a single intraperitoneal bolus of 400 µg of crocidolite asbestos. Three days post asbestos exposure, mice were evaluated for abdominal inflammation, proinflammatory/profibrogenic cytokine release, WBC gene expression changes and oxidative and nitrosative stress in peritoneal lavage fluid (PLF). Asbestos-exposed mice fed CTL diet developed acute inflammation, with significant (P < 0.0001) elevations in WBCs and proinflammatory/profibrogenic cytokines (IL-1ß, IL-6, TNFα, HMGB1 and active TGFß1) relative to baseline (BL) levels. Alternatively, asbestos-exposed FLC-fed mice had a significant (P < 0.0001) decrease in PLF WBCs and proinflammatory/profibrogenic cytokine levels relative to CTL-fed mice. Importantly, PLF WBC gene expression of cytokines (IL-1ß, IL-6, TNFα, HMGB1 and TGFß1) and cytokine receptors (TNFαR1 and TGFßR1) were also downregulated by FLC. FLC also significantly (P < 0.0001) blunted asbestos-induced nitrosative and oxidative stress. FLC reduces acute asbestos-induced peritoneal inflammation, nitrosative and oxidative stress and may thus prove to be a promising agent in the chemoprevention of MM.


Asunto(s)
Asbesto Crocidolita/toxicidad , Butileno Glicoles/administración & dosificación , Glucósidos/administración & dosificación , Inflamación/patología , Lignanos/administración & dosificación , Peritoneo/patología , Animales , Antioxidantes/farmacología , Cromatografía Liquida , Dieta , Suplementos Dietéticos , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Lino , Mesotelioma/patología , Ratones , Ratones Mutantes , Estrés Oxidativo/efectos de los fármacos , Lavado Peritoneal , Peritoneo/efectos de los fármacos , Lesiones Precancerosas/tratamiento farmacológico , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Semillas , Espectrometría de Masas en Tándem , Transcriptoma
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