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1.
Thorac Cancer ; 15(27): 1968-1971, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39139011

RESUMO

The distinction between separate primary lung carcinomas (SPLCs) and intrapulmonary metastases (IPMs) is crucial to accurate cancer staging. Histopathology-based classification cannot always determine the relatedness of multiple tumors taken from the lung. Recently, next-generation sequencing (NGS) has been used for biomarker determination, but it also has the potential to inform clonality determination among multiple tumors. Here we present a patient with three lung tumors, each diagnosed as adenocarcinoma by histopathology with a differential diagnosis of SPLC versus IPM. We pursued molecular profiling by NGS, which revealed three unique mutational patterns ruling out the possibility of clonal relatedness among the cancers. Our case supports the utility of NGS in supplementing histopathological methods to distinguish between SPLCs and IPMs and to guide treatment decisions.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Masculino , Diagnóstico Diferencial , Pessoa de Meia-Idade , Metástase Neoplásica , Feminino , Idoso , Biomarcadores Tumorais/genética
2.
Neurosurgery ; 94(2): 379-388, 2024 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-37728367

RESUMO

BACKGROUND AND OBJECTIVES: Neurological manifestations may occur in more than 80% of patients hospitalized with COVID-19 infection, including severe disruptions of the central nervous system (CNS), such as strokes, encephalitis, or seizures. Although the primary pathophysiological mechanism for the effects of COVID-19 in CNS remains unknown, evidence exists for both direct injury from neuroinvasion and indirect effects from disruptions in systemic inflammatory and coagulation pathways. In this study, we analyzed CNS tissue from living patients to better understand these processes. METHODS: With institutional review board approval and patient consent, samples that would be otherwise discarded from patients with active or recent (within 6 days of surgery) COVID-19 infection undergoing neurosurgical intervention were collected and tested for the presence of SARS-CoV-2 using immunohistochemistry, in situ hybridization, electron microscopy, and reverse transcription polymerase chain reaction. RESULTS: Five patients with perioperative mild-to-moderate COVID-19 infection met inclusion criteria (2 male, 3 female; mean age 38.8 ± 13.5 years). Neurosurgical diagnoses included a glioblastoma, a ruptured arteriovenous malformation, a ruptured posterior inferior cerebellar artery aneurysm, a middle cerebral artery occlusion, and a hemorrhagic pontine cavernous malformation. Samples analyzed included the frontal lobe cortex, olfactory nerve, arteriovenous malformation/temporal lobe parenchyma, middle cerebral artery, cerebellum, and cavernous malformation/brainstem parenchyma. Testing for the presence of SARS-CoV-2 was negative in all samples. CONCLUSION: The CNS is likely not a significant viral reservoir during mild-to-moderate COVID-19 infection, although direct neuroinvasion is not definitively excluded. Additional testing to help elucidate the relative contributions of direct and indirect pathways for CNS injury from COVID is warranted.


Assuntos
Malformações Arteriovenosas , COVID-19 , Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , SARS-CoV-2 , Sistema Nervoso Central , Tronco Encefálico
3.
Cancer Res ; 83(19): 3305-3319, 2023 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-37477508

RESUMO

A greater understanding of molecular, cellular, and immunological changes during the early stages of lung adenocarcinoma development could improve diagnostic and therapeutic approaches in patients with pulmonary nodules at risk for lung cancer. To elucidate the immunopathogenesis of early lung tumorigenesis, we evaluated surgically resected pulmonary nodules representing the spectrum of early lung adenocarcinoma as well as associated normal lung tissues using single-cell RNA sequencing and validated the results by flow cytometry and multiplex immunofluorescence (MIF). Single-cell transcriptomics revealed a significant decrease in gene expression associated with cytolytic activities of tumor-infiltrating natural killer and natural killer T cells. This was accompanied by a reduction in effector T cells and an increase of CD4+ regulatory T cells (Treg) in subsolid nodules. An independent set of resected pulmonary nodules consisting of both adenocarcinomas and associated premalignant lesions corroborated the early increment of Tregs in premalignant lesions compared with the associated normal lung tissues by MIF. Gene expression analysis indicated that cancer-associated alveolar type 2 cells and fibroblasts may contribute to the deregulation of the extracellular matrix, potentially affecting immune infiltration in subsolid nodules through ligand-receptor interactions. These findings suggest that there is a suppression of immune surveillance across the spectrum of early-stage lung adenocarcinoma. SIGNIFICANCE: Analysis of a spectrum of subsolid pulmonary nodules by single-cell RNA sequencing provides insights into the immune regulation and cell-cell interactions in the tumor microenvironment during early lung tumor development.


Assuntos
Adenocarcinoma de Pulmão , Adenocarcinoma , Neoplasias Pulmonares , Nódulos Pulmonares Múltiplos , Humanos , Monitorização Imunológica , Tomografia Computadorizada por Raios X/métodos , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Neoplasias Pulmonares/patologia , Adenocarcinoma/genética , Adenocarcinoma/patologia , Microambiente Tumoral
6.
Med Sci (Basel) ; 10(3)2022 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-35893116

RESUMO

Lung adenocarcinoma with lepidic growth pattern (LPA) is characterized by tumor cell proliferation along intact alveolar walls, and further classified as adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and invasive lepidic predominant adenocarcinoma (iLPA). Accurate diagnosis of lepidic lesions is critical for appropriate prognostication and management as five-year survival in patients with iLPA is lower than in those with AIS and MIA. We aimed to evaluate the accuracy of CT-guided core needle lung biopsy classifying LPA lesions and identify clinical and radiologic predictors of invasive disease in biopsied lesions. Thirty-four cases of adenocarcinoma with non-invasive lepidic growth pattern on core biopsy pathology that subsequently were resected between 2011 and 2018 were identified. Invasive LPA vs. non-invasive LPA (AIS or MIA) was defined based on explant pathology. Histopathology of core biopsy and resected tumor specimens was compared for concordance, and clinical, radiologic and pathologic variables were analyzed to assess for correlation with invasive disease. The majority of explanted tumors (70.6%) revealed invasive disease. Asian race (p = 0.03), history of extrathoracic malignancy (p = 0.02) and absence of smoking history (p = 0.03) were associated with invasive disease. CT-measured tumor size was not associated with invasiveness (p = 0.15). CT appearance of density (p = 0.61), shape (p = 0.78), and margin (p = 0.24) did not demonstrate a significant difference between the two subgroups. Invasiveness of tumors with lepidic growth patterns can be underestimated on transthoracic core needle biopsies. Asian race, absence of smoking, and history of extrathoracic malignancy were associated with invasive disease.


Assuntos
Adenocarcinoma in Situ , Adenocarcinoma de Pulmão , Adenocarcinoma , Neoplasias Pulmonares , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/patologia , Adenocarcinoma in Situ/patologia , Adenocarcinoma de Pulmão/diagnóstico por imagem , Adenocarcinoma de Pulmão/patologia , Humanos , Pulmão/diagnóstico por imagem , Pulmão/patologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias
7.
iScience ; 25(2): 103780, 2022 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-35169685

RESUMO

Many acute and chronic diseases affect the distal lung alveoli. Alveolar epithelial cell (AEC) lines are needed to better model these diseases. We used de-identified human remnant transplant lungs to develop a method to establish AEC lines. The lines grow well in 2-dimensional (2D) culture as epithelial monolayers expressing lung progenitor markers. In 3-dimensional (3D) culture with fibroblasts, Matrigel, and specific media conditions, the cells form alveolar-like organoids expressing mature AEC markers including aquaporin 5 (AQP5), G-protein-coupled receptor class C group 5 member A (GPRC5A), and surface marker HTII280. Single-cell RNA sequencing of an AEC line in 2D versus 3D culture revealed increased cellular heterogeneity and induction of cytokine and lipoprotein signaling in 3D organoids. Our approach yields lung progenitor lines that retain the ability to differentiate along the alveolar cell lineage despite long-term expansion and provides a valuable system to model and study the distal lung in vitro.

8.
Eur J Gastroenterol Hepatol ; 34(4): 449-456, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-34907982

RESUMO

BACKGROUND AND OBJECTIVES: Portopulmonary hypertension (PoPH) is a rare complication of portal hypertension associated with poor survival. Scarce data is available on predictors of survival in PoPH with conflicting results. We sought to characterize the outcomes and variables associated with survival in a large cohort of patients with PoPH in an American population of patients. STUDY DESIGN AND METHODS: We identified PoPH patients from the Cleveland Clinic Pulmonary Hypertension Registry between 1998 and 2019. We collected prespecified data, particularly focusing on hepatic and cardiopulmonary assessments and tested their effect on long-term survival. RESULTS: Eighty patients with PoPH with a mean ± SD age of 54 ± 10 years, (54% females) were included in the analysis. The median Model for End-Stage Liver Disease with sodium (MELD-Na) score was 13.0 (10.0-18.0) at PoPH diagnosis. World Health Association functional class III-IV was noted in 57%. Mean pulmonary arterial pressure was 47 ± 10 mmHg and pulmonary vascular resistance 6.0 ± 2.8 Woods units. A total of 63 (78.5%) patients were started on pulmonary arterial hypertension (PAH)-specific treatment during the first 6 months of diagnosis. Survival rates at 1-, 3- and 5-year were 77, 52 and 34%, respectively. Cardiopulmonary hemodynamics as well as PAH-specific treatment did not affect survival. In the multivariable model, MELD-Na, resting heart rate and the presence of hepatic encephalopathy were independent predictors of survival. CONCLUSION: PoPH patients have poor 5-year survival which is strongly associated to the severity of underlying liver disease and not to the hemodynamic severity of PoPH; therefore efforts should be focused in facilitating liver transplantation for these patients.


Assuntos
Doença Hepática Terminal , Hipertensão Portal , Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Adulto , Doença Hepática Terminal/complicações , Feminino , Humanos , Hipertensão Portal/complicações , Hipertensão Portal/diagnóstico , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/etiologia , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença
9.
Cell Stem Cell ; 27(4): 663-678.e8, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32891189

RESUMO

Mutant KRAS is a common driver in epithelial cancers. Nevertheless, molecular changes occurring early after activation of oncogenic KRAS in epithelial cells remain poorly understood. We compared transcriptional changes at single-cell resolution after KRAS activation in four sample sets. In addition to patient samples and genetically engineered mouse models, we developed organoid systems from primary mouse and human induced pluripotent stem cell-derived lung epithelial cells to model early-stage lung adenocarcinoma. In all four settings, alveolar epithelial progenitor (AT2) cells expressing oncogenic KRAS had reduced expression of mature lineage identity genes. These findings demonstrate the utility of our in vitro organoid approaches for uncovering the early consequences of oncogenic KRAS expression. This resource provides an extensive collection of datasets and describes organoid tools to study the transcriptional and proteomic changes that distinguish normal epithelial progenitor cells from early-stage lung cancer, facilitating the search for targets for KRAS-driven tumors.


Assuntos
Células-Tronco Pluripotentes Induzidas , Organoides , Animais , Humanos , Pulmão , Camundongos , Proteômica , Proteínas Proto-Oncogênicas p21(ras)/genética
10.
Am J Transl Res ; 12(2): 409-427, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32194893

RESUMO

Oncogenic KRAS mutations are frequently found in non-small cell lung carcinoma (NSCLC) and cause constitutive activation of the MEK-ERK pathway. Many cancer types have been shown to overexpress PD-L1 to escape immune surveillance. FRA1 is a MEK/ERK-dependent oncogenic transcription factor and a member of the AP-1 transcriptional factor superfamily. This study assesses the hypothesis that KRAS mutation directly regulates PD-L1 expression through the MEK-ERK pathway mediated by FRA1. Premalignant human bronchial epithelial cell (HBEC) lines harboring the KRAS mutationV12, EGFR mutation, p53 knock-down, or both KRAS mutation and p53 knock-down were tested for levels of PD-L1, FRA1, and ERK activation (pERK). Our results showed that KRAS mutation alone, but not other genetic alterations, induced significantly higher expression of PD-L1 compared to its vector counterparts. The increased PD-L1 expression in the KRAS mutated cells was dramatically reduced by inhibition of ERK activation. Furthermore, the MEK-ERK pathway-dependent PD-L1 expression was markedly reduced by FRA1 silencing. Interestingly, FRA1 silencing led to inhibition of ERK activation, indicating that FRA1 plays a role in PD-L1 regulation via positive feedback of ERK activation. Correlation of PD-L1 and FRA1 mRNA expression was validated using human lung cancer specimens from The Cancer Genome Atlas (TCGA) and established NSCLC cell lines from Cancer Cell Line Encyclopedia (CCLE). FRA1 expression was significantly associated with PD-L1 expression, and high FRA1 expression was correlated with poor overall survival. Our findings suggest that oncogenic KRAS-driven PD-L1 expression is dependent on MEK-ERK and FRA1 in high risk, premalignant HBEC.

11.
Pulm Circ ; 10(1): 2045894019891912, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32128158

RESUMO

Exercise pulmonary hypertension is an underappreciated form of physical limitation related to early pulmonary vascular disease. A low diffusing capacity of lungs for carbon monoxide (DLco) can be seen in patients with resting pulmonary hypertension as well as parenchymal lung disease. It remains unclear whether low DLco% identifies early pulmonary vascular disease. We hypothesize that a reduced DLco% differentiates the presence of exercise pulmonary hypertension in patients with parenchymal lung disease. Fifty-six patients referred for unexplained exertional dyspnea with pulmonary function tests within six months of hemodynamic testing underwent exercise right heart catheterization. Exclusion criteria included resting pulmonary arterial or venous hypertension. Receiver operator characteristic curve determined the optimal DLco% cutoffs based on the presence or absence of parenchymal lung disease. Twenty-one (37%) patients had parenchymal lung disease, most common manifesting as chronic obstructive lung disease or interstitial lung disease. In patients with parenchymal lung disease, a DLco of 46% demonstrated 100% sensitivity and 73% specificity for detecting exercise pulmonary hypertension. In patients without parenchymal lung disease, a DLco of 73% demonstrated 58% sensitivity and 94% specificity for detecting exercise pulmonary hypertension. In both cohorts, DLco% below the optimum cutoffs were associated with higher peak mean pulmonary arterial pressure and peak total pulmonary resistance consistent with the hemodynamic definition of exercise pulmonary hypertension. Patients with a DLco < 46% were more often treated with pulmonary vasodilators and had a trend to higher mortality and lung transplant. DLco% is a simple non-invasive screening test for the presence of exercise pulmonary hypertension in our mixed referral population with progressive exertional dyspnea. DLco < 46% with parenchymal lung disease and DLco < 73% without parenchymal lung disease may play a role in differentiating the presence of pulmonary vascular disease prior to invasive hemodynamic testing.

12.
ACR Open Rheumatol ; 1(1): 26-36, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31777777

RESUMO

OBJECTIVE: We sought to determine if any histopathologic component of the pulmonary microcirculation can distinguish systemic sclerosis (SSc)-related pulmonary fibrosis (PF) with and without pulmonary hypertension (PH). METHODS: Two pulmonary pathologists blindly evaluated 360 histologic slides from lungs of 31 SSc-PF explants or autopsies with (n = 22) and without (n = 9) PH. The presence of abnormal small arteries, veins, and capillaries (pulmonary microcirculation) was semiquantitatively assessed in areas of preserved lung architecture. Capillary proliferation (CP) within the alveolar walls was measured by its distribution, extent (CP % involvement), and maximum number of layers (maximum CP). These measures were then evaluated to determine the strength of their association with right heart catheterization-proven PH. RESULTS: Using consensus measures, all measures of CP were significantly associated with PH. Maximum CP had the strongest association with PH (P = 0.013; C statistic 0.869). Maximum CP 2 or more layers and CP % involvement 10% or greater were the optimal thresholds that predicted PH, both with a sensitivity of 56% and specificity of 91%. The CP was typically multifocal rather than focal or diffuse and was associated with a background pattern of usual interstitial pneumonia. There was a significant but weaker relationship between the presence of abnormal small arteries and veins and PH. CONCLUSION: In the setting of advanced SSc-PF, the histopathologic feature of the pulmonary microcirculation best associated with PH was capillary proliferation in architecturally preserved lung areas.

13.
SAGE Open Med Case Rep ; 7: 2050313X19869764, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31448123

RESUMO

Membranous glomerulonephritis is the most common glomerular disease in adults. Its primary form has been characterized with formation of phospholipase A2 receptor antibodies. Malignancy, infections, and autoimmune disorders are the most common causes of secondary membranous glomerulonephritis. We present a case of a 55-year-old African American female who presented with nephrotic range proteinuria and diagnosed with secondary membranous glomerulonephritis based on distinct pathological features on kidney biopsy and absence of serum phospholipase A2 receptor antibodies. She initially underwent extensive workup for malignancies, infections, and common autoimmune disorders which were all negative. Her proteinuria remained resistant to steroid treatment and she was treated with subcutaneous adrenocorticotropic hormone injections. Meanwhile, she was also diagnosed with the anti-muscle specific kinase antibody variant of myasthenia gravis. In literature, there are few case reports of myasthenia gravis as a cause of secondary membranous glomerulonephritis. In our case, the lack of other inciting factors also suggested this association.

14.
Cancer Res ; 79(19): 5022-5033, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31142513

RESUMO

Epithelial cells in the field of lung injury can give rise to distinct premalignant lesions that may bear unique genetic aberrations. A subset of these lesions may escape immune surveillance and progress to invasive cancer; however, the mutational landscape that may predict progression has not been determined. Knowledge of premalignant lesion composition and the associated microenvironment is critical for understanding tumorigenesis and the development of effective preventive and interception strategies. To identify somatic mutations and the extent of immune cell infiltration in adenomatous premalignancy and associated lung adenocarcinomas, we sequenced exomes from 41 lung cancer resection specimens, including 89 premalignant atypical adenomatous hyperplasia lesions, 15 adenocarcinomas in situ, and 55 invasive adenocarcinomas and their adjacent normal lung tissues. We defined nonsynonymous somatic mutations occurring in both premalignancy and the associated tumor as progression-associated mutations whose predicted neoantigens were highly correlated with infiltration of CD8+ and CD4+ T cells as well as upregulation of PD-L1 in premalignant lesions, suggesting the presence of an adaptive immune response to these neoantigens. Each patient had a unique repertoire of somatic mutations and associated neoantigens. Collectively, these results provide evidence for mutational heterogeneity, pathway dysregulation, and immune recognition in pulmonary premalignancy.Significance: These findings identify progression-associated somatic mutations, oncogenic pathways, and association between the mutational landscape and adaptive immune responses in adenomatous premalignancy.See related commentary by Merrick, p. 4811.


Assuntos
Adenocarcinoma , Adenoma , Neoplasias Pulmonares , Lesões Pré-Cancerosas , Genômica , Humanos , Microambiente Tumoral
16.
Pulm Circ ; 8(3): 2045894018787381, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29916285

RESUMO

Exercise pulmonary hypertension (ePH) is an underappreciated form of exertional limitation. Despite normal resting pulmonary artery pressures, patients with ePH demonstrate early pulmonary vascular changes with reduced pulmonary arterial compliance (PAC) and vascular distensibility (α). Recent data suggest that targeted vasodilator therapy may improve hemodynamics in ePH, but it is not well-known whether such medications alter pulmonary vascular distensibility. Thus, we sought to evaluate if vasodilator therapy improved α a marker of early pulmonary vascular disease in ePH. Ten patients performed supine exercise right heart catheterization (exRHC) with bicycle ergometer to peak exercise. Patients diagnosed with ePH were treated with pulmonary vasodilators. A repeat symptom-limited exercise RHC was performed at least six months after therapy. Patients with ePH had evidence of early pulmonary vascular disease, as baseline PAC and α were reduced. After pulmonary vasodilator therapy, a number of peak exercise hemodynamics statistically improved, including a decrease of total pulmonary resistance and pulmonary vascular resistance, while cardiac output increased. Importantly, vasodilator therapy partially reversed the pathogenic decreases of α at the time of repeat exRHC. Pulmonary vascular distensibility, α, a marker of early pulmonary vascular disease, improves in ePH after therapy with pulmonary vasodilators.

17.
Pulm Circ ; 7(4): 813-820, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28782988

RESUMO

Pulmonary tumor thrombotic microangiopathy (PTTM) is a disease process wherein tumor cells are thought to embolize to the pulmonary circulation causing pulmonary hypertension (PH) and death from right heart failure. Presented herein are clinical, laboratory, radiographic, and histologic features across seven cases of PTTM. Highlighted in this publication are also involvement of pulmonary venules and clinical features distinguishing PTTM from clinical mimics. We conducted a retrospective chart review of seven cases of PTTM from hospitals in the greater Los Angeles metropolitan area. Patients in this series exhibited: symptoms of cough and progressive dyspnea; PH and/or heart failure on physical exam; laboratory abnormalities of anemia, thrombocytopenia, elevated LDH, and elevated D-dimer; chest computed tomography (CT) showing diffuse septal thickening, mediastinal and hilar lymphadenopathy and nodules; elevated pulmonary artery pressures on transthoracic echocardiogram and/or right heart catheterization; and presence of malignancy. Tumor emboli and fibrocellular intimal proliferation were seen in pulmonary arterioles, while two patients had pulmonary venopathy. PTTM is a devastating disease occurring in patients with metastatic carcinoma. An early diagnosis is challenging. Understanding the clinical presentation of PTTM and distinguishing PTTM from clinical mimics may help achieve an early diagnosis and allow time for initiation of treatment.

18.
Clin Cancer Res ; 23(16): 4556-4568, 2017 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-28468947

RESUMO

Purpose: A phase I study was conducted to determine safety, clinical efficacy, and antitumor immune responses in patients with advanced non-small cell lung carcinoma (NSCLC) following intratumoral administration of autologous dendritic cells (DC) transduced with an adenoviral (Ad) vector expressing the CCL21 gene (Ad-CCL21-DC). We evaluated safety and tumor antigen-specific immune responses following in situ vaccination (ClinicalTrials.gov: NCT01574222).Experimental Design: Sixteen stage IIIB/IV NSCLC subjects received two vaccinations (1 × 106, 5 × 106, 1 × 107, or 3 × 107 DCs/injection) by CT- or bronchoscopic-guided intratumoral injections (days 0 and 7). Immune responses were assessed by tumor antigen-specific peripheral blood lymphocyte induction of IFNγ in ELISPOT assays. Tumor biopsies were evaluated for CD8+ T cells by IHC and for PD-L1 expression by IHC and real-time PCR (RT-PCR).Results: Twenty-five percent (4/16) of patients had stable disease at day 56. Median survival was 3.9 months. ELISPOT assays revealed 6 of 16 patients had systemic responses against tumor-associated antigens (TAA). Tumor CD8+ T-cell infiltration was induced in 54% of subjects (7/13; 3.4-fold average increase in the number of CD8+ T cells per mm2). Patients with increased CD8+ T cells following vaccination showed significantly increased PD-L1 mRNA expression.Conclusions: Intratumoral vaccination with Ad-CCL21-DC resulted in (i) induction of systemic tumor antigen-specific immune responses; (ii) enhanced tumor CD8+ T-cell infiltration; and (iii) increased tumor PD-L1 expression. Future studies will evaluate the role of combination therapies with PD-1/PD-L1 checkpoint inhibition combined with DC-CCL21 in situ vaccination. Clin Cancer Res; 23(16); 4556-68. ©2017 AACR.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Quimiocina CCL21/imunologia , Células Dendríticas/imunologia , Imunoterapia Adotiva/métodos , Neoplasias Pulmonares/terapia , Adulto , Idoso , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/imunologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Quimiocina CCL21/genética , Estudos de Coortes , Células Dendríticas/metabolismo , Células Dendríticas/transplante , Dispneia/etiologia , Feminino , Humanos , Imunoterapia Adotiva/efeitos adversos , Injeções Intralesionais , Interferon gama/imunologia , Interferon gama/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/etiologia , Dor/etiologia
20.
Cell Stem Cell ; 15(2): 199-214, 2014 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-24953182

RESUMO

Airways are exposed to myriad environmental and damaging agents such as reactive oxygen species (ROS), which also have physiological roles as signaling molecules that regulate stem cell function. However, the functional significance of both steady and dynamically changing ROS levels in different stem cell populations, as well as downstream mechanisms that integrate ROS sensing into decisions regarding stem cell homeostasis, are unclear. Here, we show in mouse and human airway basal stem cells (ABSCs) that intracellular flux from low to moderate ROS levels is required for stem cell self-renewal and proliferation. Changing ROS levels activate Nrf2, which activates the Notch pathway to stimulate ABSC self-renewal and an antioxidant program that scavenges intracellular ROS, returning overall ROS levels to a low state to maintain homeostatic balance. This redox-mediated regulation of lung stem cell function has significant implications for stem cell biology, repair of lung injuries, and diseases such as cancer.


Assuntos
Fator 2 Relacionado a NF-E2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores Notch/metabolismo , Células-Tronco/citologia , Traqueia/citologia , Animais , Antioxidantes/metabolismo , Ciclo Celular , Diferenciação Celular , Proliferação de Células , Homeostase , Humanos , Camundongos , Oxirredução , Polidocanol , Polietilenoglicóis/química , Transdução de Sinais , Cicatrização
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