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BACKGROUND: Regimens combining pemetrexed (PEM) and immune checkpoint inhibitors (ICIs) targeting programmed cell death-1 (PD-1) or programmed death-ligand 1 (PD-L1) are widely used for the treatment of advanced non-squamous non-small-cell lung cancer (NSq-NSCLC). Recently, PEM was shown to induce immunogenic cell death (ICD) and to enhance immune-regulatory genes. Some patients demonstrate an extremely long-term response to PEM. It is possible that the continued response in these patients is dependent on not only the pharmacological induction of cytotoxic cell death but also antitumor immunity. However, factors that can predict outcomes associated with long-term PEM administration using blood test results have not yet been elucidated. We investigated the clinical characteristics and predictive factors in patients with advanced NSq-NSCLC who underwent long-term PEM maintenance therapy. METHODS: In total, 504 patients with advanced NSq-NSCLC who received PEM combination therapy/monotherapy (n = 414) or paclitaxel (PTX) combination therapy (n = 90) between January 2010 and November 2019 were recruited; 381 patients were retained for the final analysis. Patients treated with PEM (n = 301) were divided into subgroups according to the total cycles of PEM (≥ 17 [n = 25] for the long-term administration group and ≤ 16 [n = 276] for the intermediate/short-term group) and compared with another population (n = 80) treated with PTX combination regimen. We investigated clinical features and predictive biomarkers, focusing on immune-regulatory factors, absolute lymphocyte count (ALC), neutrophil-to-lymphocyte ratio (NLR), and PD-1 and PD-L1 expression, to predict long-term response to PEM. RESULTS: The long-term PEM administration group exhibited a higher ALC and a lower NLR than the shorter-term group did. Both these markers displayed greater association with progression-free survival and overall survival in the PEM combination therapy group than in the PTX combination therapy group. Increased PD-1 lymphocytes were associated with the long-term PEM response group, as PD-L1 expression in tumors was associated with a high incidence of immune-related adverse effects following ICI administration. CONCLUSIONS: ALC, NLR, and PD-1 expression are PEM-mediated predictive biomarkers that are indirectly related to tumor immunity and can provide useful predictive information on the long-term response to PEM in patients with NSq-NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Antígeno B7-H1 , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Recuento de Linfocitos , Linfocitos , Pemetrexed/uso terapéuticoRESUMEN
BACKGROUND/AIMS: Lung fibrosis is associated with lung tissue contraction due to abnormal accumulation of myofibroblasts, which aggressively promote the fibrotic process. Transforming growth factor (TGF)-ß signaling in fibroblasts promotes extracellular matrix (ECM) synthesis and fibroblast migration and differentiation into myofibroblasts. Inhibition of extracellular signal-regulated kinase (ERK)5 blocks lung fibroblast activation by suppressing TGF-ß signaling. Here, we examined the effects of an ERK5 inhibitor on TGF-ß1-induced fibrosis in lung fibroblasts. METHODS: The effects of ERK5 inhibition following TGF-ß1 exposure were evaluated in lung fibroblasts isolated from fibrotic human lung tissues. Fibroblast-mediated collagen gel contraction and fibroblast migration towards fibronectin were assessed. Phenotypic differences in fibrotic fibroblasts were examined using the cap analysis gene expression method for genome-wide quantification of promoter activity. RESULTS: TGF-ß1stimulated contraction of collagen gels, fibroblast migration, and α-smooth muscle actin and fibronectin expression, and Smad3 phosphorylation were increased in fibrotic fibroblasts as compared to normal lung fibroblasts. Treatment with the ERK5 inhibitor blocked these responses to a greater extent in fibroblasts from patients with usual interstitial pneumonia as compared to nonspecific interstitial pneumonia, independent of bone morphogenetic protein/Smad1 regulation. Moreover, 223 genes including fibulin-5 -which is involved in the TGF-ß1-ERK5 signaling network- were upregulated in fibrotic fibroblasts, and ECM regulation was found to be enriched in the Reactome analysis. CONCLUSION: ERK5 inhibition attenuated the high sensitivity of fibrotic fibroblasts to TGF-ß1/Smad3 signaling. Thus, the ERK5 pathway components and fibulin-5 are potential therapeutic targets to prevent lung fibrosis progression.
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Proteína Quinasa 7 Activada por Mitógenos/metabolismo , Fibrosis Pulmonar/patología , Transducción de Señal/efectos de los fármacos , Factor de Crecimiento Transformador beta1/farmacología , Actinas/metabolismo , Anciano , Compuestos de Anilina/farmacología , Biomarcadores/metabolismo , Movimiento Celular/efectos de los fármacos , Quimiotaxis/efectos de los fármacos , Femenino , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibronectinas/metabolismo , Humanos , Indoles/farmacología , Masculino , Persona de Mediana Edad , Proteína Quinasa 7 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 7 Activada por Mitógenos/genética , Fibrosis Pulmonar/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Proteína smad3/metabolismo , Regulación hacia Arriba/efectos de los fármacosRESUMEN
BACKGROUND: Pirfenidone, an antifibrotic agent used for the treatment of idiopathic pulmonary fibrosis (IPF), functions by inhibiting myofibroblast differentiation, which is involved in transforming growth factor (TGF)-ß1-induced IPF pathogenesis. However, unlike normal lung fibroblasts, the relationship between pirfenidone responses of TGF-ß1-induced human fibrotic lung fibroblasts and lung fibrosis has not been elucidated. METHODS: The effects of pirfenidone were evaluated in lung fibroblasts isolated from fibrotic human lung tissues after TGF-ß1 exposure. The ability of two new pharmacological targets of pirfenidone, collagen triple helix repeat containing protein 1(CTHRC1) and four-and-a-half LIM domain protein 2 (FHL2), to mediate contraction of collagen gels and migration toward fibronectin were assessed in vitro. RESULTS: Compared to control lung fibroblasts, pirfenidone significantly restored TGF-ß1-stimulated fibroblast-mediated collagen gel contraction, migration, and CTHRC1 release in lung fibrotic fibroblasts. Furthermore, pirfenidone attenuated TGF-ß1- and CTHRC1-induced fibroblast activity, upregulation of bone morphogenic protein-4(BMP-4)/Gremlin1, and downregulation of α-smooth muscle actin, fibronectin, and FHL2, similar to that observed post-CTHRC1 inhibition. In contrast, FHL2 inhibition suppressed migration and fibronectin expression, but did not downregulate CTHRC1. CONCLUSIONS: Overall, pirfenidone suppressed fibrotic fibroblast-mediated fibrotic processes via inverse regulation of CTHRC1-induced lung fibroblast activity. Thus, CTHRC1 can be used for predicting pirfenidone response and developing new therapeutic targets for lung fibrosis.
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Antiinflamatorios no Esteroideos/farmacología , Fibroblastos/efectos de los fármacos , Pulmón/efectos de los fármacos , Piridonas/farmacología , Factor de Crecimiento Transformador beta1/toxicidad , Adulto , Anciano , Animales , Células Cultivadas , Relación Dosis-Respuesta a Droga , Femenino , Fibroblastos/patología , Humanos , Pulmón/patología , Masculino , Persona de Mediana Edad , RatasRESUMEN
BACKGROUND: Airway fibrosis is one of the pathological features of chronic obstructive pulmonary disease (COPD), and recent studies revealed that acetylcholine plays an important role in the development of airway remodeling by stimulating proliferation and collagen synthesis of lung fibroblasts. This study was designed to examine the effects of a long-acting muscarinic receptor antagonist (LAMA) glycopyrronium and a long-acting ß2 adrenergic receptor agonist (LABA) indacaterol on acetylcholine-mediated fibrotic responses in lung fibroblasts. METHODS: After carbachol (CCh) or transforming growth factor-ß1 (TGF-ß1) exposure, the response to glycopyrronium and indacaterol was determined in vitro in fibroblasts isolated from mild-to-moderate COPD lung tissue. The ability of fibroblasts to mediate the contraction of collagen gels was assessed. The expression of α-smooth muscle actin (α-SMA) and the phosphorylation of extracellular-signal-regulated kinase 5 (ERK5) were determined by immunoblot. TGF-ß1 was quantified by ELISA and acetylcholine was quantified by liquid chromatography tandem-mass spectrometry. RESULTS: CCh stimulated fibroblast-mediated collagen gel contraction and α-SMA expression and TGF-ß1 release by fibroblasts. Blockade of autocrine TGF-ß1 attenuated CCh-mediated fibrotic responses, while TGF-ß1 did not stimulate acetylcholine release. Glycopyrronium plus indacaterol significantly attenuated CCh- and TGF-ß1-mediated fibrotic responses through inhibition of ERK5 phosphorylation. Notably, the magnitudes of CCh- and TGF-ß1-stimulated gel contraction, CCh-induced TGF-ß1 release, and ERK5 phosphorylation were greater in fibroblasts isolated from COPD subjects than in those from non-smokers. CONCLUSIONS: CCh induced TGF-ß1 self-sustaining signaling loops by potentiating ERK5 signaling and promoted myofibroblast activity. This autocrine signaling mechanism may be an attractive therapeutic target to block the fibrotic response, which was modulated by the combination of glycopyrronium and indacaterol.
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Glicopirrolato/administración & dosificación , Indanos/administración & dosificación , Proteína Quinasa 7 Activada por Mitógenos/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/prevención & control , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/prevención & control , Quinolonas/administración & dosificación , Antagonistas de Receptores Adrenérgicos beta 2/administración & dosificación , Anciano , Carbacol , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Antagonistas Muscarínicos/administración & dosificación , Enfermedad Pulmonar Obstructiva Crónica/inducido químicamente , Fibrosis Pulmonar/inducido químicamente , Transducción de Señal/efectos de los fármacos , Resultado del TratamientoRESUMEN
Nintedanib reduces the decline in forced vital capacity and extends the time to the first acute exacerbation of interstitial lung disease (AE-ILD). However, the effect of additional nintedanib administration after AE-ILD onset is unknown. This study aimed to investigate the efficacy and safety of nintedanib administration after AE-ILD development. We retrospectively collected the data of 33 patients who developed AE-ILD between April 2014 and January 2022. Eleven patients who received nintedanib after AE-ILD development and the remaining who did not were classified into the N and No-N groups, respectively. The survival time in the N group tended to be longer than that in the No-N group. The generalized Wilcoxson test revealed that the cumulative mortality at 90 days from AE-ILD onset was significantly lower in the N group. The time to subsequent AE-ILD development was significantly longer in the N group than that in the No-N group. The incidence of adverse gastrointestinal effects and liver dysfunction in the N group was 9-18%. Treatment without nintedanib after AE-ILD development and the ratio of arterial oxygen partial pressure to fractional inspired oxygen were significant independent prognostic factors in the multivariate analysis. Thus, nintedanib administration may be a treatment option for AE-ILD.
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Enfermedades Pulmonares Intersticiales , Humanos , Progresión de la Enfermedad , Estudios Retrospectivos , Enfermedades Pulmonares Intersticiales/etiología , Oxígeno , PronósticoRESUMEN
Pleural disease in silicosis remains an underrecognized entity. Herein, we describe the case of an 85-year-old man with a 20-year history of silica exposure between the ages of 9-28 years. He presented with bilateral exudative pleural effusions, and chest computed tomography revealed typical silicosis findings. Thoracentesis was performed thrice, but did not reveal the cause of effusion. However, pleural fluid cell-block elemental analysis revealed a silicon compound, suggesting that silicosis-related pleural effusion had developed after a long latency period. Therefore, elemental analysis of the pleural fluid cell block may help diagnose occupational lung diseases with pleural effusion.
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Cancer-associated fibroblasts (CAFs) regulate cancer progression through the modulation of extracellular matrix (ECM) and cancer cell adhesion. While undergoing a series of phenotypic changes, CAFs control cancer-stroma interactions through integrin receptor signaling. Here, we isolated CAFs from patients with non-small-cell lung cancer (NSCLC) and examined their gene expression profiles. We identified collagen type XI α1 (COL11A1), integrin α11 (ITGA11), and the ITGA11 major ligand collagen type I α1 (COL1A1) among the 390 genes that were significantly enriched in NSCLC-associated CAFs. Increased ITGA11 expression in cancer stroma was correlated with a poor clinical outcome in patients with NSCLC. Increased expression of fibronectin and collagen type I induced ITGA11 expression in CAFs. The cellular migration of CAFs toward collagen type I and fibronectin was promoted via ERK1/2 signaling, independently of the fibronectin receptor integrin α5ß1. Additionally, ERK1/2 signaling induced ITGA11 and COL11A1 expression in cancer stroma. We, therefore, propose that targeting ITGA11 and COL11A1 expressing CAFs to block cancer-stroma interactions may serve as a novel, promising anti-tumor strategy.
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Fibroblastos Asociados al Cáncer/fisiología , Carcinoma de Pulmón de Células no Pequeñas/patología , Cadenas alfa de Integrinas/genética , Neoplasias Pulmonares/patología , Células A549 , Adulto , Anciano , Carcinoma de Pulmón de Células no Pequeñas/genética , Estudios de Casos y Controles , Movimiento Celular/genética , Células Cultivadas , Cadena alfa 1 del Colágeno Tipo I/genética , Cadena alfa 1 del Colágeno Tipo I/metabolismo , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Matriz Extracelular/patología , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Cadenas alfa de Integrinas/metabolismo , Neoplasias Pulmonares/genética , Masculino , Persona de Mediana Edad , Unión Proteica , Regulación hacia Arriba/genéticaRESUMEN
Anti-anaplastic lymphoma kinase (ALK)-targeted therapy dramatically improves therapeutic responses in patients with ALK-rearranged lung adenocarcinoma (Ad-LC). A few cases of squamous cell lung carcinoma (Sq-LC) with ALK rearrangement have been reported; however, the clinicopathological features and clinical outcomes following treatment with ALK inhibitors are unknown. We addressed this in the present study by retrospectively comparing the clinical characteristics of five patients with ALK-rearranged Sq-LC with those of patients with ALK-rearranged Ad-LC and by evaluating representative cases of ALK inhibitor responders and non-responders. The prevalence of ALK rearrangement in Sq-LCs was 1.36%. Progression-free survival (PFS) after initial treatment with crizotinib was significantly shorter in Sq-LC than in Ad-LC with ALK rearrangement (p = 0.033). Two ALK rearrangements assayed by fluorescence in situ hybridization (FISH)-positive/immunohistochemistry-negative cases did not respond to crizotinb, and PFS decreased following alectinib treatment of ALK-rearranged Sq-LC (p = 0.045). A rebiopsy revealed that responders to ceritinib harbored the L1196M mutation, which causes resistance to other ALK inhibitors. However, non-responders were resistant to all ALK inhibitors, despite the presence of ALK rearrangement in FISH-positive circulating tumor cells and circulating free DNA and absence of the ALK inhibitor resistance mutation. These results indicate that ALK inhibitors remain a reasonable therapeutic option for ALK-rearranged Sq-LC patients who have worse outcomes than ALK-rearranged Ad-LC patients and that resistance mechanisms are heterogeneous. Additionally, oncologists should be aware of the possibility of ALK-rearranged Sq-LC based on clinicopathological features, and plan second-line therapeutic strategies based on rebiopsy results in order to improve patient outcome.