No abstract

Chronic obstructive pulmonary disease (COPD) is a lethal progressive lung disease culminating in permanent airway obstruction and alveolar enlargement. Previous studies suggest CTL involvement in COPD progression; however, their precise role remains unknown. Here, we investigated whether the CTL activation receptor NK cell group 2D (NKG2D) contributes to the development of COPD. Using primary murine lung epithelium isolated from mice chronically exposed to cigarette smoke and cultured epithelial cells exposed to cigarette smoke extract in vitro, we demonstrated induced expression of the NKG2D ligand retinoic acid early transcript 1 (RAET1) as well as NKG2D-mediated cytotoxicity. Furthermore, a genetic model of inducible RAET1 expression on mouse pulmonary epithelial cells yielded a severe emphysematous phenotype characterized by epithelial apoptosis and increased CTL activation, which was reversed by blocking NKG2D activation. We also assessed whether NKG2D ligand expression corresponded with pulmonary disease in human patients by staining airway and peripheral lung tissues from never smokers, smokers with normal lung function, and current and former smokers with COPD. NKG2D ligand expression was independent of NKG2D receptor expression in COPD patients, demonstrating that ligand expression is the limiting factor in CTL activation. These results demonstrate that aberrant, persistent NKG2D ligand expression in the pulmonary epithelium contributes to the development of COPD pathologies.

Although adenocarcinoma (ADC) is the most frequent lung cancer, its diagnosis is often late, when the local invasion is important and/or the metastases have already appeared. Therefore, the mortality at 5 years is still very high, ranging from 51% to 99%, depending on the stage. The implementation of different molecular techniques has allowed genomic studies even in relatively small histological samples such as obtained with non-invasive or minimally invasive techniques, facilitating a better phenotyping of lung ADC. Thus, current classification differentiates between preinvasive lesions (atypical adenomatous hyperplasia and in situ ADC), minimally invasive ADC (MIA) and invasive ADC. 'Field cancerization' is a concept that refers to progressive loco-regional changes occurring in tissues exposed to carcinogens, due to the interaction of the latter with a predisposing genetic background and an appropriate tissue microenvironment. Somatic genetic alterations, including mutations but also other changes, are necessary for oncogenesis, being especially frequent in lung ADC. Changes in the epidermal growth factor receptor () gene, Kirsten rat sarcoma viral oncogene (), v-Raf murine sarcoma viral oncogene homolog B (), gene encoding neurofibromin (), anaplastic lymphoma kinase () and are the main genes that suffer alterations in the tumors of patients with ADC. Molecular profiling of these tumors allows more targeted treatments through two distinct strategies, genome-guided therapy and immunotherapy. The former, targets the aberrant pathways secondary to the genomic alteration, whereas the latter may be based on the administration of antibodies [such as those against cytotoxic T-lymphocyte antigen 4 (CTLA-4) or the programmed cell death ligand 1/protein 1 pathway (PD-L1/PD-1)] or the stimulation of the patient's own immune system to produce a specific response. These strategies are obtaining better results in selected ADC patients.

Chronic respiratory diseases such as obstructive pulmonary disease (COPD) and oxidative stress may underlie lung cancer (LC). We hypothesized that the profile of oxidative and antioxidant events may differ in lung tumors and blood compartments of patients with non-small cell LC (NSCLC) with and without COPD. Redox markers (immunoblotting, ELISA, chemiluminescence, 2D electrophoresis and proteomics) were analyzed in blood samples of 17 control subjects and 80 LC patients (59 LC-COPD and 21 LC) and lung specimens (tumor and nontumor) from those undergoing thoracotomy (35 patients: 23 LC-COPD and 12 LC). As smoking history was more prevalent in LC-COPD patients, these were further analyzed post hoc as heavy and moderate smokers (cutoff, 60 pack-years). Malondialdehyde (MDA)-protein adducts and SOD1 levels were higher in tumor and nontumor samples of LC-COPD than in LC. In tumors compared with nontumors, SOD2 protein content was greater, whereas catalase levels were decreased in both LC and LC-COPD patients. Blood superoxide anion levels, protein carbonylation and nitration were greater in LC and LC-COPD patients than in the controls, and in the latter patients compared with the former. Systemic superoxide anion, protein carbonyls and nitrotyrosine above specific cutoff values best identified underlying COPD among all patients. Smoking did not influence the study results. A differential expression profile of oxidative stress markers exists in blood and, to a lesser extent, in the tumors of LC-COPD patients. These findings suggest that systemic oxidative stress and lung antioxidants (potential biomarkers) may predispose patients with chronic respiratory diseases to a higher risk for LC.

No abstract

The relative predominance of T helper 1 cytokines and M1 macrophages in the blood and tumors of patients with underlying COPD imply that a stronger proinflammatory pattern exists in these patients. Inflammation should not be targeted systematically in all patients with LC. Screening for the presence of underlying respiratory diseases and identification of the specific inflammatory pattern should be carried out in patients with LC, at least in early stages of their disease.

Immune profile of B and T cells and tertiary lymphoid structures (TLSs) may differ in tumors of lung cancer (LC) patients with/without chronic obstructive pulmonary disease (COPD), and may also influence patient survival. We sought to analyze: (1) TLSs, germinal centers (GCs), B and T cells, and (2) associations of the immune biomarkers with the patients’ 10-year overall survival (OS). TLSs (numbers and area), B [cluster of differentiation (CD) 20], and T (CD3), and GCs cells were identified in both tumor and non-tumor specimens (thoracotomy) from 90 LC-COPD patients and 43 LC-only patients. Ten-year OS was analyzed in the patients. Immune profile in tumors of LC-COPD versus LC: TLS numbers and areas significantly decreased in tumors of LC-COPD compared to LC patients. No significant differences were observed in tumors between LC-COPD and LC patients for B or T cells. Immune profile in tumors versus non-tumor specimens: TLS areas and B cells significantly increased, T cells significantly decreased in tumors of both LC and LC-COPD patients. Survival: in LC-COPD patients: greater area of TLSs and proportion of B cells were associated with longer survival rates. The immune tumor microenvironment differs in patients with underlying COPD and these different phenotypes may eventually impact the response to immunotherapy in patients with LC.

Lung cancer (LC) has become one of the leading causes of preventable death in the last few decades. Cigarette smoking (CS) stays as the main etiologic factor of LC despite that many other causes such as occupational exposures, air pollution, asbestos, or radiation have also been implicated. Patients with chronic obstructive pulmonary disease (COPD), which also represents a major cause of morbidity and mortality in developed countries, exhibit a significantly greater risk of LC. The study of the underlying biological mechanisms that may predispose patients with chronic respiratory diseases to a higher incidence of LC has also gained much attention in the last few years. The present review has been divided into three major sections in which different aspects have been addressed: (I) relevant etiologic agents of LC; (II) studies confirming the hypothesis that COPD patients are exposed to a greater risk of developing LC; and (III) evidence on the most relevant underlying biological mechanisms that support the links between COPD and LC. Several carcinogenic agents have been described in the last decades but CS remains to be the leading etiologic agent in most geographical regions in which the incidence of LC is very high. Growing evidence has put the line forward the implications of COPD and especially of emphysema in LC development. Hence, COPD represents a major risk factor of LC in patients. Different avenues of research have demonstrated the presence of relevant biological mechanisms that may predispose COPD patients to develop LC. Importantly, the so far identified biological mechanisms offer targets for the design of specific therapeutic strategies that will further the current treatment options for patients with LC. Prospective screening studies, in which patients with COPD should be followed up for several years will help identify biomarkers that may predict the risk of LC among these patients.