Sheng‐Wen Sun

Many studies have proved that the pathogenesis of the chronic obstructive pulmonary disease (COPD) and lung cancer is related, and may cause and affect each other to a certain extent. In fact, the change of chronic airway obstruction will continue to have an impact on the screening, treatment, and prognosis of lung cancer.In this comprehensive review, we outlined the links and heterogeneity between COPD and lung cancer and finds that factors such as gene expression and genetic susceptibility, epigenetics, smoking, epithelial mesenchymal transformation (EMT), chronic inflammation, and oxidative stress injury may all play a role in the process. Although the relationship between these two diseases have been largely determined, the methods to prevent lung cancer in COPD patients are still limited. Early diagnosis is still the key to a better prognosis. Thus, it is necessary to establish more intuitive screening evaluation criteria and find suitable biomarkers for lung cancer screening in high-risk populations with COPD. Some studies have indicated that COPD may change the efficacy of anti-tumor therapy by affecting the response of lung cancer patients to immune checkpoint inhibitors (ICIs). And for lung cancer patients with COPD, the standardized management of COPD can improve the prognosis. The treatment of lung cancer patients with COPD is an individualized, comprehensive, and precise process. The development of new targets and new strategies of molecular targeted therapy may be the breakthrough for disease treatment in the future.

BMP and activin membrane-bound inhibitor (BAMBI) is postulated to inhibit or modulate transforming growth factor β (TGF-β) signaling. Furthermore, strong upregulation of BAMBI expression following in vitro infection of chronic obstructive pulmonary disease (COPD) lung tissue has been demonstrated. In this study, we investigated whether TGF-β/BAMBI pathway is associated with COPD. Blood samples were obtained from 27 healthy controls (HC), 24 healthy smokers (HS) and 29 COPD patients. Elevated Th17/Treg ratios, and increased levels of BAMBI protein and mRNA (in plasma and CD4(+) T cells respectively), were observed in COPD compared with HC and HS. BAMBI expression was first observed on human CD4(+) T cells, with a typical membrane-bound pattern. The enhanced plasma BAMBI levels in COPD positively correlated with the increased plasma TGF-β1 levels and Th17/Treg ratio. Together, an impaired TGF-β/BAMBI pathway may promote the inflammation leading to Th17/Treg imbalance, which is a new mechanism in smokers who develop COPD.

The imbalance of CD4+Foxp3+ T cell subsets is reportedly involved in abnormal inflammatory immune responses in patients with chronic obstructive pulmonary disease (COPD). However, the possible role of CD4+CD25−Foxp3+ T cells in immune regulation in COPD remains to be investigated. In the current study, distribution and phenotypic characteristics of CD4+CD25−Foxp3+ T cells from peripheral blood were determined by flow cytometry; the origin, immune function and ultimate fate of CD4+CD25−Foxp3+ T cells were further explored in vitro. It was observed that circulating CD4+CD25−Foxp3+ T cells were significantly increased in stable COPD patients (SCOPD) and resembled central memory or effector memory T cells. Compared with peripheral CD4+CD25+Foxp3+ T cells, peripheral CD4+CD25−Foxp3+ T cells showed a lower expression of Foxp3, CTLA-4, HELIOS and TIGIT, but a higher expression of CD127 and KI-67, suggesting that CD4+CD25−Foxp3+ T cells lost the expression of Tregs-associated molecules following the reduction in CD25. Unexpectedly, our study found that transforming growth factor-β1 (TGFβ1) decreased CD25 expression and played a critical role in the generation of CD4+CD25−Foxp3+ T cells from CD4+CD25+Foxp3+ T cells. Phenotypic analysis further revealed that both inducible and peripheral CD4+CD25−Foxp3+ T cells exhibit the features of activated conventional T cells. Importantly, memory CD4+CD25−Foxp3+ T cells facilitated the proliferation and differentiation of naïve CD4+ T cells into Th17 cells in the presence of IL-1β, IL-6, IL-23 and TGFβ1. Finally, a fraction of CD4+CD25−Foxp3+ T cells, exhibiting instability and plasticity, were converted to Th17 cells when subjected to Th17 cell-polarizing condition. Taken together, we propose that TGFβ1 is responsible for the generation of CD4+CD25−Foxp3+ T cells, which functionally exert an auxiliary effect on Th17 cells generation and might perpetuate chronic inflammation in COPD.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by continuous flow limitation and the immune system including macrophages and regulatory T lymphocytes (Tregs) is involved in COPD pathogenesis. In our previous study, we investigated that TGF-β/BAMBI pathway was associated with COPD by regulating the balance of Th17/Treg. However, the role of bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI), a pseudoreceptor of TGF-β signalling pathway, in regulating the immune system of COPD patients has not been fully studied. Hence, we speculate that the pseudoreceptor BAMBI may play roles in the regulation of M2 macrophages to induce the differentiation of CD4+ naïve T cells into Tregs and influence the immune response in COPD. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from healthy nonsmokers (n = 12), healthy smokers (n = 10) and COPD patients (n = 20). Naïve CD4+ T cells and monocytes-induced macrophages were used for coculture assays. The phenotypic characteristics of macrophages and Tregs were determined by flow cytometry. The expression levels of BAMBI and the TGF-β/Smad pathway members in M2 macrophages were measured by a Western blot analysis. The monocyte-derived macrophages were stimulated with cigarette smoke extract (CSE, concentration of 0.02%) to simulate the smoking process in humans. pCMV-BAMBI was transfected into monocyte-derived M2 macrophages for subsequent co-culture assays and signalling pathway analysis. RESULTS: Our results showed that M2 macrophages could induce the differentiation of Tregs through the TGF-β/Smad signalling pathway. In addition, monocyte-derived macrophages from COPD patients highly expressed BAMBI, and had a low capacity to induce Tregs differentiation. The expression of BAMBI and the forced expiratory volume in 1 second (FEV1%) were negatively correlated in COPD. Furthermore, overexpression of BAMBI promoted the conversion of M2 macrophages to M1 macrophages via the TGF-β/Smad pathway. CONCLUSIONS: We demonstrated that BAMBI could promote the polarization process of M2 macrophages to M1 macrophages via the TGF-β/Smad signalling pathway and that overexpression of BAMBI could decrease the ability of M2 macrophages to induce Treg differentiation. These findings may provide a potential mechanism by which blocking BAMBI could improve immune function to regulate COPD inflammatory conditions.

Background. CD8(+) T lymphocytes are known to play a critical role in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, systematic analyses of CD8(+) T cell (Cytotoxic T cells, Tc) subsets in COPD patients have yet to be well conducted. Methods. The whole Tc subsets, including Tc1/2/10/17, CD8(+) regulatory T cells (Tregs) and CD8(+) α7(+) T cells, were quantified by flow cytometry in peripheral blood from 24 stable COPD subjects (SCOPD), 14 patients during acute exacerbations (AECOPD), and 14 healthy nonsmokers (HN). Results. Acute exacerbations of COPD were accompanied by elevated levels of circulating CD8(+) T cells. Tc1 cells were increased in both SCOPD and AECOPD patients, whereas the percentage of Tc2 cells was decreased in SCOPD patients but remained normal in AECOPD patients. Tc17 cells were increased only in AECOPD patients, and the percentage of Tc10 cells was reduced in both SCOPD and AECOPD patients. The imbalances of pro/anti-inflammatory Tc subsets observed in COPD may be caused by the lack of Tc10 cells and the impaired anti-inflammatory capacity of CD8(+) Tregs. Conclusions. The imbalances between subsets of CD8(+) peripheral blood T cells contribute to the immune response dysfunction in COPD pathogenesis.