Immune infiltration landscape on prognosis and therapeutic response and relevant epigenetic and transcriptomic mechanisms in lung adenocarcinoma.

Objective: Lung adenocarcinoma (LUAD) is the most prevalent lung cancer subtype, but its immune infiltration features are not comprehensively understood. To address the issue, the present study was initiated to describe the immune infiltrations across LUAD from cellular compositional, functional, and mechanism perspectives. Methods: We adopted five LUAD datasets (GSE32863, GSE43458, GSE75037, TCGA-LUAD, and GSE72094). Differentially expressed genes between LUAD and controls were selected for co-expression network analysis. Risky immune cell types were determined for classifying LUAD patients as diverse subtypes, followed by a comparison of antitumor immunity and therapeutic response between subtypes. Then, LUAD- and subtype-related key module genes affected by DNA methylation were determined for quantifying a scoring scheme. EXO1 was chosen for functional analysis via in vitro assays. Results: Two immune cell infiltration-based subtypes (C1 and C2) were established across LUAD, with poorer prognostic outcomes and lower infiltration of immune cell types in C1. Additionally, C1 presented higher responses to immune checkpoint blockade and targeted agents (JNK inhibitor VIII, BI-D1870, RO-3306, etc.). The scoring system (comprising GAPDH, EXO1, FYN, CFTR, and KLF4) possessed higher accuracy in estimating patients' prognostic outcomes. EXO1 upregulation contributed to the growth, migration, and invasion of LUAD cells. In addition, EXO1 facilitated PD-L1 and sPD-L1 expression in LUAD cells. Conclusion: Altogether, our findings offer a comprehensive understanding of the immune infiltration landscape on prognosis and therapeutic response of LUAD as well as unveil potential epigenetic and transcriptomic mechanisms, which might assist personalized treatment.

Mycobacterium Vaccae Regulate γδT17 and γδTreg Cells in Mice Asthmatic Lung.

Background Dysregulation of the balance between different T cell populations is believed to be an important basis for asthma.Objective To observe the changes in γδT subtypes in transgenic asthmatic mice after aerosol inhalation of Mycobacterium vaccae, and to further investigate the mechanism of M. vaccae in asthmatic mice and its relationship with γδT cells.Methods TCR-ß-/- mice were exposed to atomized normal saline or M. vaccae for 5 days and the γδT cells from the lung tissues were isolated. Changes in γδT17 and γδTreg populations were detected. Asthma was induced in BALB/c mice using ovalbumin, which was then transplanted with control or M. vaccae-primed γδT cells. First we analyzed the content of γδT cells that secrete IL-17 (IL-17 γδT cells) and Foxp3+ γδT cells in lung tissues and then measured the content of IL-17 in the bronchoalveolar lavage fluid (BALF) by ELISA.Results Exposure to M. vaccae increased and decreased the relative proportions of Foxp3+ γδT cells and IL-17+ γδT cells, respectively, thereby decreasing airway reactivity and inflammation levels in asthmatic mice, and significantly decreasing IL-17 levels in BALF. Furthermore, mice treated with these primed T cells showed a decrease in IL-17+ γδT cells, and a concomitant increase in Foxp3+ γδT cells in their lung tissues. Furthermore, adoptive transfer of M. vaccae-primed γδT cells decreased GATA3 and NICD and increased T-bet in lung.Conclusions The M. vaccae-primed γδT cells alleviated the symptoms of asthma by reversing Th2 polarization in the lungs and inhibiting the Notch/GATA3 pathway.

Aerosol inhalation of Mycobacterium bovis can reduce the Th2 dominant immune response induced by ovalbumin sensitization.

OBJECTIVE: To investigate whether M. vaccae inhalation affects asthma via γδ T cell regulation. METHODS: Forty male Balb/c mice were randomly divided into 4 groups: normal group, asthma group, control group and intervention group. The normal group was given no treatment. For the asthma group, control group and intervention group, the mice were sensitized and stimulated with ovalbumin (OVA) to establish asthma models. Mice in the asthma group were not treated. Mice in the control group were treated with γδ T cell suspension from normal mice, and those in the intervention group were treated with γδ T cell suspension from mice intervened by Mycobacterium bovis. ELISA assay was adopted for quantification of IL-4 and IFN-γ in mouse alveolar fluid (BALF), and flow cytometry for determining the percentage of IL-4 and IFN-γ from mononuclear cells of lung tissues. RESULTS: The airway responsiveness of the asthma group was higher than that of the normal group. The degree of airway inflammation in the intervention group was lighter than that in the control group, and it was significantly alleviated compared with the asthma group (P<0.05). Compared with the asthma group, the level of IL-4 in the BALF of the control group and the intervention group decreased significantly, while the level of IFN-γ increased significantly (P<0.05). Compared with the control group, the level of IL-4 in the BALF of the intervention group was significantly lower, while the level of IFN-γ was significantly higher (P<0.05). In addition, the results of flow cytometry were basically consistent with the results of Elisa. CONCLUSION: Aerosol inhalation of Mycobacterium bovis can alleviate the Th2 dominant immune response induced by OVA sensitization and regulate the Th1/Th2 immune imbalance in patients with asthma.

γδT17/γδTreg cell subsets: a new paradigm for asthma treatment.

Bronchial asthma (abbreviated as asthma), is a heterogeneous disease characterized by chronic airway inflammation and airway hyperresponsiveness. The main characteristics of asthma include variable reversible airflow limitation and airway remodeling. The pathogenesis of asthma is still unclear. Th1/Th2 imbalance, Th1 deficiency and Th2 hyperfunction are classic pathophysiological mechanisms of asthma. Some studies have shown that the imbalance of the Th1/Th2 cellular immune model and Th17/Treg imbalance play a key role in the occurrence and development of asthma; however, these imbalances do not fully explain the disease. In recent years, studies have shown that γδT and γδT17 cells are involved in the pathogenesis of asthma. γδTreg has a potential immunosuppressive function, but its regulatory mechanisms have not been fully elucidated. In this paper, we reviewed the role of γδT17/γδTreg cells in bronchial asthma, including the mechanisms of their development and activation. Here we propose that γδT17/Treg cell subsets contribute to the occurrence and development of asthma, constituting a novel potential target for asthma treatment.

Effects of bevacizumab combined with oxaliplatin intrathoracic injection on tumor markers and survival rate in patients with malignant pleural effusion of lung cancer.

OBJECTIVE: This study aims to explore the therapeutic effects of bevacizumab combined with oxaliplatin on patients with malignant pleural effusion of lung cancer. METHODS: A total of 109 patients with malignant pleural effusion of lung cancer admitted to our hospital from March 2015 to April 2017 were selected as research objects. Among them, 59 patients treated with bevacizumab combined with oxaliplatin intrathoracic injection were enrolled in the observation group, and another 50 patients treated with oxaliplatin intrathoracic injection were enrolled in the regular group. Clinical efficacy and safety of the two groups were compared, as well as the expression of vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor (VEGFR) and tumor markers before and after treatment. The two groups of patients were followed up for 3 years to compare their prognosis, survival and quality of life. RESULTS: The cure rate of the observation group was higher than that of the regular group (P < 0.05), but there was no difference in the incidence of adverse reactions (P > 0.05). After treatment, VEGF, VEGFR and tumor markers in the observation group were significantly lower than those in the regular group (P < 0.05), while the survival rate and quality of life of the observation group were significantly higher than those in the regular group (P < 0.05). CONCLUSION: Bevacizumab combined with oxaliplatin intrathoracic injection is effective in treating malignant pleural effusion of lung cancer.