SWI/SNF family mutations in advanced NSCLC: genetic characteristics and immune checkpoint inhibitors' therapeutic implication.

BACKGROUND: SWItch/Sucrose NonFermentable (SWI/SNF) mutations have garnered increasing attention because of their association with unfavorable prognosis. However, the genetic landscape of SWI/SNF family mutations in Chinese non-small-cell lung cancer (NSCLC) is poorly understood. In addition, the optimal treatment strategy has not yet been determined. PATIENTS AND METHODS: We collected sequencing data on 2027 lung tumor samples from multiple centers in China to comprehensively analyze the genomic characteristics of the SWI/SNF family within the Chinese NSCLC population. Meanwhile, 519 patients with NSCLC from Sun Yat-sen University Cancer Center were enrolled to investigate the potential implications of immunotherapy on patients with SWI/SNF mutations and to identify beneficial subpopulations. We also validated our findings in multiple publicly available cohorts. RESULTS: Approximately 15% of Chinese patients with lung cancer harbored mutations in the SWI/SNF chromatin remodeling complex, which were mutually exclusive to the EGFR mutations. Patients with SWI/SNFmut NSCLC who received first-line chemoimmunotherapy had better survival outcomes than those who received chemotherapy alone (median progression-free survival: 8.70 versus 6.93 months; P = 0.028). This finding was also confirmed by external validation using the POPLAR/OAK cohort. SWI/SNFmut NSCLC is frequently characterized by high tumor mutational burden and concurrent TP53 or STK11/KEAP mutations. Further analysis indicated that TP53 and STK11/KEAP1 mutations could be stratifying factors in facilitating personalized immunotherapy and guiding patient selection. CONCLUSIONS: This study provides a step forward in understanding the genetic and immunological characterization of SWI/SNF genetic alterations. Moreover, our study reveals substantial benefits of immunotherapy over chemotherapy for SWI/SNF-mutant patients, especially the SWI/SNFmut and TP53mut subgroups.

Dose dependency PM2.5 aggravated airway inflammation in asthmatic mice via down-regulating expression of ITGB4.

OBJECTIVE: We aimed to investigate whether PM2.5 has the potential to exacerbate neutrophil airway inflammation and to analyze the underlying mechanisms. MATERIALS AND METHODS: The high-volume air sampler (Laoying 2033B, Qingdao, China) was used to collect PM2.5 from January 01, 2016 to December 21, 2016 in Yantai, Shandong Province, China. BALB/c mice were divided into the following four groups: control group, ovalbumin (OVA) group, low-dose PM2.5 group and high-dose PM2.5 group. Mice except for control group were sensitized and challenged by OVA, and those in low-dose PM2.5 group and high-dose PM2.5 group were intranasally administered by PM2.5 suspension. Airway responsiveness of mice was measured. Enzyme-linked immunosorbent assay (ELISA) kit was used to evaluate the expressions of interleukin 17 (IL-17) and tumor necrosis factor-α (TNF-α) in bronchoalveolar lavage fluid (BALF) and serum samples. Cell counting in BALF and histological examination were measured to explore PM2.5-induced airway inflammation. Protein expression of Integrin ß4 (ITGB4) was assessed by Western blot. RESULTS: Airway hyperresponsiveness (AHR) exacerbated in PM2.5 exposed asthmatic mice in progressively increased doses of acetylcholine chloride (ACH). Levels of IL-17 and TNF-αin BALF and serum increased significantly in PM2.5 groups compared with other groups with significant differences between two PM2.5 groups. PM2.5 exposure exacerbated inflammatory cell infiltration and mucus secretion in airways of asthmatic mice. Percentage of neutrophils in PM2.5 groups was significantly higher in dose-dependent manner. OVA and PM2.5 co-exposure inhibited the expression of ITGB4. In particular, ITGB4 expression in mice of high-dose PM2.5 group was significantly lowered than the low-dose PM2.5 group. CONCLUSIONS: We showed that PM2.5 exposure exacerbates neutrophil airway inflammation in asthmatic mice though up-regulating expressions of IL-17 and TNF-α but down-regulating the expression of ITGB4.

IL-9 exacerbates the development of chronic obstructive pulmonary disease through oxidative stress.

OBJECTIVE: To investigate the role of IL-9 in chronic obstructive pulmonary disease (COPD), and to explore its potential mechanism. MATERIALS AND METHODS: A mouse COPD model was established by exposure to cigarette smoke. COPD mice were then randomly assigned into two groups, including: the PBS group and the IL-9 antibody group. The above two groups were treated with phosphate-buffered saline (PBS) or IL-9 injection, respectively. The histopathological changes in lung tissues of mice were observed by hematoxylin-eosin (H&E) staining. Immunohistochemistry was performed to detect IL-9-positive (IL-9+) cells in lung tissues. Expression levels of IL-9, sIL-9R, STAT3, and p-STAT3 in peripheral blood of mice were determined by quantitative Real time-polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay (ELISA), and Western blot, respectively. In addition, the expression levels of superoxide dismutase (SOD), malondialdehyde (MDA), and reactive oxygen species (ROS) were detected. RESULTS: H&E staining results showed that the airway wall structure of COPD mice in the PBS group was irregular. Ciliated columnar epithelium exhibited marked degeneration, necrosis and shedding. Besides, numerous inflammatory cell infiltration, narrowing and rupture of the alveolar septa, and larger cysts fused by adjacent alveoli were observed. H&E staining also indicated that the structure of alveolar epithelium was severely impaired in COPD mice. However, the pathological changes in lung tissues of mice in the IL-9 antibody group were much milder than those of the PBS group. Immunohistochemistry results showed a significant deposition of IL-9+ cells in the lung tissues of the PBS group. Meanwhile, the mRNA and protein levels of IL-9, sIL-9R, and p-STAT3 in the PBS group were also remarkably higher than those of the IL-9 antibody group. In addition, SOD content in the PBS group was significantly decreased, whereas the levels of MDA and ROS were significantly increased than those of the IL-9 antibody group. CONCLUSIONS: IL-9 activated STAT3 and aggravated lung injury in COPD mice by increasing inflammatory and oxidative stress.