The Roles and Mechanisms of TRAT1 in the Progression of Non-Small Cell Lung Cancer.

OBJECTIVE: T cell receptor-associated transmembrane adaptor 1 (TRAT1) is one of the hub genes regulating T cell receptors (TCRs). Herein, the roles of TRAT1 in the prognosis and immune microenvironment of non-small cell lung cancer (NSCLC) were investigated. METHODS: The expression and prognosis values of TRAT1 in NSCLC, and the relationship between TRAT1 expression levels and cancer immune cell infiltration was identified via the TIMER, UALCAN, TISIDB, and other databases. The mechanism of TRAT1 in NSCLC was analyzed using gene set enrichment analysis (GSEA). RESULTS: The expression level of TRAT1 was decreased in NSCLC tissues. Low TRAT1 expression was associated with shorter overall survival of patients with NSCLC and was related to gender, smoking, and tumor grade. TRAT1 was involved in regulating immune response, TCR signaling pathway, PI3K/AKT, and other processes. TRAT1 expression levels were positively correlated with immune cell infiltration in NSCLC. CONCLUSION: Down-regulation of TRAT1 expression was associated with an unfavorable prognosis and immune infiltration of NSCLC.

Clinical Roles of Risk Model Based on Differentially Expressed Genes in Mesenchymal Stem Cells in Prognosis and Immunity of Non-small Cell Lung Cancer.

The tumor microenvironment (TME) plays an important regulatory role in the progression of non-small cell lung cancer (NSCLC). Mesenchymal stem cells (MSCs) in the TME might contribute to the occurrence and development of cancer. This study evaluates the role of differentially expressed genes (DEGs) of MSCs and the development of NSCLC and develops a prognostic risk model to assess the therapeutic responses. The DEGs in MSCs from lung tissues and from normal tissues were analyzed using GEO2R. The functions and mechanisms of the DEGs were analyzed using the Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Additionally, the Cancer Genome Atlas (TCGA) database was used to determine the expression levels of the DEGs of MSCs in the NSCLC tissues. The prognostic factors of NSCLC related to MSCs were screened by survival analysis, meta-analysis, Cox regression analysis, and a prognostic risk model and nomogram was developed. The signaling mechanisms and immune roles that risk model participate in NSCLC development were determined via Gene Set Enrichment Analysis and CIBERSORT analysis. Compared to the normal tissues, 161 DEGs were identified in the MSCs of the lung tissues. These DEGs were associated with mechanisms, such as DNA replication, nuclear division, and homologous recombination. The overexpression of DDIT4, IL6, ITGA11, MME, MSX2, POSTN, and TRPA1 were associated with dismal prognosis of NSCLC patients. A high-risk score based on the prognostic risk model indicated the dismal prognosis of NSCLC patients. The nomogram showed that the age, clinical stage, and risk score affected the prognosis of NSCLC patients. Further, the high-risk model was associated with signaling mechanisms, such as the ECM-receptor interaction pathways, cytokine-cytokine receptor interaction, and MAPK pathways, involved in the progression of NSCLC and was also related to the components of the immune system, such as macrophages M0, T follicular helper cells, regulatory T cells. Therefore, the risk model and nomogram that was constructed on the basis of MSC-related factors such as POSTN, TRPA1, and DDIT4 could facilitate the discovery of target molecules that participate in the progression of NSCLC, which might also serve as new candidate markers for evaluating the prognosis of NSCLC patients.

Nlrp3 Inflammasome Inhibitor MCC950 Ameliorates Obliterative Bronchiolitis by Inhibiting Th1/Th17 Response and Promoting Treg Response After Orthotopic Tracheal Transplantation in Mice.

BACKGROUND: Obliterative bronchiolitis (OB) remains the major complication limiting long-term survival of patients after lung transplantation. We aimed to explore the effects of the selective NACHT, LRR, and PYD domains-containing protein 3 (Nlrp3) inflammasome inhibitor MCC950 on the pathogenesis of OB. METHODS: Mouse orthotopic tracheal transplants were performed to mimic OB. MCC950 (50 mg/kg) or saline was intraperitoneally injected daily. The luminal occlusion rate and collagen deposition were evaluated by hematoxylin and eosin and Masson's trichrome staining, respectively. Infiltration of CD4+, CD8+ T cells, and neutrophils was detected with immunohistochemical staining. The frequencies of T helper 1 cell (Th1), T helper 17 cell (Th17), and regulatory T cells (Treg) were measured by flow cytometry. Cytokine levels were measured by ELISA kits. RESULTS: MCC950 treatment significantly inhibited Nlrp3 inflammasome activation after allogeneic tracheal transplant and markedly decreased the luminal occlusion rate and collagen deposition in the allograft. The numbers of infiltrating CD4+, CD8+ T cells, and neutrophils in the allograft were also significantly reduced by MCC950 treatment. MCC950 dramatically decreased the frequencies of Th1/Th17 cells and the levels of interferon gamma/interleukin (IL)-17A and increased the Treg cell frequencies and IL-10 level; however, these effects were abolished by the addition of IL-1ß and IL-18 both in vitro and in vivo. OB was also rescued by the addition of IL-1ß and/or IL-18. CONCLUSIONS: Blocking Nlrp3 inflammasome activation with MCC950 ameliorates OB lesions. The mechanistic analysis showed that MCC950 regulated the balance of Th1/Th17 and Treg cells and that this process is partially mediated by inhibition of IL-1ß and IL-18. Therefore, targeting the Nlrp3 inflammasome is a promising strategy for controlling OB after lung transplantation.