The neutrophils exhibit both anti-tumor and pro-tumor effects in cancers. The correlation between neutrophils and tumor development in lung adenocarcinoma (LUAD) is still uncertain, possibly due to a lack of specific neutrophil infiltration evaluation methods. In this study, we identified 30 hub genes that were significantly associated with neutrophil infiltration in LUAD through data mining, survival analysis, and multiple tumor-infiltrating immune cells (TICs) analysis, including TIMER, CIBERSORT, QUANTISEQ, XCELL, and MCPCOUNTER. Consensus clustering analysis showed that these 30 hub genes were correlated with clinical features in LUAD. We further developed a neutrophil scoring system based on these hub genes. The neutrophil score was significantly correlated with prognosis and tumor immune microenvironment (TIME) in LUAD. It was also positively associated with PD-L1 expression and negatively associated with tumor mutational burden (TMB). When combined with the neutrophil score, the predictive capacity of PD-L1 and TMB for prognosis was significantly improved. Thus, the 30 hub genes might play an essential role in the interaction of neutrophils and LUAD, and the neutrophil scoring system might effectually assess the infiltration of neutrophils. Furthermore, we verified the expression of these 30 genes in the LUAD tumor tissues collected from our department. We further found that overexpressed TNFAIP6 and TLR6 and downregulated P2RY13, SCARF1, DPEP2, PRAM1, CYP27A1, CFP, GPX3, and NCF1 in LUAD tissue might be potentially associated with neutrophils pro-tumor effects. The following in vitro experiments demonstrated that TNFAIP6 and TLR6 were significantly overexpressed, and P2RY13 and CYP27A1 were significantly downregulated in LUAD cell lines, compared to BEAS-2B cells. Knocking down TNFAIP6 in A549 and PC9 resulted in the upregulation of FAS, CCL3, and ICAM-1, and the downregulation of CCL2, CXCR4, and VEGF-A in neutrophils when co-culturing with the conditioned medium (CM) from LUAD cells. Knocking down TNFAIP6 in LUAD also led to an elevated early apoptosis rate of neutrophils. Therefore, overexpressed TNFAIP6 in LUAD cancer cells might lead to neutrophils “N2” polarization, which exhibited pro-tumor effects. Further research based on the genes identified in this pilot study might shed light on neutrophils’ effects on LUAD in the future.

Background: Lung cancer is the first cause of cancer mortality worldwide. Chronic obstructive pulmonary disease (COPD) is an independent risk factor for lung cancer. An epidemiological survey discovered that the presence of COPD increases the risk of lung cancer by 4.5‐fold. Lobectomy is considered to be the standard surgical method for early stage non‐small cell lung cancer (NSCLC). However, the influence of lobectomy on the loss of pulmonary function has not been fully investigated in NSCLC patients with COPD.Methods: We searched the PubMed database using the following strategies: COPD and pulmonary function test (MeSH term) and lobectomy (MeSH term) from 01 January 1990 to 01 January 2019. We selected the articles of patients with COPD. A total of six studies, including 195 patients with COPD, provided lung function values before and after surgery.Results: Five out of six studies focused on the short‐term change of pulmonary function (within 3–6 months) after lobectomy, and the average loss of FEV1 was 0.11 L (range: −0.33–0.09 L). One study investigated the long‐term change of pulmonary function (within 1–2 years) after lobectomy, and the average loss of FEV1 was 0.15 L (range: −0.29–0.05 L).Conclusions: A short‐term (3–6 months) loss of pulmonary function after operation is acceptable for lung cancer patients with COPD. However, there may be a high risk of postoperative complications in NSCLC patients with COPD. Therefore, surgical treatment needs to be carefully considered for these patients.

Background: While neutrophil extracellular traps (NETs) have been shown to contribute to cancer progression, including that of lung adenocarcinoma, the mechanisms underlying NET formation within the tumor immune microenvironment (TIME) remain incompletely understood. Notably, neutrophil infiltration has been strongly linked to tumor necrosis factor alpha-inducible protein 6 (TNFAIP6) expression. Methods: In vitro and in vivo experiments were performed. DNA pulldown coupled with mass spectrometry, bioinformatics analyses, immunohistochemistry, and dual-luciferase reporter assays were conducted. DNA pulldown Western blotting, chromatin immunoprecipitation–quantitative PCR, and dual-luciferase reporter assays using truncated promoter constructs were also employed. Results: TNFAIP6 expressed by lung adenocarcinoma cells was shown to induce NET formation (a form of programmed cell death called NETosis). Mechanistically, TNFAIP6 interacted with CD44 in lung adenocarcinoma cells, leading to increased extracellular availability of secreted phosphoprotein 1 (SPP1) within the TIME and the subsequent promotion of NETosis. Additionally, nucleophosmin 1 (NPM1) significantly enhances the transcriptional activation of TNFAIP6 and associates with the −2000 to −1700 bp region of its promoter. Conclusions: These findings delineate a regulatory model in which lung adenocarcinoma cells directly stimulate NETosis through the NPM1–TNFAIP6–CD44–SPP1 axis, suggesting that therapeutic targeting of this pathway may attenuate tumor progression.

Background: Neutrophil extracellular traps (NETs) promote tumor progression and immune evasion across multiple cancers. However, the mechanisms governing NET formation (NETosis) within the tumor immune microenvironment remain incompletely understood. Low P2RY13 expression is associated with the pro-tumor activity of neutrophils in lung adenocarcinoma. Methods: Pan-cancer bioinformatics analyses were performed, including differential gene expression, prognostic, tumor-infiltrating immune cell, and NET scoring analyses. Single-cell profiling was conducted using the Tumor Immune Single-cell Hub 2 database. Immunohistochemical (IHC) and multiplex immunofluorescence (mIF) staining of tissue microarrays (TMAs) was performed to validate findings in lung adenocarcinoma (LUAD), liver hepatocellular carcinoma (LIHC), and colorectal cancer (CRC). In vitro validation was conducted using gene modulation, tumor-cell-conditioned medium (CM) education, tumor-associated macrophage (TAM)-like macrophage CM transfer, immunofluorescence staining, and ELISA. Results: Bioinformatics analyses suggested that P2RY13 is frequently dysregulated in multiple cancers and that low P2RY13 expression is associated with poor prognosis and reduced immunotherapy responsiveness. Single-cell analyses revealed that P2RY13 is predominantly expressed in TAMs rather than tumor cells. Macrophages without detectable P2RY13 transcripts were markedly enriched in tumor tissues compared with paired normal tissues, and their high infiltration appeared to be associated with elevated NET scores. Tissue microarray-based IHC and mIF analyses further validated this infiltration pattern in LUAD, LIHC, and CRC. In vitro, CM from P2RY13-silenced, tumor-educated TAM-like macrophages enhanced neutrophil NETosis, whereas P2RY13 re-expression attenuated this effect. Furthermore, TMA staining indicated a positive correlation between P2RY13⁻CD68⁺ TAM infiltration and NET expression in the three malignancies. Conclusions: We identified a potentially conserved NETosis-regulating pattern in multiple cancers in which P2RY13-negative TAMs promote NET formation and are associated with adverse clinical outcomes. These findings suggest a previously unrecognized tumor-promoting mechanism and highlight potential therapeutic targets for cancer treatment.