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Background: Programmed cell death ligand 1 (PD‐L1) is widely known as an immune checkpoint molecule in tumor cells. Osteopontin (OPN) is expressed by both tumor cells and tumor‐associated macrophages (TAMs), and both autocrine and paracrine of OPN are considered to be involved in tumor metastasis, proliferation and immunosuppression. However, little is known about the relationship between OPN expressed in TAMs (TOPN) and PD‐L1 in non‐small cell lung cancer (NSCLC). Methods: Tissue microarray was used to detect the expression of TOPN, TAMs and PD‐L1 by multiple quantitative fluorescence staining in 509 NSCLC patients undergoing complete pulmonary resection. The correlations between TOPN, PD‐L1 and clinicopathological data were analyzed. An in vitro coculture system was established to investigate the crosstalk between TOPN and neoplastic PD‐L1. In vivo, the intrinsic features of PD‐L1 in NSCLC xenografts were evaluated after being coinjected with OPN‐positive TAMs, and a series of key cytokines and chemokines were detected in the tumor microenvironment. Results: A positive association between the TOPN and PD‐L1 expression in tumor tissues from 509 patients with NSCLC was verified. In addition, TOPN and PD‐L1 were independent prognostic factors for overall survival (OS) and disease‐free survival (DFS) of NSCLC patients. Moreover, TOPN upregulated PD‐L1 expression in NSCLC cells through the nuclear factor‐κB (NF‐κB) pathway in vitro TOPN induced the PD‐L1 expression promoted the tumor growth in tumor‐bearing mice, altering immune‐related cytokines and chemokines. Conclusions: TOPN regulates PD‐L1 expression through the NF‐κB pathway in NSCLS, which is a potential independent biomarker and target for prognosis as well as immunotherapy. [ABSTRACT FROM AUTHOR]

Background: With the ongoing development of targeted therapy and immunotherapy in recent years, the overall five‐year survival rate of NSCLC patients has not improved, and the search for novel diagnostic and prognostic markers for lung adenocarcinoma continues. Methods: Lung adenocarcinoma (LUAD) gene expression data and relevant clinical information were obtained from the TCGA. Hub genes were identified with weighted gene co‐expression network analysis (WGCNA) and protein–protein interaction network (PPI). Survival analyses were also performed using GEPIA. The 536 LUAD patients were divided into two groups according to the SPRR1B expression level and analyzed by gene set enrichment analysis (GSEA) and verified by immunoblotting. The effects of SPRR1B on cell proliferation and cell metastasis and apoptosis were evaluated by 5‐ethynyl‐2′‐deoxyuridine (EdU) staining, colony formation assay, transwell migration and invasion assay, and flow cytometry, respectively. Results: A total of 2269 DEGs were analyzed by WGCNA and five hub genes (CCK, FETUB, PCSK9, SPRR1B, and SPRR2D) were identified. Among them, SPRR1B was selected as one of the most significant prognostic genes in LUAD. SPRR1B was found to be highly expressed in lung adenocarcinoma cells compared with that in normal bronchial epithelial cells. In addition, silencing of SPRR1B could inhibit the cell proliferation, invasion, and migration of lung adenocarcinoma cells, but induced cell apoptosis and G2/M phase arrest in vitro. The result of GSEA and immunoblotting revealed that SPRR1B activated the MAPK signaling pathway involved in the proliferation and metastasis of lung cancer. Conclusions: Our findings demonstrate that SPRR1B may function as a prognosis predictor in lung adenocarcinoma. [ABSTRACT FROM AUTHOR]