• Jianfei Zhu, Zhenzhen Li, Jie Chen, Wensheng Li, Hongtao Wang, Tao Jiang, and Yu Ma.
• Department of Thoracic Surgery, Shaanxi Provincial People's Hospital, Xi'an City, Shaanxi Province, China.
• Medicine (Baltimore). 2022 Dec 16; 101 (50): e32102e32102.

AbstractFork head box p3 (FOXP3), the specific transcription factors of Tregs, not only in Tregs, but also expressed in cancer cells of certain malignant tumors. The histological positioning of FOXP3 in nonsmall cell lung cancer (NSCLC) and its biological significance are still unclear. This study aims to clarify the biological function of FOXP3 in NSCLC through bioinformatics analysis. Tumor immune estimation resource database was used to analyze the mRNA expression of FOXP3 in pan cancer, and to analyze the correlation between FOXP3 expression and tumor microenvironment cell infiltration. Overall survival and disease-free survival analyses were performed using a Kaplan-Meier plotter. Immunohistochemistry staining of FOXP3 was performed using human protein atalas (HPA) database, and immunofluorescence (IF) staining was used to verify gene expression and identify cell types. Protein-protein interaction (PPI) networks were drawn using STRING and visualized by Cytoscape. The functional and pathway enrichment analysis of FOXP3 used the DAVID database. In NSCLC, whether it is lung squamous cell carcinoma (P < .001) or lung adenocarcinoma (P < .001), FOXP3 is highly expressed in cancer tissue compared with normal tissue. Immunohistochemistry results showed that FOXP3 was mainly expressed in Tregs, but not in lung cancer tissues. IF staining showed that FOXP3 and CD3 (a marker of T cells) were co-expressed in immune cells. Moreover, survival analysis showed that high FOXP3 expression could be used as a predictor of poor overall survival (HR: 1.25, P = .00065) and disease-free survival (HR: 1.88, P = 1.1E-10) in patients with NSCLC. Next, we identified an important module containing 11 genes in the PPI network, including JUN, NFATC, STAT3, IRF4, IL2, IFGN, CTLA4, TNFRSF18, IL2A, KAT5, and FOXP3. KEGG signaling pathway was enriched in T cell receptor signaling pathway, Jak-STAT signaling pathway, cytokine-cytokine receptor interaction. Finally, we observed that FOXP3 expression correlated with infiltration of CD8 + T cells (R = 0.276, P = 5.90E-10), CD4 + T cells (R = 0.643, P = 6.81E-58), neutrophils (R = 0.525, P = 1.57E-35), and dendritic cells (R = 0.608, P = 1.35E-50) in lung adenocarcinoma, the same results were observed in lung squamous cell carcinoma. The infiltration of FOXP3-positive Tregs might promote the malignant progression of NSCLC, and targeted intervention of Tregs may be a potential treatment option for patients with NSCLC.Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.

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