Clinical Characterization of the Expression of Insulin-Like Growth Factor Binding Protein 1 and Tumor Immunosuppression Caused by Ferroptosis of Neutrophils in Non-Small Cell Lung Cancer

Yuandi Wang; Lijuan Xing; Lexiu Deng; Xinsheng Wang; Dandan Xu; Bu Wang; Zhihua Zhang

doi:10.2147/IJGM.S401225

Clinical Characterization of the Expression of Insulin-Like Growth Factor Binding Protein 1 and Tumor Immunosuppression Caused by Ferroptosis of Neutrophils in Non-Small Cell Lung Cancer

Int J Gen Med. 2023 Mar 21:16:997-1015. doi: 10.2147/IJGM.S401225. eCollection 2023.

Authors

Yuandi Wang^#^{1

2}, Lijuan Xing^#², Lexiu Deng^{1

2}, Xinsheng Wang², Dandan Xu², Bu Wang², Zhihua Zhang^#²

Affiliations

¹ Graduate School, Hebei North University, Zhangjiakou City, Hebei Province, People's Republic of China.
² Department of Respiratory and Critical Care Clinical Medicine, The First Affiliated Hospital of Hebei North University, Zhangjiakou City, Hebei Province, People's Republic of China.

^# Contributed equally.

Abstract

Purpose: The efficacy of immunotherapy for non-small cell lung cancer (NSCLC) is limited owing to cold tumors and drug resistance. Therefore, it is important to identify the molecular mechanisms underlying immune evasion in NSCLC. Spontaneous ferroptosis of neutrophils has been suggested as a key mechanism of immunosuppression in cancer. Insulin-like growth factor binding protein 1 (IGFBP1) plays an important role in immune infiltration in several cancers. However, the role of IGFBP1 in NSCLC is unknown. Therefore, in this study, we aimed to investigate the association of IGFBP1 mRNA expression with infiltration of myeloid-derived suppressor cells and prognosis in NSCLC.

Patients and methods: Retrospective RNA-seq data from 990 patients in the Cancer Genome Atlas (TCGA) database were analyzed in relation to patient clinical characteristics. The Timer2 database was used to assess immune infiltration, and the FerrDb V2 database was used to obtain ferroptosis-related genes. Finally, the results were validated by the proteomic analysis of serum samples collected from six patients with NSCLC and six healthy individuals.

Results: IGFBP1 expression was enriched in lung adenocarcinoma samples and positively correlated with the pathological grade of NSCLC. IGFBP1 expression was an independent prognostic factor for the overall survival of patients with NSCLC. In addition, IGFBP1 expression correlated with myeloid-derived suppressor cell infiltration. Notably, Gene Ontology analysis of IGFBP1-related genes revealed that the major molecular functions of their protein products were related to NADP⁺ 1-oxidoreductase activity. Furthermore, expression levels of multiple ferroptosis suppressor genes positively correlated with IGFBP1 expression.

Conclusion: High IGFBP1 expression indicates a poor prognosis in patients with NSCLC, which may be related to tumor immunosuppression caused by neutrophil ferroptosis.

Keywords: immune infiltration; immunotherapy; lung adenocarcinoma; lung squamous cell carcinoma; myeloid-derived suppressor cells.