ITGB4/GNB5 axis promotes M2 macrophage reprogramming in NSCLC metastasis

Xiaofeng Huang; Guiping Yu; Xuewei Jiang; Fei Shen; Dengshu Wang; Song Wu; Yedong Mi

doi:10.1016/j.intimp.2024.113564

ITGB4/GNB5 axis promotes M2 macrophage reprogramming in NSCLC metastasis

Int Immunopharmacol. 2024 Nov 21:144:113564. doi: 10.1016/j.intimp.2024.113564. Online ahead of print.

Authors

Xiaofeng Huang¹, Guiping Yu¹, Xuewei Jiang¹, Fei Shen¹, Dengshu Wang¹, Song Wu², Yedong Mi³

Affiliations

¹ Department of Cardiothoracic Surgery, Jiangyin Clinical College of Xuzhou Medical University, Jiangyin 214400, China.
² Department of Cardiothoracic Surgery, Jiangyin Clinical College of Xuzhou Medical University, Jiangyin 214400, China. Electronic address: wu_song@126.com.
³ Department of Cardiothoracic Surgery, Jiangyin Clinical College of Xuzhou Medical University, Jiangyin 214400, China. Electronic address: miyedong@126.com.

PMID: 39577216
DOI: 10.1016/j.intimp.2024.113564

Abstract

Objective: Metastasis of non-small cell lung cancer (NSCLC) is a leading cause of high mortality. In recent years, the role of M2 macrophages in promoting tumor metastasis within the tumor microenvironment has garnered increasing attention. This study aims to investigate the role and potential mechanisms of the ITGB4/GNB5 axis in regulating M2 macrophage reprogramming and influencing NSCLC metastasis.

Methods: This study first used single-cell sequencing technology to reveal the diverse subpopulation structure of NSCLC tumor tissues. Data analysis then identified the correlation between M2 macrophages and the malignant phenotype of NSCLC. Flow cytometry and immunohistochemistry were used to detect changes in M2 macrophages in NSCLC tissues. The impact of the ITGB4/GNB5 axis on M2 macrophage function was assessed through RNA sequencing and proteomic analysis. Finally, in vitro cell experiments and in vivo mouse models were used to validate the function and regulatory mechanisms of this axis.

Results: Our study found diverse cellular subpopulations in NSCLC tumor tissues, with M2 macrophages closely associated with the malignant phenotype of NSCLC. We identified ITGB4 as a characteristic gene of NSCLC and predicted GNB5 as an interacting gene through database analysis. Activation of the ITGB4/GNB5 axis was shown to enhance M2 macrophage polarization, promoting their accumulation in the tumor microenvironment. This change further facilitated NSCLC invasion and metastasis by modulating related cytokines and signaling pathways. Animal experiments demonstrated that inhibition of the ITGB4/GNB5 axis significantly reduced tumor growth and metastasis.

Conclusion: The ITGB4/GNB5 axis reshapes the TME by promoting M2 macrophage polarization and functional enhancement, thereby facilitating tumor invasion and metastasis in NSCLC. This research provides new insights into the molecular mechanisms of NSCLC and offers potential molecular targets for future targeted therapies.

Keywords: ITGB4/GNB5 axis; M2 macrophages; Macrophage reprogramming; Non-small cell lung cancer; Single-cell transcriptome sequencing; Tumor immune microenvironment.