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Bioinformatics-based screening and analysis of the key genes involved in the influence of antiangiogenesis on myeloid-derived suppressor cells and their effects on the immune microenvironment

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Abstract

This study aimed to screen differentially expressed genes (DEGs) involved in the influence of antiangiogenic therapy on myeloid-derived suppressor cell (MDSC) infiltration and investigate their mechanisms of action. Data on DEGs after the action of antiangiogenic drugs in a pan-cancer context were obtained from the Gene Expression Omnibus (GEO) database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using the clusterProfiler package in R software. Single-sample gene set enrichment analysis was performed using the gene set variation analysis package to evaluate the levels of immune cells and the activity of immune-related pathways. The relationships of DEGs with the infiltration levels of MDSCs and specific immune cell subpopulations were investigated via gene module analysis. The top 10 key genes were subsequently obtained from PPI network analysis using the cytoHubba plugin of the Cytoscape platform. When the DEGs of the four datasets were intersected, a DEG in the intersection of three datasets and 12 DEGs in the intersection of two datasets were upregulated, and 28 DEGs in the intersection of two datasets were downregulated. GO and KEGG pathway enrichment analyses revealed that the DEGs were associated with multiple important signaling pathways closely related to tumor onset and development, including cell differentiation, cell proliferation, the cell cycle, and immune responses. Most downregulated genes in lung adenocarcinoma (LUAD) were positively correlated with MDSC expression. Only MGP was negatively correlated; the correlation between CACNG6 and MDSC expression was statistically insignificant. In lung squamous cell carcinoma (LUSC), the relationships of PMEPA1, PCDH7, NEURL1B, and CACNG6 with MDSC expression were statistically insignificant; MGP was negatively correlated with MDSC expression. The top 10 key genes with the highest degree scores obtained using the cytoHubba plugin of Cytoscape were AURKB, RRM2, BUB1, NUSAP1, PRC1, TOP2A, NCAPH, CENPA, KIF2C, and CCNA2. Most of these genes were upregulated in LUAD and associated with immune cell infiltration and prognosis in tumors. An analysis of the relationships between DEGs and infiltration by other specific immune cells revealed the presence of consistent patterns in the downregulated genes, which exhibited positive correlations with the levels of Th2 cells, γδ T cells, and CD56dim NK cells, and negative correlations with other infiltrating immune cells. Antiangiogenic therapy may regulate MDSC infiltration through multiple important signaling pathways closely associated with tumor onset and development, such as cell differentiation, cell proliferation, the cell cycle, and immune responses. Antiangiogenic drugs may exert effects by affecting various types of infiltrating cells associated with immune suppression.

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Data availability

These data were derived from the following resources available in the public domain: GEO (Gene Expression Omnibus) https://www.ncbi.nlm.nih.gov/gds, TCGA (The cancer genome atlas) https://portal.gdc.cancer.gov/, TIMER (Tumor Immune Estimation Resource) https://cistrome.shinyapps.io/timer/.

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Acknowledgements

The authors thank and extend their appreciation to all the staff members of Department of Oncology of PLA General Hospital and Devices for their assistance and support. We also sincerely acknowledge the anonymous reviewers for their insights and comments to improve the quality of the manuscript.

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  1. XiangFei Zhao and RuGang Zhao contributed equally to this work as co-first authors.

Authors and Affiliations

  1. Department of Oncology, 5th Medical Center of Chinese, PLA General Hospital, Dongdajie 8th, Fengtai District, Beijing, 100853, China

    XiangFei Zhao, RuGang Zhao, JuYi Wen, Xia Zhang, ShanShan Wu, Juan Fang & Yi Hu

  2. Department of Oncology, 6th Medical Center of Chinese, PLA General Hospital, Beijing, China

    JunPeng Ma & LiPin Gao

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  1. XiangFei Zhao
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Zhao, X., Zhao, R., Wen, J. et al. Bioinformatics-based screening and analysis of the key genes involved in the influence of antiangiogenesis on myeloid-derived suppressor cells and their effects on the immune microenvironment. Med Oncol 41, 96 (2024). https://doi.org/10.1007/s12032-024-02357-x

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