Exploring the link between heart failure and cancer: insights into immune mechanisms and therapeutic targets for CD8 + T-cells

Abstract

Background Heart failure (HF) is a terminal condition of multiple cardiovascular disorders. Cancer is a highly prevalent and deadly disease worldwide. However, the relationship between HF and cancer remains poorly understood. Therefore, there is a critical need to explore the potential mechanisms and therapeutic targets shared between HF and cancer. Method The Gene Expression Omnibus (GEO) database was used to download the RNA sequencing (RNA-seq) data of 356 patients, including individuals with HF and those without HF, to establish a co-expression network using the weighted correlation network analysis (WGCNA) algorithm, to calculate the compositions of immune infiltrating cells in the CIBERSORT algorithm, and to identify candidate hub genes within the modules of individuals with HF. Pearson Correlation Analysis was employed to identify the correlation between hub genes and CD8+T-cells in HF, as well as between hub genes and both tumor mutation burden (TMB) and microsatellite instability (MSI) across cancers. Molecular biology experiments were conducted to confirm the correlation between the hub genes and HF. Finally, the NetworkAnalyst database and the CellMiner database were utilized to predict the transcription factors (TFs) and potential therapeutic drugs of hub genes, respectively. Results HF was significantly linked to immune response pathway by the analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). The brown and blue modules, identified by WGCNA, were the primary modules related to CD8+T-cells. Concomitantly, we observed a positive correlation between the expression levels of the four hub genes and the infiltration of CD8+T-cells in pan-cancer. Additionally, western blotting and real-time polymerase chain reaction (RT-PCR) validated the high expression of three hub genes (GZMM, NKG7, and ZAP70) in both mice and patients with HF compared to those in the control group. Finally, the hub gene-associated TF-gene networks and 11 agents targeting the hub genes were successfully predicted. Conclusion Our study highlights the shared pathogenesis of HF and cancer and provides valuable insights for developing novel therapeutic strategies that target shared pathways, offering new opportunities for improving the management and treatment outcomes of both HF and cancer.