CD5 mediates the link between CD4+ CD39+ activated Treg cells and gastric cancer: A Mendelian randomization study

Gastric cancer (GC) remains one of the leading causes of cancer mortality worldwide. The tumor immune microenvironment plays a pivotal role in GC progression, with regulatory T cells (Tregs), particularly the CD4+ CD39+ subset, implicated in immune suppression. However, the causal role of CD4+ CD39+ Treg cells in GC remains unclear. Additionally, CD5, a T cell surface glycoprotein, may influence immune responses in cancer. This study aims to clarify the relationship between CD4+ CD39+ Treg cells and GC risk and explore the potential mediating role of CD5 using a Mendelian randomization (MR) approach. A bidirectional 2-sample MR analysis was conducted using genome-wide association study data. CD4+ CD39+ Treg cell data were sourced from the IEU genome-wide association study database (N = 2920), and GC data were retrieved from the FennGenn consortium (N = 2,88,444; 1307 cases, 2,87,137 controls). Analyses included inverse variance weighted, MR-Egger regression, weighted median, and Mendelian randomization-Pleiotropy RESidual Sum and Outlier to test robustness and pleiotropy. A 2-step MR was performed to evaluate the mediating role of CD5. Results indicated that increased CD4+ CD39+ Treg cell levels were associated with a reduced risk of GC (odds ratio [OR] = 0.907, 95% confidence interval [CI] = 0.829-0.993, P = .035). No heterogeneity or pleiotropy was observed, and reverse causality was excluded (OR = 0.983, 95% CI = 0.931-1.038, P = .530). Additionally, CD4+ CD39+ Treg cells influenced CD5 expression (OR = 0.970, 95% CI = 0.943-0.998, P = .035), and elevated CD5 levels were linked to increased GC risk (OR = 1.285, 95% CI = 1.030-1.603, P = .026). Mediation analysis revealed that CD5 accounted for 7.74% of the protective effect of CD4+ CD39+ Treg cells on GC. CD4+ CD39+ Treg cells are causally linked to a reduced risk of GC, with CD5 mediating a small but significant portion of this protective effect. These findings highlight the importance of immune regulation in GC and suggest that targeting CD5 could be a therapeutic strategy. Further research is needed to investigate additional mediators contributing to GC development.