Genetic association between immune cells and oral cancer: A Mendelian randomization study

Oral cancer is a common malignancy with an increasing incidence. Although the tumor microenvironment is essential for oral cancer development, the causal relationships between immune cell phenotypes, cytokines, and oral cancer remain unclear.

To investigate the causal relationships between immune cells, cytokines, and oral cancer.

Using large-scale genome-wide association study (GWAS) data, we performed bidirectional Mendelian randomization to evaluate causal relationships among 731 immune cell phenotypes, 41 cytokines, and oral cancer. Single-cell RNA sequencing data were used for validation.

A causal link was identified between 29 immune cell phenotypes and oral cancer. The absolute counts of activated and secretory CD4 Tregs (OR=1.056, 95% CI: 1.005-1.109) and their ratio to total CD4 Tregs (OR=1.064, 95% CI: 1.022-1.107) were positively correlated with the risk of oral cancer. In contrast, the ratios of resting CD4 Tregs to total CD4 Tregs (OR=0.931, 95% CI: 0.891-0.972) and resting CD4 Tregs to CD4+ T cells (OR=0.925, 95% CI: 0.885-0.967) were negatively correlated with the risk of oral cancer. Reverse analysis indicated that oral cancer could influence 41 immune cell phenotypes. Elevated levels of RANTES (CCL5) were found to increase the risk of oral cancer, while oral cancer significantly raised β-nerve growth factor (NGF) levels. These findings were corroborated by single-cell sequencing analyses.

This study reveals multiple causal relationships between various immune cell phenotypes and oral cancer, highlighting that activated and secretory CD4 Tregs may increase the risk of oral cancer. It also identifies CCL5 and NGF as potentially important cytokines in oral tumorigenesis, providing possible therapeutic targets for oral cancer treatment.