Association of Immune Cells, Inflammatory Cytokines, and Lung Cancer: A Mediating Mendelian Randomization Study

Lung cancer oncogenesis involves interactions between immune cells and inflammatory cytokines. However, their causal relationships and mediating mechanism remain unclear.

Using a mediating Mendelian randomization (MR) approach, we analyzed genome-wide association study (GWAS) data for 731 immune-cellular phenotypes, 41 cytokines, and eight related lung cancer phenotypes.

BAFF-R expression in IgD⁺ CD24⁺ B cells was positively associated with lung adenocarcinoma (LUAD) risk (odds ratio [OR], 1.0168 [95% confidence interval [CI], 1.0006-1.0332]), mediated by macrophage migration inhibition factor (MIF) with a mediation proportion of 14.2% (95% CI, 0.00007-0.0046). CD39 expression on secreting CD4 Tregs was related to an increased risk of small-cell lung cancer (SCLC) (OR, 1.0306 [95% CI, 1.0006-1.0616]), mediated by interleukin (IL)-2 and IL-6 with mediation proportions of 8.43% (95% CI, 0.00005-0.005) and 5.1% (95% CI, 0.00006-0.003), respectively. CD28 expression on CD39⁺ CD4⁺ T cells was positively correlated to lung squamous cell carcinoma (LUSC) risk (OR, 1.0335 [95% CI, 1.009-1.0586]), inversely mediated by IL-16 (95% CI, -0.01 to -0.0003).

These findings reveal the associations between immune cells, inflammatory cytokines, and lung cancer risk, providing insights into cancer diagnosis and treatment.