IL-18 and Lower Risk for Lung Cancer: Triangulated Evidence from Germline Predictions, Pre-Diagnostic Measurements, and Tumor Expression

Abstract

Lung cancer remains the most common cause of cancer death globally. Dysregulation of immune response and inflammatory signaling is known to play an important role in lung tumorigenesis, but the causal drivers of this process have yet to be elucidated. To identify circulating inflammatory and immune-related proteins that influence risk for lung cancer we related genetically predicted plasma levels for 85 inflammation and immune proteins with susceptibility to lung cancer. Mendelian randomization (MR) analyses in 29,266 cases and 56,450 controls identified a candidate causal marker, IL-18, which conferred lower risk of lung cancer (OR per standard deviation increase: 0.85 [95% CI: 0.79-0.92]), in particular for adenocarcinoma (OR: 0.80 [95% CI: 0.72-0.89]). We subsequently validated this association using polygenic IL-18 predictions in the UK Biobank (HR highest vs. lowest quartile: 0.83 [95% CI: 0.72-0.95]) and using pre-diagnostic blood concentrations of IL-18 in 732 cases and 732 controls after controlling for the inhibitory role of IL-18BP (OR highest vs. lowest quartile: 0.63 [95% CI: 0.41-0.91]). Genetic colocalization suggested that IL-18 may act on lung cancer risk locally via lung tissue expression, and joint MR and tumor microenvironment analyses highlight CD8 T cells and NK cells as potential mediators. In addition to risk, IL-18 expression in adenocarcinoma tumor tissue was found to be associated with all-cause mortality in 480 TCGA samples after controlling for IL-18BP (HR per SD: 0.87 [95% CI: 0.78, 0.98]), which is in line with recent studies showing anti-tumor effects of IL-18. Our comprehensive genomic triangulation study thus highlights the potential for IL-18 as an aetiological biomarker and targetable for immune-oncology therapies.

Mendelian randomization study of interleukin (IL)-1 family and lung cancer

“…For example, MABp1, lowering IL-1α, appears to increase the risk of symptoms in patients with advanced colorectal cancer 9 , 19 . IL-18 is reported to be a candidate causal marker for lung cancer, as it confers a lower risk of developing lung cancer 20 . Furthermore, dysregulation of IL-36 signaling may have a role in cancer development, including lung, kidneys, and intestines, although few studies were conducted and suggested limited anti-tumor effects 21 .…”