Prospective examination of cellular and soluble mediators of immune dysregulation and their association with lung cancer risk.

Abstract

Background: There are currently no blood-based biomarkers for early detection of lung cancer. We explored cellular and soluble mediators of immune dysregulation as potential biomarkers of lung cancer risk and development. We conducted a prospective nested case-control study of incident lung cancer cases and individually matched healthy controls from the Pittsburgh Lung Screening Study (PLuSS) cohort of current and former smokers at high risk for developing lung cancer.

Methods: Peripheral blood mononuclear cells (PBMCs) were analyzed by Flow Cytometry, and Meso Scale Discovery multiplex platform immunoassay was used for detection of serum cytokines and chemokines at a distal (~7 years prior) and a proximal (~9 months prior) timepoint prior to cancer diagnosis. A linear mixed model was used to assess differences of analytes between cases and controls. Conditional logistic regression models were used to evaluate associations between levels of analytes and lung cancer risk.

Results: No significant PBMC differences were found between cases and controls. Serum interleukin-6 (IL-6), IL-12/IL-23p40, IL-17A, and tumor-necrosis factor-α (TNFα) were significantly higher in cases than controls (P < 0.05) at the proximal timepoint. Cases had higher levels of angiogenic protein-placental growth factor (PlGF) in sera from both distal and proximal timepoints (P < 0.05). Doubling concentrations of these analytes were associated with a 40% to 300% increase in lung cancer risk (P < 0.05).

Conclusions: These circulating candidate biomarkers warrant further validation for early detection of lung cancer and identification of elevated risk.

Impact: If validated in larger studies, these biomarkers could have clinical relevance.