A Nested Case-Control Study of Lung Cancer for Immune Biomarkers

Abstract

<h3>Purpose/Objective(s)</h3> Smoking is the leading cause of lung cancer, which is the leading cause of cancer mortality worldwide, with 1.2 million deaths a year. Lung cancer has a very poor prognosis; over half of people diagnosed die within one year of diagnosis and the 5-year survival is less than 18%. Prior to cancer development, smokers develop multiple lung problems associated with chronic inflammation, which can promote progression to cancer. The aim of the study was to examine if immune competence would enhance or reduce the risk of lung cancer development among high-risk smokers. The hypothesis is that smokers who developed lung cancer would have a higher frequency of chronic inflammation induced myeloid-derived suppressor cells (MDSC) and/or regulatory T cells (Treg), three years or more prior to lung cancer diagnosis (baseline), compared to smokers who remained cancer-free. Additionally, smokers who developed cancer would have higher levels of certain inflammatory cytokines at baseline. <h3>Materials/Methods</h3> A case-control study of incident lung cancer was conducted within the participants of the Pittsburgh Lung Screening Study (PLuSS), a longitudinal low-dose CT screening study for early detection of lung cancer among smokers with a history of heavy smoking (median 47 pack-years of cigarette smoking). Cases consisted of 40 current or former smokers who developed lung cancer during follow-up after repeated blood draws and the control group consisted of 40 PLuSS participants, free of cancer, who were individually matched to the index case by age, sex, smoking status, and year of blood draw. Live peripheral blood mononuclear cells (PBMC) were thawed and analyzed for MDSC, CD4 T cells, and Treg by flow cytometry. Cytokines and chemokines were quantified in two repeated serum samples per subject using the next generation multiplex immunoassays. <h3>Results</h3> There was no statistically significant difference in overall MDSC percentage of PBMC nor in subtypes (PMN-MDSC, M-MDSC and e-MDSC) between cases and controls. There was also no difference found for Tregs. However, CD4 T cells were elevated in lung cancer cases and were associated with an increased risk of lung cancer overall (odds ratio [OR] = 2.61, 95% confidence interval [CI] = 0.73-9.32, p trend = 0.1409). Lung cancer cases had significantly higher levels of serum inflammatory cytokines IL-17A and Il-12/IL-23p40 at both early (median 84 months) and late time points (7 months prior to cancer diagnosis) (all <i>P</i>s < 0.05). <h3>Conclusion</h3> Lung cancer cases are associated with elevated levels of CD4 T cells and pro-inflammatory cytokines, specifically IL-17A and IL-12/IL-23p40, as early as 7 years before cancer diagnosis. The study has the potential to identify immune cells and soluble factors that mediate lung cancer development in smokers and could be used as early biomarkers for risk assessment or early diagnosis of lung cancer.