Lifetime Exposure to Cigarette Smoke, B Cell Tumor Immune Infiltration, and Immunoglobulin Abundance in Ovarian Tumors

Abstract Background: Cigarette smoke exposure has been linked to systemic immune dysfunction, including for B cell and immunoglobulin (Ig) production, and poor outcomes in ovarian cancer patients. No study has evaluated the impact of smoke exposure across the lifecourse on B cell infiltration and Ig abundance in ovarian tumors. Methods: We measured markers of B and plasma cells and Ig isotypes using multiplex immunofluorescence on 395 ovarian cancer tumors in the Nurses’ Health Study (NHS)/NHSII. We conducted beta-binomial analyses evaluating odds ratios (OR) and 95% confidence intervals (CI) for positivity of immune markers by cigarette exposure among cases and Cox proportional hazards models to evaluate hazard ratios (HR) and 95%CI for developing tumors with low (<median) or high (≥median) immune cell/Ig percentage. Results: There were no associations between smoke exposure and B cell or IgM infiltration in ovarian tumors. Among cases, we observed higher odds of IgA+ among ever smokers (OR: 1.54, 95%CI: 1.14, 2.07) and ever smokers with no parental smoke exposure (OR: 2.03, 95%CI: 1.18, 3.49) versus never smokers. Women with parental cigarette smoke exposure versus not had higher risk of developing ovarian cancer with low IgG+ (HR: 1.51, 95%CI: 1.10, 2.09), while ever versus never smokers had a lower risk (HR: 0.74, 95%CI: 0.56,0.99). Conclusions: Ever smoking was associated with increased odds of IgA in ovarian tumors. Impact: IgA has been associated with improved ovarian cancer outcomes, suggesting that although smoking is associated with poor outcomes in ovarian cancer patients, it may lead to improved tumor immunogenicity.