Lifetime Exposure to Cigarette Smoke and Risk of Ovarian Cancer by T-cell Tumor Immune Infiltration

Abstract

Abstract Background: Exposure to cigarette smoke, particularly in early life, is modestly associated with ovarian cancer risk and may impact systemic immunity and the tumor immune response. However, no studies have evaluated whether cigarette smoke exposure impacts the ovarian tumor immune microenvironment. Methods: Participants in the Nurses’ Health Study (NHS) and NHSII reported on early life exposure to cigarette smoke and personal smoking history on questionnaires (n = 165,760). Multiplex immunofluorescence assays were used to measure markers of T cells and immune checkpoints in tumor tissue from 385 incident ovarian cancer cases. We used Cox proportional hazards models to evaluate HRs and 95% confidence intervals (CI) for developing ovarian tumors with a low (<median) or high (≥median) immune cell percentage by cigarette exposure categories. Results: Women exposed versus not to cigarette smoke early in life had a higher risk of developing ovarian cancer with low levels of T cells overall (CD3+: HR: 1.54, 95% CI: 1.08–2.20) and recently activated cytotoxic T cells (CD3+CD8+CD69+: HR: 1.45, 95% CI: 1.05–2.00). These findings were not statistically significant at the Bonferroni-corrected P value of 0.0083. Adult smoking was not significantly associated with tumor immune markers after Bonferroni correction. Conclusions: These results suggest early life cigarette smoke exposure may modestly increase risk of developing ovarian tumors with low abundance of total T cells and recently activated cytotoxic T cells. Impact: Future research should focus on understanding the impact of exposures throughout the life course on the ovarian tumor immune microenvironment.