OBJECTIVE: Lung cancer remains a major cause of mortality worldwide, necessitating further understanding of carcinogenesis and its driving factors, including those influenced by sex-dependent variables. We hypothesized that sex-specific lung immune composition may contribute to a greater risk of lung cancer in women. METHODS: Data from 1056 lung cancer screenings were examined for an association between sex and lung cancer risk using time-to-event analyses. Immune profiling by flow cytometry was performed on male and female lungs of 3 independent mouse models: nontumor bearing, KRAS mutated, and urethane-exposed carcinogenic. A comparable analysis was performed on human bronchoalveolar lavage samples (n = 81) from patients with lung cancer. RESULTS: Of the high-risk screening cohort examined, 60 patients (5.7%) developed lung cancer during median follow-up of 43.4 months. Multivariable stepwise modeling retained female sex (hazard ratio, 1.56
P <
.01) and age (P <
.01) as prognostic indicators for lung cancer development. Female lung immune profiles in patients included T-cell phenotypes consistent with exhaustion (eg, higher proportions of PD-1+ Ki67-
P = .02), an expanded pool of regulatory T-cells (P = .03), reduced effector T-cell frequencies (P = .008), and enhancements in suppressive myeloid populations (P = .02) versus male patients, and this is recapitulated in mouse studies. CONCLUSIONS: Female smokers display higher risk for lung cancer. In murine models and humans, female sex is associated with robust immunosuppression within the lung. Further examination of this link will be important in developing immune-based approaches to lung cancer interception and their optimal application across the sexes.